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Mukherjee S, Islam S, Sarkar O, Chattopadhyay A. Oxidative Stress in Kidney of Zebrafish due to Individual and Combined Exposure to Amoxicillin, Arsenic, and Fluoride: Involving Nrf2-Keap1-ARE Pathway. J Appl Toxicol 2025; 45:964-975. [PMID: 39910692 DOI: 10.1002/jat.4763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/07/2025]
Abstract
Toxic manifestations of different antibiotics and metal compounds have been studied comprehensively in the last decades; however, their co-toxicity on aquatic organisms is poorly investigated. This study aimed to evaluate the oxidative stress imposed on zebrafish kidney tissue when exposed to amoxicillin (AMX, 10 μg/L) alone or in combination with 50 μg/L of As2O3 (equivalent to 37.87 μg/L of As) and/or 15 mg/L of NaF (equivalent to 6.8 mg/L of F) for 15 days. We observed increased levels of cellular ROS, MDA, and GSH along with increased activity of CAT enzyme in all the treated groups. Disrupted histoarchitecture, including degeneration of tubular cells, vacuolation, and necrotic spots, was indicative of oxidative damage. mRNA expression of stress responsive genes like nrf2, gpx1, hsp70, keap1, nqo1, cat, and ho1 corroborated the data. Translocation of Nrf2 from cytoplasm to nucleus and its subsequent expression was higher for all the treated groups. Moreover, the mixture effects of AMX + As + F were more severe than the other combinations, while unique exposure with AMX had minimum effects. Highlighting the involvement of the Nrf2-Keap1-ARE pathway, these findings make us aware of the synergistic response of AMX, As, and F in the ecosystem, putting forward a great threat to humankind.
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Affiliation(s)
- Sunanda Mukherjee
- Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, India
| | - Shehnaz Islam
- Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, India
| | - Olivia Sarkar
- Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, India
| | - Ansuman Chattopadhyay
- Toxicology and Cancer Biology Laboratory, Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, India
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Kousar R, Akhtar T, Lin CJ, Lebedev T, Li YC, Yang CC, Wang WJ, Chen HF, Su WC, Biswas PK, Saqib NU, Belay SA, Chang TC, Guo DW, Li Q, Patrick B, Usama M, Wu CS, Ma WL, Sher YP, Huang CC, Hung MC, Li XG. Anti-SARS-CoV-2 and anticancer properties of triptolide and its derived carbonized nanomaterials. Cancer Lett 2025; 619:217677. [PMID: 40147583 DOI: 10.1016/j.canlet.2025.217677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/22/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
The COVID-19 pandemic remains an ongoing global health threat, yet effective treatments are still lacking. This has led to a high demand for complementary/alternative medicine, such as Chinese herbal medicines for curbing the COVID-19 pandemic. Given the dual anticancer and antiviral activities of many herbal drugs, they may hold a multifaceted potential to tackle both cancer and SARS-CoV-2. Triptolide is the major bioactive compound isolated from Tripterygium wilfordii Hook F (TwHF), a traditional Chinese medicinal herb recognized for its beneficial pharmacological properties in many diseases, including cancer and viral infection. However, its application in the clinic has been greatly limited due to its toxicity and poor water solubility. Here, from a screen of a natural compound library of Chinese Pharmacopoeia, we identified triptolide as a top candidate to inhibit cell entry of SARS-CoV-2. We demonstrated that triptolide robustly blocked viral entry at nanomolar concentrations in cellular models, with broad range activity against emerging Omicron variants of SARS-CoV-2. Mechanistically, triptolide disrupted the interaction of SARS-CoV-2 spike protein with its receptor ACE2. Furthermore, we synthesized water-soluble, triptolide-derived carbon quantum dots. Compared to triptolide, these highly biocompatible nanomaterials exhibited prominent antiviral capabilities against Omicron variants of SARS-CoV-2 with less cytotoxicity. Finally, we showed that triptolide-derived carbonized materials excelled in their anticancer properties compared to triptolide and Minnelide, a water-soluble analog of triptolide. Together, our results provide a rationale for the potential development of triptolide-carbonized derivatives as a promising antiviral candidate for the current pandemic and future outbreaks, as well as anticancer agents.
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Affiliation(s)
- Rubina Kousar
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan
| | - Tahira Akhtar
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, 406040, Taiwan
| | - Chin-Jung Lin
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 20224, Taiwan
| | - Timofey Lebedev
- Department of Cancer Cell Biology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia
| | - Yi-Chuan Li
- Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan
| | - Chih-Chao Yang
- Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan
| | - Wei-Jan Wang
- Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan
| | - Hsiao-Fan Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Cell Biology, China Medical University, Taichung, 406040, Taiwan
| | - Wen-Chi Su
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; International Master's Program of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, 404327, Taiwan
| | - Pulak Kumar Biswas
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan
| | - Najm Us Saqib
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan
| | - Sefealem Assefa Belay
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan
| | - Tzu-Chi Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan
| | - Da-Wei Guo
- Department of Post-Baccalaureate Veterinary Medicine, Asia University, Taichung, 413305, Taiwan
| | - Qiangdu Li
- Department of Psychiatry, The Third Municipal Hospital of Weihai, Shandong Province, China
| | - Bbumba Patrick
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; International Master's Program of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan
| | - Muhammad Usama
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, 406040, Taiwan
| | - Chen-Shiou Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung, 407219, Taiwan
| | - Wen-Lung Ma
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan
| | - Yuh-Pyng Sher
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, 404327, Taiwan
| | - Chih-Ching Huang
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 20224, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, 404327, Taiwan.
| | - Xing-Guo Li
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan.
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Woo W, Park B, Ahadi A, Chung LIY, Jung CM, Bharat A, Chae YK. The Role of Pulmonary Metastasectomy for Non-Primary Lung Cancer: Umbrella Review of Meta-Analyses. J Surg Oncol 2024. [PMID: 39674949 DOI: 10.1002/jso.28033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/16/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND AND OBJECTIVES Due to heterogeneous characteristics of primary cancers, the efficacy of pulmonary metastasectomy (PM) in nonprimary lung cancers has not been investigated. This study aims to investigate the clinical outcomes of PM for non-primary lung cancer. METHODS A systematic search for meta-analyses on PM for nonprimary lung cancers was conducted, encompassing publications up to January 3, 2024. This included seven primary cancers: renal cell, breast, adrenocortical, head and neck cancers, melanoma, germ cell tumors, and sarcoma. Overall survival and recurrence rates post-PM were assessed using random-effect models. RESULTS This study included 16 systematic-review articles and 101 individual studies, involving 10 277 patients who underwent PM for nonprimary lung cancer. About half of the patients (47.1%) presented with multiple metastasis, and complete resection achieved in 87.2% [95% CI: 83.0-90.8]. The pooled 5-year overall survival rate post-PM was 41.2% [95%CI: 37.1%-45.4%]. Patients with germ cell tumors demonstrated higher survival rate (p < 0.05), while melanoma exhibited the worst outcome (p < 0.05). During follow-up, 57.6% [95% CI: 46.4-68.1] had recurrence; 48% of them had intrathoracic-only recurrence. CONCLUSION This study underscores the survival benefits associated with PM. Overall survival rates following PM did not differ based on primary cancer types. These findings highlight the importance of recognizing and incorporating PM into clinical practice when appropriate.
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Affiliation(s)
- Wongi Woo
- Department of Internal Medicine, Dignity Health St. Joseph Medical Center Stockton, Stockton, California, USA
| | - Brandon Park
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Awranoos Ahadi
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Liam Il-Young Chung
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Chan Mi Jung
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ankit Bharat
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Young Kwang Chae
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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Asadi M, Zafari V, Sadeghi-Mohammadi S, Shanehbandi D, Mert U, Soleimani Z, Caner A, Zarredar H. The role of tumor microenvironment and self-organization in cancer progression: Key insights for therapeutic development. BIOIMPACTS : BI 2024; 15:30713. [PMID: 40256216 PMCID: PMC12008505 DOI: 10.34172/bi.30713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/08/2024] [Accepted: 11/20/2024] [Indexed: 04/22/2025]
Abstract
Introduction The tumor microenvironment (TME) plays a pivotal role in cancer progression, influencing tumor initiation, growth, invasion, metastasis, and response to therapies. This study explores the dynamic interactions within the TME, particularly focusing on self-organization-a process by which tumor cells and their microenvironment reciprocally shape one another, leading to cancer progression and resistance. Understanding these interactions can reveal new prognostic markers and therapeutic targets within the TME, such as extracellular matrix (ECM) components, immune cells, and cytokine signaling pathways. Methods A comprehensive search method was employed to investigate the current academic literature on TME, particularly focusing on self-organization in the context of cancer progression and resistance across the PubMed, Google Scholar, and Science Direct databases. Results Recent studies suggest that therapies that disrupt TME self-organization could improve patient outcomes by defeating drug resistance and increasing the effectiveness of conventional therapy. Additionally, this research highlights the essential of understanding the biophysical properties of the TME, like cytoskeletal alterations, in the development of more effective malignancy therapy. Conclusion This review indicated that targeting the ECM and immune cells within the TME can improve therapy effectiveness. Also, by focusing on TME self-organization, we can recognize new therapeutic plans to defeat drug resistance.
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Affiliation(s)
- Milad Asadi
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Venus Zafari
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Sanam Sadeghi-Mohammadi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ufuk Mert
- Institute of Health Sciences, Department of Basic Oncology, Ege University, Izmir, Turkey
| | - Zahra Soleimani
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayşe Caner
- Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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5
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Baugh AG, Gonzalez E, Narumi VH, Kreger J, Liu Y, Rafie C, Castanon S, Jang J, Kagohara LT, Anastasiadou DP, Leatherman J, Armstrong T, Chan I, Karagiannis GS, Jaffee EM, MacLean A, Torres ETR. A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer. Clin Exp Metastasis 2024; 41:733-746. [PMID: 38717519 PMCID: PMC11499368 DOI: 10.1007/s10585-024-10289-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/21/2024] [Indexed: 07/15/2024]
Abstract
Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.
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Affiliation(s)
- Aaron G Baugh
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Edgar Gonzalez
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Valerie H Narumi
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jesse Kreger
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Yingtong Liu
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Christine Rafie
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sofi Castanon
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Julie Jang
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Luciane T Kagohara
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Dimitra P Anastasiadou
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - James Leatherman
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Todd Armstrong
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Isaac Chan
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - George S Karagiannis
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Elizabeth M Jaffee
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Adam MacLean
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Evanthia T Roussos Torres
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA.
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Strathearn LS, Spender LC, Schoenherr C, Mason S, Edwards R, Blyth K, Inman GJ. C1orf106 ( INAVA) Is a SMAD3-Dependent TGF-β Target Gene That Promotes Clonogenicity and Correlates with Poor Prognosis in Breast Cancer. Cells 2024; 13:1530. [PMID: 39329715 PMCID: PMC11429573 DOI: 10.3390/cells13181530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 09/02/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
Transforming Growth Factor-β (TGF-β) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-β signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-β directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-β target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-β stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer.
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Affiliation(s)
- Lauren S. Strathearn
- Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK; (L.S.S.); (L.C.S.)
- Cancer Research UK Scotland Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; (C.S.); (S.M.); (K.B.)
| | - Lindsay C. Spender
- Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK; (L.S.S.); (L.C.S.)
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK
| | - Christina Schoenherr
- Cancer Research UK Scotland Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; (C.S.); (S.M.); (K.B.)
| | - Susan Mason
- Cancer Research UK Scotland Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; (C.S.); (S.M.); (K.B.)
| | - Ruaridh Edwards
- Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK; (L.S.S.); (L.C.S.)
| | - Karen Blyth
- Cancer Research UK Scotland Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; (C.S.); (S.M.); (K.B.)
| | - Gareth J. Inman
- Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK; (L.S.S.); (L.C.S.)
- Cancer Research UK Scotland Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; (C.S.); (S.M.); (K.B.)
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK
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7
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Shi Q, Huang F, Wang Y, Liu H, Deng H, Chen YG. HER2 phosphorylation induced by TGF-β promotes mammary morphogenesis and breast cancer progression. J Cell Biol 2024; 223:e202307138. [PMID: 38407425 PMCID: PMC10896696 DOI: 10.1083/jcb.202307138] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/15/2023] [Accepted: 01/16/2024] [Indexed: 02/27/2024] Open
Abstract
Transforming growth factor β (TGF-β) and HER2 signaling collaborate to promote breast cancer progression. However, their molecular interplay is largely unclear. TGF-β can activate mitogen-activated protein kinase (MAPK) and AKT, but the underlying mechanism is not fully understood. In this study, we report that TGF-β enhances HER2 activation, leading to the activation of MAPK and AKT. This process depends on the TGF-β type I receptor TβRI kinase activity. TβRI phosphorylates HER2 at Ser779, promoting Y1248 phosphorylation and HER2 activation. Mice with HER2 S779A mutation display impaired mammary morphogenesis, reduced ductal elongation, and branching. Furthermore, wild-type HER2, but not S779A mutant, promotes TGF-β-induced epithelial-mesenchymal transition, cell migration, and lung metastasis of breast cells. Increased HER2 S779 phosphorylation is observed in human breast cancers and positively correlated with the activation of HER2, MAPK, and AKT. Our findings demonstrate the crucial role of TGF-β-induced S779 phosphorylation in HER2 activation, mammary gland development, and the pro-oncogenic function of TGF-β in breast cancer progression.
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Affiliation(s)
- Qiaoni Shi
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Fei Huang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yalong Wang
- Guangzhou National Laboratory, Guangzhou, China
| | - Huidong Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
- Guangzhou National Laboratory, Guangzhou, China
- School of Basic Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
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8
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Moustakas A. Crosstalk between TGF-β and EGF receptors via direct phosphorylation. J Cell Biol 2024; 223:e202403075. [PMID: 38506732 PMCID: PMC10955040 DOI: 10.1083/jcb.202403075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024] Open
Abstract
Aristidis Moustakas discusses work from Ye-Guang Chen and colleagues (https://doi.org/10.1083/jcb.202307138) on a new mechanism by which TGF-β modulates HER2 signaling in mammary epithelia.
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Affiliation(s)
- Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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9
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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10
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Baugh AG, Gonzalez E, Narumi VH, Kreger J, Liu Y, Rafie C, Castanon S, Jang J, Kagohara LT, Anastasiadou DP, Leatherman J, Armstrong TD, Chan I, Karagiannis GS, Jaffee EM, MacLean A, Roussos Torres ET. Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2 + breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.25.577282. [PMID: 38352476 PMCID: PMC10862766 DOI: 10.1101/2024.01.25.577282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/19/2024]
Abstract
Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.
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Affiliation(s)
- Aaron G. Baugh
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Edgar Gonzalez
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Valerie H. Narumi
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jesse Kreger
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Yingtong Liu
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Christine Rafie
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sofi Castanon
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Julie Jang
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Luciane T. Kagohara
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Dimitra P. Anastasiadou
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Tumor Microenvironment & Metastasis Program, Montefiore-Einstein Cancer Center, Bronx, NY, USA
| | - James Leatherman
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Todd D. Armstrong
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Isaac Chan
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - George S. Karagiannis
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Tumor Microenvironment & Metastasis Program, Montefiore-Einstein Cancer Center, Bronx, NY, USA
- Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA
- Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Elizabeth M. Jaffee
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Adam MacLean
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Evanthia T. Roussos Torres
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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11
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Liu X, Tian F, Cui J, Gong L, Xiang L, Fan B, Liu S, Zhan J, Zhou Y, Jiang B, Wang M, Sun G, Gong Y, Zou Y. CUL4B functions as a tumor suppressor in KRAS-driven lung tumors by inhibiting the recruitment of myeloid-derived suppressor cells. Oncogene 2023; 42:3113-3126. [PMID: 37653114 DOI: 10.1038/s41388-023-02824-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/02/2023]
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. KRAS mutations are the most common oncogenic alterations found in lung cancer. Unfortunately, treating KRAS-mutant lung adenocarcinoma (ADC) remains a major oncotherapeutic challenge. Here, we used both autochthonous and transplantable KRAS-mutant tumor models to investigate the role of tumor-derived CUL4B in KRAS-driven lung cancers. We showed that knockout or knockdown of CUL4B promotes lung ADC growth and progression in both models. Mechanistically, CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. CUL4B deletion increases the expression of CXCL2, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration to the tumor microenvironment. Targeting of MDSCs significantly delayed the growth of CUL4B knockdown KRAS-mutant tumors. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating KRAS-driven lung tumor development.
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Affiliation(s)
- Xiaochen Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fei Tian
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jianfeng Cui
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li Gong
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lu Xiang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Bowen Fan
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shuangteng Liu
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jiafeng Zhan
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yadi Zhou
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Baichun Jiang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Molin Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Gongping Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yaoqin Gong
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Yongxin Zou
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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12
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Nabi N, Singh S, Saffeullah P. An updated review on distribution, biosynthesis and pharmacological effects of artemisinin: A wonder drug. PHYTOCHEMISTRY 2023; 214:113798. [PMID: 37517615 DOI: 10.1016/j.phytochem.2023.113798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/01/2023]
Abstract
Plant-based drugs have been used for centuries for treating different ailments. Malaria, one of the prevalent threats in many parts of the world, is treated mainly by artemisinin-based drugs derived from plants of genus Artemisia. However, the distribution of artemisinin is restricted to a few species of the genus; besides, its yield depends on ontogeny and the plant's geographical location. Here, we review the studies focusing on biosynthesis and distributional pattern of artemisinin production in species of the genus Artemisia. We also discussed various agronomic and in vitro methods and molecular approaches to increase the yield of artemisinin. We have summarized different mechanisms of artemisinin involved in its anti-malarial, anti-cancer, anti-inflammatory and anti-viral activities (like against Covid-19). Overall the current review provides a synopsis of a global view of the distribution of artemisinin, its biosynthesis, and pharmacological potential in treating various diseases like malaria, cancer, and coronavirus, which may provoke future research efforts in drug development. Nevertheless, long-term trials and molecular approaches, like CRISPR-Cas, are required for in-depth research.
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Affiliation(s)
- Neelofer Nabi
- Department of Botany, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India
| | - Seema Singh
- Department of Botany, University of Kashmir, Srinagar, Jammu and Kashmir, 190006, India
| | - Peer Saffeullah
- Department of Botany, Jamia Hamdard, New Delhi, 110062, India.
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13
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Massagué J, Sheppard D. TGF-β signaling in health and disease. Cell 2023; 186:4007-4037. [PMID: 37714133 PMCID: PMC10772989 DOI: 10.1016/j.cell.2023.07.036] [Citation(s) in RCA: 284] [Impact Index Per Article: 142.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/21/2023] [Accepted: 07/28/2023] [Indexed: 09/17/2023]
Abstract
The TGF-β regulatory system plays crucial roles in the preservation of organismal integrity. TGF-β signaling controls metazoan embryo development, tissue homeostasis, and injury repair through coordinated effects on cell proliferation, phenotypic plasticity, migration, metabolic adaptation, and immune surveillance of multiple cell types in shared ecosystems. Defects of TGF-β signaling, particularly in epithelial cells, tissue fibroblasts, and immune cells, disrupt immune tolerance, promote inflammation, underlie the pathogenesis of fibrosis and cancer, and contribute to the resistance of these diseases to treatment. Here, we review how TGF-β coordinates multicellular response programs in health and disease and how this knowledge can be leveraged to develop treatments for diseases of the TGF-β system.
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Affiliation(s)
- Joan Massagué
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Dean Sheppard
- Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
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14
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He Y, Goyette MA, Chapelle J, Boufaied N, Al Rahbani J, Schonewolff M, Danek EI, Muller WJ, Labbé DP, Côté JF, Lamarche-Vane N. CdGAP is a talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis. Cell Rep 2023; 42:112936. [PMID: 37552602 DOI: 10.1016/j.celrep.2023.112936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/10/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor β (TGF-β)-induced EMT transcriptional signature. CdGAP is positively regulated by TGF-β signaling during EMT and interacts with the adaptor talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and integrin/talin signaling pathways.
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Affiliation(s)
- Yi He
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Marie-Anne Goyette
- Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
| | - Jennifer Chapelle
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Nadia Boufaied
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Jalal Al Rahbani
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Maribel Schonewolff
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Eric I Danek
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - William J Muller
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada
| | - David P Labbé
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Division of Urology, Department of Surgery, McGill University, Montréal, QC H4A 3J1, Canada
| | - Jean-François Côté
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
| | - Nathalie Lamarche-Vane
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada.
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15
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Jacob JB, Wei KC, Bepler G, Reyes JD, Cani A, Polin L, White K, Kim S, Viola N, McGrath J, Guastella A, Yin C, Mi QS, Kidder BL, Wagner KU, Ratner S, Phillips V, Xiu J, Parajuli P, Wei WZ. Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model. iScience 2023; 26:106320. [PMID: 36968078 PMCID: PMC10034465 DOI: 10.1016/j.isci.2023.106320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 01/16/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
HER2-targeted therapy has improved breast cancer survival, but treatment resistance and disease prevention remain major challenges. Genes that enable HER2/Neu oncogenesis are the next intervention targets. A bioinformatics discovery platform of HER2/Neu-expressing Diversity Outbred (DO) F1 Mice was established to identify cancer-enabling genes. Quantitative Trait Loci (QTL) associated with onset ages and growth rates of spontaneous mammary tumors were sought. Twenty-six genes in 3 QTL contain sequence variations unique to the genetic backgrounds that are linked to aggressive tumors and 21 genes are associated with human breast cancer survival. Concurrent identification of TSC22D3, a transcription factor, and its target gene LILRB4, a myeloid cell checkpoint receptor, suggests an immune axis for regulation, or intervention, of disease. We also investigated TIEG1 gene that impedes tumor immunity but suppresses tumor growth. Although not an actionable target, TIEG1 study revealed genetic regulation of tumor progression, forming the basis of the genetics-based discovery platform.
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Affiliation(s)
- Jennifer B. Jacob
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Kuang-Chung Wei
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Gerold Bepler
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Joyce D. Reyes
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Andi Cani
- Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Lisa Polin
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Kathryn White
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Seongho Kim
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Nerissa Viola
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Julie McGrath
- Clinical and Translational Research, Caris Life Sciences, Irving, TX75039, USA
| | - Anthony Guastella
- Clinical and Translational Research, Caris Life Sciences, Irving, TX75039, USA
| | - CongCong Yin
- Department of Immunology, Henry Ford Health System, Detroit, MI48202, USA
| | - Qing-Shen Mi
- Department of Immunology, Henry Ford Health System, Detroit, MI48202, USA
| | - Benjamin L. Kidder
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Kay-Uwe Wagner
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Stuart Ratner
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Victoria Phillips
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Joanne Xiu
- Clinical and Translational Research, Caris Life Sciences, Irving, TX75039, USA
| | - Prahlad Parajuli
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
| | - Wei-Zen Wei
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA
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16
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Ortiz B, Driscoll A, Menon R, Taylor BD, Richardson LS. Chlamydia trachomatis antigen induces TLR4-TAB1-mediated inflammation, but not cell death, in maternal decidua cells. Am J Reprod Immunol 2023; 89:e13664. [PMID: 36495029 PMCID: PMC10436189 DOI: 10.1111/aji.13664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/15/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND During gestation, the decidua is an essential layer of the maternal-fetal interface, providing immune support and maintaining inflammatory homeostasis. Although Chlamydia (C.) trachomatis is associated with adverse pregnancy outcomes the pathogenic effects on maternal decidua contributing to adverse events are not understood. This study examined how C. trachomatis antigen affects cell signaling, cell death, and inflammation in the decidua. METHODS Primary decidua cells (pDECs) from term, not-in-labor, fetal membrane-decidua were cultured using the following conditions: (1) control - standard cell culture conditions, (2) 100 ng/ml or (3) 200 ng/ml of C. trachomatis antigen to model decidual cell infection in vitro. Differential expression of Toll-like receptor (TLR) 4 (receptor for C. trachomatis antigen), signaling pathway markers phosphorylated TGF-Beta Activated Kinase 1 (PTAB1), TAB1, phosphorylated p38 mitogen-activated protein kinases (Pp38 MAPK), and p38 MAPK (western blot), decidual cell apoptosis and necrosis (flow cytometry), and inflammation (ELISA for cytokines) were determined in cells exposed to C. trachomatis antigen. T-test was used to assess statistical significance (p < 0.05). RESULTS C. trachomatis antigen significantly induced expression of TLR4 (p = 0.03) and activation of TAB1 (p = 0.02) compared to controls. However, it did not induce p38 MAPK activation. In addition, pDECs maintained their stromal cell morphology when exposed to C. trachomatis antigen showing no signs of apoptosis and/or necrosis but did induce pro-inflammatory cytokine interleukin (IL)-6 (100 ng/ml: p = 0.02 and 200 ng/ml: p = 0.03), in pDECs compared to controls. CONCLUSION Prenatal C. trachomatis infection can produce antigens that induce TLR4-TAB1 signaling and IL-6 inflammation independent of Pp38 MAPK and apoptosis and necrosis. This suggests that C. trachomatis can imbalance decidual inflammatory homeostasis, potentially contributing to adverse events during pregnancy.
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Affiliation(s)
- Briana Ortiz
- School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Ashley Driscoll
- School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Ramkumar Menon
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USA
| | - Brandie D. Taylor
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USA
| | - Lauren S. Richardson
- Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USA
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17
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Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases. Viruses 2023; 15:v15020568. [PMID: 36851782 PMCID: PMC9966946 DOI: 10.3390/v15020568] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/22/2023] Open
Abstract
Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.
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Fonta CM, Loustau T, Li C, Poilil Surendran S, Hansen U, Murdamoothoo D, Benn MC, Velazquez-Quesada I, Carapito R, Orend G, Vogel V. Infiltrating CD8+ T cells and M2 macrophages are retained in tumor matrix tracks enriched in low tension fibronectin fibers. Matrix Biol 2023; 116:1-27. [PMID: 36669744 DOI: 10.1016/j.matbio.2023.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 12/31/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Tracks rich in matrix and cells, as described in several cancer types, have immunosuppressive functions and separate tumor nests and stroma, yet their origin is unknown. Immunostainings of cryosections from mouse breast tumors show that these tracks are bordered by an endothelial-like basement membrane, filled with fibers of collagen adjacent to tenascin-C (TNC) and low-tension fibronectin (Fn) fibers. While present in early-stage tumors and maturing with time, tracks still form under TNC KO conditions, however, host (not tumor cell)-derived TNC is important for track maturation. Tumor infiltrating leukocytes (mostly M2 macrophages and CD8+ T cells) are retained in tracks of early-stage tumors. Following track maturation, retained tumor infiltrating leukocyte (TIL) numbers get reduced and more CD8+ TIL enter the tumor nests in the absence of TNC. As these tracks are enriched with platelets and fibrinogen and have a demarcating endothelial-like basement membrane often adjacent to endothelial cells, this suggests a role of blood vessels in the formation of these tracks. The Fn fiber tension probe FnBPA5 colocalizes with TNC and immune cells in the tracks and shows decreased binding in tracks lacking TNC. Consequently, FnBPA5 can serve as probe for tumor matrix tracks that have immune suppressive properties.
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Affiliation(s)
- Charlotte M Fonta
- Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zurich, Vladimir Prelog Weg, Zurich CH-8093, Switzerland
| | - Thomas Loustau
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France
| | - Chengbei Li
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France
| | - Suchithra Poilil Surendran
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine (IMM), University Hospital Muenster, Muenster, Federal Republic of Germany
| | - Devadarssen Murdamoothoo
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; MN3T (The Microenvironmental Niche in Tumorigenesis and Targeted Therapy), INSERM U1109, 3 avenue Molière, Strasbourg, Hautepierre, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France
| | - Mario C Benn
- Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zurich, Vladimir Prelog Weg, Zurich CH-8093, Switzerland
| | - Ines Velazquez-Quesada
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; MN3T (The Microenvironmental Niche in Tumorigenesis and Targeted Therapy), INSERM U1109, 3 avenue Molière, Strasbourg, Hautepierre, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France
| | - Raphael Carapito
- Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France; Platform GENOMAX, INSERM UMR_S 1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, LabEx TRANSPLANTEX, Strasbourg 67091, France
| | - Gertraud Orend
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d' Hématologie et d'Immunologie, 1 Place de l'Hôpital, Strasbourg 67091, France; MN3T (The Microenvironmental Niche in Tumorigenesis and Targeted Therapy), INSERM U1109, 3 avenue Molière, Strasbourg, Hautepierre, France; Université Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France.
| | - Viola Vogel
- Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zurich, Vladimir Prelog Weg, Zurich CH-8093, Switzerland.
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Rodriguez Calleja L, Lavaud M, Tesfaye R, Brounais-Le-Royer B, Baud’huin M, Georges S, Lamoureux F, Verrecchia F, Ory B. The p53 Family Members p63 and p73 Roles in the Metastatic Dissemination: Interactions with microRNAs and TGFβ Pathway. Cancers (Basel) 2022; 14:cancers14235948. [PMID: 36497429 PMCID: PMC9741383 DOI: 10.3390/cancers14235948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 11/29/2022] [Indexed: 12/02/2022] Open
Abstract
TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73's pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy.
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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21
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Nakayama T, Azegami T, Hayashi K, Hishikawa A, Yoshimoto N, Nakamichi R, Sugita E, Itoh H. Vaccination against connective tissue growth factor attenuates the development of renal fibrosis. Sci Rep 2022; 12:10933. [PMID: 35768626 PMCID: PMC9243061 DOI: 10.1038/s41598-022-15118-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/20/2022] [Indexed: 11/26/2022] Open
Abstract
There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin–creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-β-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis.
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Affiliation(s)
- Takashin Nakayama
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tatsuhiko Azegami
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Keio University Health Center, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama-shi, Kanagawa, 223-8521, Japan.
| | - Kaori Hayashi
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Akihito Hishikawa
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Norifumi Yoshimoto
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Ran Nakamichi
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Erina Sugita
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroshi Itoh
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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22
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Song P, Zhao F, Li D, Qu J, Yao M, Su Y, Wang H, Zhou M, Wang Y, Gao Y, Li F, Zhao D, Zhang F, Rao Y, Xia M, Li H, Wang J, Cheng M. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells. Acta Pharm Sin B 2022; 12:2905-2922. [PMID: 35755272 PMCID: PMC9214071 DOI: 10.1016/j.apsb.2022.02.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/26/2022] [Accepted: 02/10/2022] [Indexed: 11/25/2022] Open
Abstract
The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).
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23
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Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT. Oncogene 2022; 41:1492-1506. [PMID: 35075245 PMCID: PMC8897192 DOI: 10.1038/s41388-022-02190-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 12/21/2021] [Accepted: 01/12/2022] [Indexed: 12/12/2022]
Abstract
Local invasion is the initial step towards metastasis, the main cause of cancer mortality. In human colorectal cancer (CRC), malignant cells predominantly invade as cohesive collectives and may undergo partial epithelial-mesenchymal transition (pEMT) at the invasive front. How this particular mode of stromal infiltration is generated is unknown. Here we investigated the impact of oncogenic transformation and the microenvironment on tumor cell invasion using genetically engineered organoids as CRC models. We found that inactivation of the Apc tumor suppressor combined with expression of oncogenic KrasG12D and dominant-negative Trp53R172H did not cell-autonomously induce invasion in vitro. However, oncogenic transformation primed organoids for activation of a collective invasion program upon exposure to the prototypical microenvironmental factor TGFβ1. Execution of this program co-depended on a permissive extracellular matrix which was further actively remodeled by invading organoids. Although organoids shed some epithelial properties particularly at the invasive edge, TGFβ1-stimulated organoids largely maintained epithelial gene expression while additionally implementing a mesenchymal transcription pattern, resulting in a pEMT phenotype that did not progress to a fully mesenchymal state. Notably, while TGFβ1 induced pEMT and promoted collective invasion, it abrogated self-renewal capacity of TKA organoids which correlated with the downregulation of intestinal stem cell (ISC) marker genes. Mechanistically, induction of the non-progressive pEMT required canonical TGFβ signaling mediated by Smad transcription factors (TFs), whereas the EMT master regulators Snail1 and Zeb1 were dispensable. Gene expression profiling provided further evidence for pEMT of TGFβ1-treated organoids and showed that their transcriptomes resemble those of human poor prognosis CMS4 cancers which likewise exhibit pEMT features. We propose that collective invasion in colorectal carcinogenesis is triggered by microenvironmental stimuli through activation of a novel, transcription-mediated form of non-progressive pEMT independently of classical EMT regulators.
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Kong Y, Zhang Y, Wang H, Kan W, Guo H, Liu Y, Zang Y, Li J. Inner nuclear membrane protein TMEM201 promotes breast cancer metastasis by positive regulating TGFβ signaling. Oncogene 2022; 41:647-656. [PMID: 34799661 DOI: 10.1038/s41388-021-02098-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 12/31/2022]
Abstract
Emerging evidence shows the association between nuclear envelope and tumor progression, however, the functional contributions of specific constituents of the nuclear envelope remain largely unclear. We found that the expression level of transmembrane protein 201 (TMEM201), an integral inner nuclear membrane protein of unknown function, was significantly elevated in invasive breast cancer and predicted poor breast cancer prognosis. We showed that TMEM201, as a positive modulator, was both necessary and sufficient to regulate the migration and invasion of breast cancer cells in vitro and in vivo. Mechanistically, RNA-sequencing analysis and validation showed that TMEM201 deficiency inhibited epithelial-to-mesenchymal transition and transforming growth factor-β signaling. Finally, we showed that TMEM201 physically interacted with SMAD2/3 and was required for the phosphorylation of SMAD2/3, nuclear translocation and transcriptional activation of the TGFβ. Thus, we demonstrated that specific inner nuclear membrane component mediated signal-dependent transcriptional effects to control breast cancer metastasis.
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Affiliation(s)
- Ya Kong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yutian Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hanlin Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Department of Pharmacology, Fudan University, Shanghai, 201203, China
| | - Weijuan Kan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Haoran Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yun Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, China
| | - Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China.
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China.
- Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China.
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25
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The induction of a mesenchymal phenotype by platelet cloaking of cancer cells is a universal phenomenon. Transl Oncol 2021; 14:101229. [PMID: 34592589 PMCID: PMC8488306 DOI: 10.1016/j.tranon.2021.101229] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 11/21/2022] Open
Abstract
Platelet cancer cell interactions are a key factor in driving the pro-metastatic phenotype. Platelet cancer cell interactions appear to be mediated by 5 key genes which have established roles in metastasis. Targeting these mediators of metastasis could improve outcomes for cancer patients. Tumour metastasis accounts for over 90% of cancer related deaths. The platelet is a key blood component, which facilitates efficient metastasis. This study aimed to understand the molecular mechanisms involved in tumour-platelet cell interactions. The interaction between cancer cells and platelets was examined in 15 epithelial cell lines, representing 7 cancer types. Gene expression analysis of EMT-associated and cancer stemness genes was performed by RT-PCR. Whole transcriptome analysis (WTA) was performed using Affymetrix 2.0ST arrays on a platelet co-cultured ovarian model. Platelet adhesion and activation occurred across all tumour types. WTA identified increases in cellular movement, migration, invasion, adhesion, development, differentiation and inflammation genes and decreases in processes associated with cell death and survival following platelet interaction. Increased invasive capacity was also observed in a subset of cell lines. A cross-comparison with a platelet co-cultured mouse model identified 5 common altered genes; PAI-1, PLEK2, CD73, TNC, and SDPR. Platelet cancer cell interactions are a key factor in driving the pro-metastatic phenotype and appear to be mediated by 5 key genes which have established roles in metastasis. Targeting these metastasis mediators could improve cancer patient outcomes.
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Ray T, Ryusaki T, Ray PS. Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis. Front Oncol 2021; 11:721959. [PMID: 34540690 PMCID: PMC8446626 DOI: 10.3389/fonc.2021.721959] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/15/2021] [Indexed: 12/28/2022] Open
Abstract
Metastasis accounts for more than 90% of cancer related mortality, thus the most pressing need in the field of oncology today is the ability to accurately predict future onset of metastatic disease, ideally at the time of initial diagnosis. As opposed to current practice, what would be desirable is that prognostic, biomarker-based detection of metastatic propensity and heightened risk of cancer recurrence be performed long before overt metastasis has set in. Without such timely information it will be impossible to formulate a rational therapeutic treatment plan to favorably alter the trajectory of disease progression. In order to help inform rational selection of targeted therapeutics, any recurrence/metastasis risk prediction strategy must occur with the paired identification of novel prognostic biomarkers and their underlying molecular regulatory mechanisms that help drive cancer recurrence/metastasis (i.e. recurrence biomarkers). Traditional clinical factors alone (such as TNM staging criteria) are no longer adequately prognostic for this purpose in the current molecular era. FOXC1 is a pivotal transcription factor that has been functionally implicated to drive cancer metastasis and has been demonstrated to be an independent predictor of heightened metastatic risk, at the time of initial diagnosis. In this review, we present our viewpoints on the master regulatory role that FOXC1 plays in mediating cancer stem cell traits that include cellular plasticity, partial EMT, treatment resistance, cancer invasion and cancer migration during cancer progression and metastasis. We also highlight potential therapeutic strategies to target cancers that are, or have evolved to become, “transcriptionally addicted” to FOXC1. The potential role of FOXC1 expression status in predicting the efficacy of these identified therapeutic approaches merits evaluation in clinical trials.
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Affiliation(s)
- Tania Ray
- R&D Division, Onconostic Technologies (OT), Inc., Champaign, IL, United States
| | | | - Partha S Ray
- R&D Division, Onconostic Technologies (OT), Inc., Champaign, IL, United States
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27
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Rai S, Alsaidan OA, Yang H, Cai H, Wang L. Heparan sulfate inhibits transforming growth factor β signaling and functions in cis and in trans to regulate prostate stem/progenitor cell activities. Glycobiology 2021; 30:381-395. [PMID: 31829419 DOI: 10.1093/glycob/cwz103] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 12/15/2022] Open
Abstract
Prostate stem/progenitor cells (PrSCs) are responsible for adult prostate tissue homeostasis and regeneration. However, the related regulatory mechanisms are not completely understood. In this study, we examined the role of heparan sulfate (HS) in PrSC self-renewal and prostate regeneration. Using an in vitro prostate sphere formation assay, we found that deletion of the glycosyltransferase exostosin 1 (Ext1) abolished HS expression in PrSCs and disrupted their ability to self-renew. In associated studies, we observed that HS loss inhibited p63 and CK5 expression, reduced the number of p63+- or CK5+-expressing stem/progenitor cells, elevated CK8+ expression and the number of differentiated CK8+ luminal cells and arrested the spheroid cells in the G1/G0 phase of cell cycle. Mechanistically, HS expressed by PrSCs (in cis) or by neighboring cells (in trans) could maintain sphere formation. Furthermore, HS deficiency upregulated transforming growth factor β (TGFβ) signaling and inhibiting TGFβ signaling partially restored the sphere-formation activity of the HS-deficient PrSCs. In an in vivo prostate regeneration assay, simultaneous loss of HS in both epithelial cell and stromal cell compartments attenuated prostate tissue regeneration, whereas the retention of HS expression in either of the two cellular compartments was sufficient to sustain prostate tissue regeneration. We conclude that HS preserves self-renewal of adult PrSCs by inhibiting TGFβ signaling and functions both in cis and in trans to maintain prostate homeostasis and to support prostate regeneration.
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Affiliation(s)
- Sumit Rai
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
| | - Omar Awad Alsaidan
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Hua Yang
- Department of Molecular Pharmacology and Physiology, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA
| | - Houjian Cai
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Lianchun Wang
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.,Department of Molecular Pharmacology and Physiology, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA
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28
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Giacobbe A, Abate-Shen C. Modeling metastasis in mice: a closer look. Trends Cancer 2021; 7:916-929. [PMID: 34303648 DOI: 10.1016/j.trecan.2021.06.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/27/2021] [Accepted: 06/29/2021] [Indexed: 02/07/2023]
Abstract
Unraveling the multifaceted cellular and physiological processes associated with metastasis is best achieved by using in vivo models that recapitulate the requisite tumor cell-intrinsic and -extrinsic mechanisms at the organismal level. We discuss the current status of mouse models of metastasis. We consider how mouse models can refine our understanding of the underlying biological and molecular processes that promote metastasis, and we envisage how the application of new technologies will further enhance investigations of metastasis at single-cell resolution in the context of the whole organism. Our view is that investigations based on state-of-the-art mouse models can propel a holistic understanding of the biology of metastasis, which will ultimately lead to the discovery of new therapeutic opportunities.
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Affiliation(s)
- Arianna Giacobbe
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Cory Abate-Shen
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, 1130 Saint Nicholas Avenue, New York, NY10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
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29
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Alves E, Taifour S, Dolcetti R, Chee J, Nowak AK, Gaudieri S, Blancafort P. Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing. Mol Ther Methods Clin Dev 2021; 21:592-606. [PMID: 34095343 PMCID: PMC8142043 DOI: 10.1016/j.omtm.2021.04.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver, and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression present novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action, and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic.
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Affiliation(s)
- Eric Alves
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Shahama Taifour
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
| | - Riccardo Dolcetti
- Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia
- Sir Peter MacCallum Centre for Cancer Immunotherapy, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Jonathan Chee
- National Centre for Asbestos Related Diseases, Institute of Respiratory Health, The University of Western Australia, Perth, WA 6009, Australia
- School of Biomedical Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Anna K. Nowak
- National Centre for Asbestos Related Diseases, Institute of Respiratory Health, The University of Western Australia, Perth, WA 6009, Australia
- School of Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Silvana Gaudieri
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA 6150, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Pilar Blancafort
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- The Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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30
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TGF Beta Induces Vitamin D Receptor and Modulates Mitochondrial Activity of Human Pancreatic Cancer Cells. Cancers (Basel) 2021; 13:cancers13122932. [PMID: 34208208 PMCID: PMC8230851 DOI: 10.3390/cancers13122932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/10/2021] [Indexed: 01/13/2023] Open
Abstract
The inflammatory cytokine TGFβ is both a tumor suppressor during cancer initiation and a promoter of metastasis along cancer progression. Inflammation and cancer are strictly linked, and cancer onset often correlates with the insufficiency of vitamin D, known for its anti-inflammatory properties. In this study, we investigated the interplay between TGFβ and vitamin D in two models of human pancreatic cancer, and we analyzed the metabolic effects of a prolonged TGFβ treatment mimicking the inflammatory environment of pancreatic cancer in vivo. We confirmed the induction of the vitamin D receptor previously described in epithelial cells, but the inhibitory effects of vitamin D on epithelial-mesenchymal transition (EMT) were lost when the hormone was given after a long treatment with TGFβ. Moreover, we detected an ROS-mediated toxicity of the acute treatment with TGFβ, whereas a chronic exposure to low doses had a protumorigenic effect. In fact, it boosted the mitochondrial respiration and cancer cell migration without ROS production and cytotoxicity. Our observations shed some light on the multifaceted role of TGFβ in tumor progression, revealing that a sustained exposure to TGFβ at low doses results in an irreversibly increased EMT associated with a metabolic modulation which favors the formation of metastasis.
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Murdamoothoo D, Sun Z, Yilmaz A, Riegel G, Abou‐Faycal C, Deligne C, Velazquez‐Quesada I, Erne W, Nascimento M, Mörgelin M, Cremel G, Paul N, Carapito R, Veber R, Dumortier H, Yuan J, Midwood KS, Loustau T, Orend G. Tenascin-C immobilizes infiltrating T lymphocytes through CXCL12 promoting breast cancer progression. EMBO Mol Med 2021; 13:e13270. [PMID: 33988305 PMCID: PMC8185552 DOI: 10.15252/emmm.202013270] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immune checkpoint therapy, where CD8 tumor infiltrating T lymphocytes (TIL) are reactivated, is a promising anti-cancer treatment approach, yet with low response rates. The extracellular matrix, in particular tenascin-C, may generate barriers for TIL. To investigate this possibility, we used a MMTV-NeuNT and syngeneic mammary gland grafting model derived thereof with engineered tenascin-C levels and observed accumulation of CD8 TIL in tenascin-C-rich stroma. Inhibition studies revealed that tenascin-C induced CXCL12 through TLR4. By binding CXCL12, tenascin-C retained CD8 TIL in the stroma. Blockade of CXCR4, the receptor of CXCL12, enhanced macrophage and CD8 TIL infiltration and reduced tumor growth and subsequent metastasis. Retention of CD8 TIL by tenascin-C/CXCL12 was also observed in human breast cancer by tissue staining. Moreover, whereas high CD8 TIL numbers correlated with longer metastasis-free survival, this was not the case when also tenascin-C and CXCL12 levels were high. Altogether, these results may be useful for improving tumor immunity as diagnostic tool and to formulate a future "TIL-matrix-release-and-reactivate" strategy.
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32
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TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases. Cells 2021; 10:cells10061382. [PMID: 34205102 PMCID: PMC8226492 DOI: 10.3390/cells10061382] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/12/2022] Open
Abstract
TGF-β/Smad signalling has been the subject of extensive research due to its role in the cell cycle and carcinogenesis. Modifications to the TGF-β/Smad signalling pathway have been found to produce disparate effects on neurogenesis. We review the current research on canonical and non-canonical TGF-β/Smad signalling pathways and their functions in neurogenesis. We also examine the observed role of neurogenesis in neuropsychiatric disorders and the relationship between TGF-β/Smad signalling and neurogenesis in response to stressors. Overlapping mechanisms of cell proliferation, neurogenesis, and the development of mood disorders in response to stressors suggest that TGF-β/Smad signalling is an important regulator of stress response and is implicated in the behavioural outcomes of mood disorders.
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33
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Zhang J, Qi J, Wei H, Lei Y, Yu H, Liu N, Zhao L, Wang P. TGFβ1 in Cancer-Associated Fibroblasts Is Associated With Progression and Radiosensitivity in Small-Cell Lung Cancer. Front Cell Dev Biol 2021; 9:667645. [PMID: 34095135 PMCID: PMC8172974 DOI: 10.3389/fcell.2021.667645] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/27/2021] [Indexed: 11/23/2022] Open
Abstract
Objective Small-cell lung cancer (SCLC) is aggressive, with early metastasis. Cytokines secreted by cancer-associated fibroblasts (CAFs) within various tumors influences these features, but the function in particular of TGFβ1 (transforming growth factor beta 1) is controversial and unknown in SCLC. This study explored the influence of TGFβ1 in CAFs on the development, immune microenvironment, and radiotherapy sensitivity of SCLC. Methods SCLC specimens were collected from 90 patients who had received no treatment before surgery. Tumor and tumor stroma were subjected to multiplex immunohistochemistry to quantitate TGFβ1 and other immune factors in CAFs. Cell proliferation and flow cytometry apoptosis assays were used to investigate associations between TGFβ1 and proliferation and radiotherapy sensitivity. The immune factors in tumors were detected by immunohistochemistry in vitro and in vivo (mice). Results TGFβ1 levels on CAFs lower or higher than the median were found, respectively, in 52.2 and 47.8% of patients; overall survival of patients with TGFβ1-high levels (53.9 mo) was significantly longer than that of the TGFβ1-low group (26.9 mo; P = 0.037). The univariate and multivariate analyses indicated that a TGFβ1-high level was an independent predictor of increased survival time. TGFβ1-high levels in CAFs were associated with inhibition of growth, proliferation, antitumor immunity, and enhanced radiotherapeutic sensitivity and tumor immunity of tumor. TGFβ1-low levels promoted tumor cell growth and radiotherapy sensitivity in vivo and in vitro. Conclusion High levels of TGFβ1 in CAFs were associated with longer overall survival in patients with SCLC and enhanced radiotherapy sensitivity.
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Affiliation(s)
- Jiaqi Zhang
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jing Qi
- National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hui Wei
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology (Nankai University), Tianjin, China
| | - Yuanyuan Lei
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Hao Yu
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ningbo Liu
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lujun Zhao
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ping Wang
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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34
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Qin F, Fan Q, Yu PKN, Almahi WA, Kong P, Yang M, Cao W, Nie L, Chen G, Han W. Properties and gene expression profiling of acquired radioresistance in mouse breast cancer cells. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:628. [PMID: 33987326 PMCID: PMC8106033 DOI: 10.21037/atm-20-4667] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Acquired radioresistant cells exhibit many characteristic changes which may influence cancer progression and further treatment options. The purpose of this study is to investigate the changes of radioresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells on both phenotypic and molecular levels. Methods We established an acquired radioresistant cell line from its parental NF639 cell line (HER2-positive) by fractionated radiation and assessed changes in cellular morphology, proliferation, migration, anti-apoptosis activity, basal reactive oxygen species (ROS) level and energy metabolism. RNA-sequencing (RNA-seq) was also used to reveal the potential regulating genes and molecular mechanisms associated with the acquired changed phenotypes. Real-time PCR was used to validate the results of RNA-seq. Results The NF639R cells exhibited increased radioresistance and enhanced activity of proliferation, migration and anti-apoptosis, but decreased basal ROS. Two main energy metabolism pathways, mitochondrial respiration and glycolytic, were also upregulated. Furthermore, 490 differentially expressed genes were identified by RNA-seq. Enrichment analysis based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes showed many differently expressed genes were significantly enriched in cell morphology, proliferation, migration, anti-apoptosis, antioxidation, tumor stem cells and energy metabolism and the signaling cascades such as the transforming growth factor-β, Wnt, Hedgehog, vascular endothelial growth factor, retinoic acid-inducible gene I (RIG-I)-like receptor, Toll-like receptor and nucleotide oligomerization domain (NOD)-like receptor were significantly altered in NF639R cells. Conclusions In clinical radiotherapy, repeat radiotherapy for short-term recurrence of breast cancer may result in enhanced radioresistance and promote malignant progression. Our research provided hints to understand the tumor resistance to radiotherapy de novo and recurrence with a worse prognosis following radiotherapy.
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Affiliation(s)
- Feng Qin
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China.,Institute of Sericultural, Anhui Academy of Agricultural Sciences, Hefei, China
| | - Qiang Fan
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China
| | - Peter K N Yu
- Department of Physics, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong, China.,State Key Laboratory in Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong, China
| | - Waleed Abdelbagi Almahi
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China
| | - Peizhong Kong
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China
| | - Miaomiao Yang
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China.,Clinical Pathology Center, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Cao
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Scinece Island Branch, Graduate School of USTC, Hefei, China
| | - Lili Nie
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China
| | - Guodong Chen
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China
| | - Wei Han
- Anhui Province Key Laboratory of Medical Physics and Technology/Institute of Health and Medical Technology, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences, Hefei, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China.,Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, China
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35
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Zhang J, Qin X, Deng Y, Lu J, Li Z, Feng Y, Yan X, Chen M, Gao L, Xu Y, Shi D, Lu F. Transforming Growth Factor-β1 Enhances Mesenchymal Characteristics of Buffalo ( Bubalus bubalis) Bone Marrow-Derived Mesenchymal Stem Cells. Cell Reprogram 2021; 23:127-138. [PMID: 33861638 DOI: 10.1089/cell.2020.0093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) from livestock are valuable resources for animal reproduction and veterinary therapeutics. Previous studies have shown that BMSCs were prone to malignant transformation of mesenchymal-to-epithelial transition in vitro, which can cause many barriers to further application of BMSCs. The transforming growth factor β (TGF-β) signaling pathway has been widely studied as the most important signaling pathway involved in regulating mesenchymal features of BMSCs. However, the effects of the TGF-β signaling pathway on mesenchymal characteristics of buffalo BMSCs (bBMSCs) remain unclear. In the present study, the impacts of the growth factor, TGF-β1, on cell proliferation, apoptosis, migration, and karyotype of bBMSCs were tested. Besides, the effects of TGF-β1 on pluripotency, mesenchymal markers, and epithelial-to-mesenchymal transition (EMT)-related gene expression of bBMSCs were also examined. Results showed that the suitable concentration and time of TGF-β1 treatment (2 ng/mL and 24 hours) promoted cell proliferation and significantly reduced cell apoptosis (p < 0.05) in bBMSCs. The cell migration capacity and normal karyotype rate of bBMSCs were significantly (p < 0.05) improved under TGF-β1 treatment. The expression levels of pluripotency-related genes (Sox2 and Nanog) and mesenchymal markers (N-cadherin and Fn1) were significantly (p < 0.05) up-regulated under TGF-β1 treatment. Furthermore, TGF-β1 activated the EMT process, thereby contributing to significantly enhancing the expression levels of EMT-related genes (Snail and Slug) (p < 0.05), which in turn improved maintenance of the mesenchymal nature in bBMSCs. Finally, bBMSCs underwent self-transformation more easily and efficiently and exhibited more characteristics of mesenchymal stem cells under TGF-β1 treatment. This study provides theoretical guidance for elucidating the detailed mechanism of the TGF-β signaling pathway in mesenchymal feature maintenance of bBMSCs and is of significance to establish a stable culture system of bBMSCs.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Xiling Qin
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Yanfei Deng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Jiaka Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Zhengda Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Yun Feng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Xi Yan
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Mengjia Chen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Lv Gao
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Ye Xu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Fenghua Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
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Roarty K, Echeverria GV. Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis. Front Oncol 2021; 11:645698. [PMID: 33777805 PMCID: PMC7988094 DOI: 10.3389/fonc.2021.645698] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/28/2021] [Indexed: 01/16/2023] Open
Abstract
While numerous therapies are highly efficacious in early-stage breast cancers and in particular subsets of breast cancers, therapeutic resistance and metastasis unfortunately arise in many patients. In many cases, tumors that are resistant to standard of care therapies, as well as tumors that have metastasized, are treatable but incurable with existing clinical strategies. Both therapy resistance and metastasis are multi-step processes during which tumor cells must overcome diverse environmental and selective hurdles. Mechanisms by which tumor cells achieve this are numerous and include acquisition of invasive and migratory capabilities, cell-intrinsic genetic and/or epigenetic adaptations, clonal selection, immune evasion, interactions with stromal cells, entering a state of dormancy or senescence, and maintaining self-renewal capacity. To overcome therapy resistance and metastasis in breast cancer, the ability to effectively model each of these mechanisms in the laboratory is essential. Herein we review historic and the current state-of-the-art laboratory model systems and experimental approaches used to investigate breast cancer metastasis and resistance to standard of care therapeutics. While each model system has inherent limitations, they have provided invaluable insights, many of which have translated into regimens undergoing clinical evaluation. We will discuss the limitations and advantages of a variety of model systems that have been used to investigate breast cancer metastasis and therapy resistance and outline potential strategies to improve experimental modeling to further our knowledge of these processes, which will be crucial for the continued development of effective breast cancer treatments.
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Affiliation(s)
- Kevin Roarty
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States.,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - Gloria V Echeverria
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States.,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States.,Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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37
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Hinz N, Baranowsky A, Horn M, Kriegs M, Sibbertsen F, Smit DJ, Clezardin P, Lange T, Schinke T, Jücker M. Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFβ/CTGF Axis. Cells 2021; 10:cells10020430. [PMID: 33670586 PMCID: PMC7922044 DOI: 10.3390/cells10020430] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Bone metastases frequently occur in breast cancer patients and lack appropriate treatment options. Hence, understanding the molecular mechanisms involved in the multistep process of breast cancer bone metastasis and tumor-induced osteolysis is of paramount interest. The serine/threonine kinase AKT plays a crucial role in breast cancer bone metastasis but the effect of individual AKT isoforms remains unclear. Therefore, AKT isoform-specific knockdowns were generated on the bone-seeking MDA-MB-231 BO subline and the effect on proliferation, migration, invasion, and chemotaxis was analyzed by live-cell imaging. Kinome profiling and Western blot analysis of the TGFβ/CTGF axis were conducted and metastasis was evaluated by intracardiac inoculation of tumor cells into NOD scid gamma (NSG) mice. MDA-MB-231 BO cells exhibited an elevated AKT3 kinase activity in vitro and responded to combined treatment with AKT- and mTOR-inhibitors. Knockdown of AKT3 significantly increased migration, invasion, and chemotaxis in vitro and metastasis to bone but did not significantly enhance osteolysis. Furthermore, knockdown of AKT3 increased the activity and phosphorylation of pro-metastatic HER2 and DDR1/2 but lowered protein levels of CTGF after TGFβ-stimulation, an axis involved in tumor-induced osteolysis. We demonstrated that AKT3 plays a crucial role in bone-seeking breast cancer cells by promoting metastatic potential without facilitating tumor-induced osteolysis.
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Affiliation(s)
- Nico Hinz
- Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (N.H.); (F.S.); (D.J.S.)
| | - Anke Baranowsky
- Center for Experimental Medicine, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (A.B.); (T.S.)
- Department of Trauma and Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Michael Horn
- University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
- Mildred Scheel Cancer Career Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Malte Kriegs
- Department of Radiotherapy & Radiation Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
- UCCH Kinomics Core Facility, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Freya Sibbertsen
- Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (N.H.); (F.S.); (D.J.S.)
| | - Daniel J. Smit
- Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (N.H.); (F.S.); (D.J.S.)
| | - Philippe Clezardin
- INSERM, Research Unit UMR S1033, LyOS, Faculty of Medicine Lyon-Est, University of Lyon 1, 69372 Lyon, France;
| | - Tobias Lange
- Center for Experimental Medicine, Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Thorsten Schinke
- Center for Experimental Medicine, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (A.B.); (T.S.)
| | - Manfred Jücker
- Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (N.H.); (F.S.); (D.J.S.)
- Correspondence: ; Tel.: +49-(0)-40-7410-56339
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Simond AM, Muller WJ. In vivo modeling of the EGFR family in breast cancer progression and therapeutic approaches. Adv Cancer Res 2020; 147:189-228. [PMID: 32593401 DOI: 10.1016/bs.acr.2020.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Modeling breast cancer through the generation of genetically engineered mouse models (GEMMs) has become the gold standard in the study of human breast cancer. Notably, the in vivo modeling of the epidermal growth factor receptor (EGFR) family has been key to the development of therapeutics and has helped better understand the signaling pathways involved in cancer initiation, progression and metastasis. The HER2/ErbB2 receptor is a member of the EGFR family and 20% of breast cancers are found to belong in the HER2-positive histological subtype. Historical and more recent advances in the field have shaped our understanding of HER2-positive breast cancer signaling and therapeutic approaches.
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Affiliation(s)
- Alexandra M Simond
- Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - William J Muller
- Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada; Faculty of Medicine, McGill University, Montreal, QC, Canada.
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Kiepas A, Voorand E, Senecal J, Ahn R, Annis MG, Jacquet K, Tali G, Bisson N, Ursini-Siegel J, Siegel PM, Brown CM. The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation. J Biol Chem 2020; 295:10535-10559. [PMID: 32299913 DOI: 10.1074/jbc.ra119.011903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/14/2020] [Indexed: 12/12/2022] Open
Abstract
SHC adaptor protein (SHCA) and lipoma-preferred partner (LPP) mediate transforming growth factor β (TGFβ)-induced breast cancer cell migration and invasion. Reduced expression of either protein diminishes breast cancer lung metastasis, but the reason for this effect is unclear. Here, using total internal reflection fluorescence (TIRF) microscopy, we found that TGFβ enhanced the assembly and disassembly rates of paxillin-containing adhesions in an SHCA-dependent manner through the phosphorylation of the specific SHCA tyrosine residues Tyr-239, Tyr-240, and Tyr-313. Using a BioID proximity labeling approach, we show that SHCA exists in a complex with a variety of actin cytoskeletal proteins, including paxillin and LPP. Consistent with a functional interaction between SHCA and LPP, TGFβ-induced LPP localization to cellular adhesions depended on SHCA. Once localized to the adhesions, LPP was required for TGFβ-induced increases in cell migration and adhesion dynamics. Mutations that impaired LPP localization to adhesions (mLIM1) or impeded interactions with the actin cytoskeleton via α-actinin (ΔABD) abrogated migratory responses to TGFβ. Live-cell TIRF microscopy revealed that SHCA clustering at the cell membrane preceded LPP recruitment. We therefore hypothesize that, in the presence of TGFβ, SHCA promotes the formation of small, dynamic adhesions by acting as a nucleator of focal complex formation. Finally, we defined a previously unknown function for SHCA in the formation of invadopodia, a process that also required LPP. Our results reveal that SHCA controls the formation and function of adhesions and invadopodia, two key cellular structures required for breast cancer metastasis.
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Affiliation(s)
- Alex Kiepas
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada.,Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada
| | - Elena Voorand
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Julien Senecal
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Division of Experimental Medicine, McGill University, Montréal H4A 3J1, Québec, Canada
| | - Ryuhjin Ahn
- Division of Experimental Medicine, McGill University, Montréal H4A 3J1, Québec, Canada.,Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Department of Medicine, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Kévin Jacquet
- Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, Québec G1R 2J6, Canada
| | - George Tali
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Nicolas Bisson
- Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, Québec G1R 2J6, Canada.,PROTEO Network and Cancer Research Centre, Université Laval, Québec, Québec G1V 0A6, Canada
| | - Josie Ursini-Siegel
- Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada.,Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.,Department of Oncology, McGill University, Montréal H4A 3T2, Québec, Canada
| | - Peter M Siegel
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada .,Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada.,Department of Medicine, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Claire M Brown
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada .,Advanced BioImaging Facility (ABIF), McGill University, Montréal H3G 0B1, Québec, Canada
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Nakamura R, Oyama T, Inokuchi M, Ishikawa S, Hirata M, Kawashima H, Ikeda H, Dobashi Y, Ooi A. The relation between anti-TGBFR1 immunohistochemical reaction and low Ki67, small tumor size and high estrogen receptor expression in invasive breast cancer. Pathol Int 2020; 70:330-339. [PMID: 32103597 DOI: 10.1111/pin.12914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 02/04/2020] [Indexed: 11/28/2022]
Abstract
Most breast cancers are derived from the luminal epithelium, which composes the inside of the breast ductal structure. Ductal carcinoma in situ (DCIS) leads to invasive ductal carcinoma, but noncancerous intraductal proliferative lesions are also a risk factor for ductal carcinoma. The transforming growth factor beta (TGFB) signaling pathway behaves as a tumor suppressor in the early stage of cancer, and conversely as a tumor growth factor in invasive stages in several cancers. In this study, we performed immunohistochemistry with an antibody that detects the cytoplasmic region of TGFB receptor 1 (TGFBR1) and elucidated TGFBR1 protein expression in luminal epithelial cells of noncancerous breast ducts and in several cases of DCIS and invasive carcinoma. TGFBR1 expression was higher in noncancerous breast tissue than in cancerous tissue, and a difference in expression was also seen among histological subtypes. Comparing the expression level of TGFBR1 in cancer cells and clinico-pathological parameters, cases expressing low TGFBR1 tended to show low estrogen receptor expression, large tumor size (≥10 mm), and a high Ki67 labeling index. These data suggested that TGFBR1 protein expression may be related to the suppression of breast cancer cell growth.
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Affiliation(s)
- Ritsuko Nakamura
- Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Takeru Oyama
- Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Masafumi Inokuchi
- Department of Breast Oncology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.,Department of Breast and Endocrine Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Satoko Ishikawa
- Department of Breast Oncology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Miki Hirata
- Department of Breast Oncology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Hiroko Kawashima
- Radiology Division, Kanazawa University Hospital, Ishikawa, Japan
| | - Hiroko Ikeda
- Diagnostic Pathology, Kanazawa University Hospital, Ishikawa, Japan
| | - Yoh Dobashi
- Department of Pathology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Akishi Ooi
- Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
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Sun Z, Velázquez-Quesada I, Murdamoothoo D, Ahowesso C, Yilmaz A, Spenlé C, Averous G, Erne W, Oberndorfer F, Oszwald A, Kain R, Bourdon C, Mangin P, Deligne C, Midwood K, Abou-Faycal C, Lefebvre O, Klein A, van der Heyden M, Chenard MP, Christofori G, Mathelin C, Loustau T, Hussenet T, Orend G. Tenascin-C increases lung metastasis by impacting blood vessel invasions. Matrix Biol 2019; 83:26-47. [PMID: 31288084 DOI: 10.1016/j.matbio.2019.07.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/30/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022]
Abstract
Metastasis is a major cause of death in cancer patients. The extracellular matrix molecule tenascin-C is a known promoter of metastasis, however the underlying mechanisms are not well understood. To further analyze the impact of tenascin-C on cancer progression we generated MMTV-NeuNT mice that develop spontaneous mammary tumors, on a tenascin-C knockout background. We also developed a syngeneic orthotopic model in which tumor cells derived from a MMTV-NeuNT tumor. Tumor cells were transfected with control shRNA or with shRNA to knockdown tenascin-C expression and, were grafted into the mammary gland of immune competent, wildtype or tenascin-C knockout mice. We show that stromal-derived tenascin-C increases metastasis by reducing apoptosis and inducing the cellular plasticity of cancer cells located in pulmonary blood vessels invasions (BVI), before extravasation. We characterized BVI as organized structures of tightly packed aggregates of proliferating tumor cells with epithelial characteristics, surrounded by Fsp1+ cells, internally located platelets and, a luminal monolayer of endothelial cells. We found extracellular matrix, in particular, tenascin-C, between the stromal cells and the tumor cell cluster. In mice lacking stromal-derived tenascin-C, the organization of pulmonary BVI was significantly affected, revealing novel functions of host-derived tenascin-C in supporting the integrity of the endothelial cell coat, increasing platelet abundance, tumor cell survival, epithelial plasticity, thereby promoting overall lung metastasis. Many effects of tenascin-C observed in BVI including enhancement of cellular plasticity, survival and migration, could be explained by activation of TGF-β signaling. Finally, in several human cancers, we also observed BVI to be surrounded by an endothelial monolayer and to express tenascin-C. Expression of tenascin-C is specific to BVI and is not observed in lymphatic vascular invasions frequent in breast cancer, which lack an endothelial lining. Given that BVI have prognostic significance for many tumor types, such as shorter cancer patient survival, increased metastasis, vessel occlusion, and organ failure, our data revealing a novel mechanism by which stromal tenascin-C promotes metastasis in human cancer, may have potential for diagnosis and therapy.
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Affiliation(s)
- Zhen Sun
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Inés Velázquez-Quesada
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Devadarssen Murdamoothoo
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Constance Ahowesso
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Alev Yilmaz
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Caroline Spenlé
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Gerlinde Averous
- Department of Pathology, University Hospital Strasbourg, Strasbourg, France
| | - William Erne
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | | | - Andre Oszwald
- Department of Pathology, Medical University of Vienna (MUW), Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna (MUW), Vienna, Austria
| | | | - Pierre Mangin
- Etablissement Français du Sang, INSERM U949, Strasbourg, France
| | - Claire Deligne
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Kim Midwood
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Chérine Abou-Faycal
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Olivier Lefebvre
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Annick Klein
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Michael van der Heyden
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | | | | | - Carole Mathelin
- Department of breast diseases and surgery, Strasbourg University Hospital, Strasbourg, France
| | - Thomas Loustau
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Thomas Hussenet
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Gertraud Orend
- INSERM U1109 - MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy and, the Tumor Microenvironment group, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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Amerizadeh F, Bahrami A, Khazaei M, Hesari A, Rezayi M, Talebian S, Maftouh M, Moetamani-Ahmadi M, Seifi S, Shahidsales S, Joudi-Mashhad M, Ferns GA, Ghasemi F, Avan A. Current status and future prospects of transforming growth factor-β as a potential prognostic and therapeutic target in the treatment of breast cancer. J Cell Biochem 2019; 120:6962-6971. [PMID: 30672016 DOI: 10.1002/jcb.27831] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 09/14/2018] [Indexed: 01/24/2023]
Abstract
The transforming growth factor-β (TGF-β) signaling pathway is one of the important pathways involved in the cancer cell proliferation, invasion, migration, angiogenesis, apoptosis, as well as in metastasis by agitation or invasion of metastasis-related factors, including matrix metalloproteinase (MMP), epithelial-to-mesenchymal transition (EMT), tumor microenvironment (TME), cancer stem cells (CSCs), and cell adhesion molecules (CAMs). These data suggest its potential value as a therapeutic object in the treatment of malignancies including breast cancer. Several pharmacological approaches have been established to suppress TGF-β pathway; such as vaccines, small molecular inhibitors, antisense oligonucleotides, and monoclonal antibodies. Some of these are now approved by the US Food and Drug Administration for targeting the TGF-β signaling pathway. This study attempts to summarize the current data about the functions of TGF-β in cancer cells, and their probable application in the cancer therapy with a specific emphasis on recent preclinical and clinical research in the treatment of breast cancer and its prognostic value.
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Affiliation(s)
- Forouzan Amerizadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - AmirReza Hesari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Talebian
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Maftouh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sima Seifi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mona Joudi-Mashhad
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
| | - Faezeh Ghasemi
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Lee J. 3,3′-Diindolylmethane Inhibits TNF-α- and TGF-β-Induced Epithelial–Mesenchymal Transition in Breast Cancer Cells. Nutr Cancer 2019; 71:992-1006. [DOI: 10.1080/01635581.2019.1577979] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Joomin Lee
- Department of Food and Nutrition, Chosun University, Gwangju, Korea
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Cao Y, Feng YH, Gao LW, Li XY, Jin QX, Wang YY, Xu YY, Jin F, Lu SL, Wei MJ. Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer cells in vitro and in vivo. Int Immunopharmacol 2019; 70:110-116. [PMID: 30798159 DOI: 10.1016/j.intimp.2019.01.041] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 01/23/2019] [Accepted: 01/28/2019] [Indexed: 12/01/2022]
Abstract
BACKGROUND Breast cancer is a prominent cause of death among women worldwide. Recent studies have demonstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we investigated the effects of ART in vitro and in vivo to determine how it influences the anti-tumor immune response. METHODS We measured the proliferation and apoptosis of 4T1 cells in vitro after ART treatment by MTT assay and FACS. To examine the effects of ART in vivo, tumor volumes and survival rates were measured in 4T1 tumor-bearing mice. FACS was used to determine the frequencies of Tregs, MDSCs, CD4+ IFN-γ+ T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR. ELISA was used to measure TGF-β protein levels in the cell culture supernatants. RESULTS ART supplementation significantly increased 4T1 cell apoptosis and decreased TGF-β levels in vitro. ART also impeded tumor growth in 4T1 TB mice and extended their survival. MDSC and Treg frequencies significantly decreased in the 4T1 TB mice after ART treatment while CD4+ IFN-γ+ T cells and CTLs significantly increased. ART significantly increased T-bet, IFN-γ, and TNF-α mRNA levels within the tumor and significantly decreased TGF-β mRNA levels. CONCLUSION ART supplementation hindered 4T1 tumor growth in vivo by promoting T cell activation and quelling immunosuppression from Tregs and MDSCs in the tumor.
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Affiliation(s)
- Yu Cao
- Laboratory of Precision Oncology, China Medial University School of Pharmacy, Shenyang, Liaoning, China; Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Yong-Hui Feng
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Li-Wei Gao
- Department of Radiation Oncology, China Japan Friendship Hospital, Beijing, China
| | - Xiao-Ying Li
- Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Quan-Xiu Jin
- Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Department of Breast Surgery, Liaoning Cancer Hospital, Shenyang, Liaoning, China
| | - Yu-Ying Wang
- Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Department of Breast Surgery, Liaoning Cancer Hospital, Shenyang, Liaoning, China
| | - Ying-Ying Xu
- Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Feng Jin
- Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shi-Long Lu
- Laboratory of Precision Oncology, China Medial University School of Pharmacy, Shenyang, Liaoning, China; Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Min-Jie Wei
- Laboratory of Precision Oncology, China Medial University School of Pharmacy, Shenyang, Liaoning, China.
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Hirata K, Takakura Y, Shibazaki M, Morii M, Honda T, Oshima M, Aoyama K, Iwama A, Nakayama Y, Takano H, Yamaguchi N, Yamaguchi N. Forkhead box protein A1 confers resistance to transforming growth factor-β-induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation. J Cell Biochem 2019; 120:2259-2270. [PMID: 30206966 DOI: 10.1002/jcb.27551] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 08/02/2018] [Indexed: 01/24/2023]
Abstract
Transforming growth factor-β (TGF-β) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF-β-induced apoptosis, the molecular mechanisms underlying this resistance are largely unknown. Here, we show that forkhead box protein A1 (FOXA1), which is known as a pioneer transcription factor, suppresses TGF-β-induced apoptosis of estrogen receptor-positive breast cancer cells. FOXA1 is found to inhibit nuclear translocation of Smad3, a key transcription factor downstream of TGF-β signaling, through suppression of the binding of Smad3 to the nuclear import receptor importin7. Furthermore, RNA sequencing analyses show that knockdown of FOXA1 upregulates Smad3-mediated proapoptotic gene expression. These results demonstrate that FOXA1 as a potent survival factor that suppresses TGF-β-induced apoptosis by inhibiting Smad3 signaling in estrogen receptor-positive breast cancer cells. Thus, we provide evidence for the first time that FOXA1 localizing to the cytoplasm negatively regulates Smad3-induced apoptosis in TGF-β-mediated signal transduction.
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Affiliation(s)
- Kensuke Hirata
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Yuki Takakura
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Misato Shibazaki
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Mariko Morii
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Takuya Honda
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Motohiko Oshima
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazumasa Aoyama
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Atsushi Iwama
- Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuji Nakayama
- Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hiroyuki Takano
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Naoto Yamaguchi
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Noritaka Yamaguchi
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.,Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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47
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Marques M, Jangal M, Wang LC, Kazanets A, da Silva SD, Zhao T, Lovato A, Yu H, Jie S, Del Rincon S, Mackey J, Damaraju S, Alaoui-Jamali M, Witcher M. Oncogenic activity of poly (ADP-ribose) glycohydrolase. Oncogene 2018; 38:2177-2191. [PMID: 30459355 PMCID: PMC6484711 DOI: 10.1038/s41388-018-0568-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 10/05/2018] [Accepted: 10/13/2018] [Indexed: 12/21/2022]
Abstract
Poly (ADP-ribosylation), known as PARylation, is a post-translational modification catalyzed by poly (ADP-ribose) polymerases (PARP) and primarily removed by the enzyme poly (ADP-ribose) glycohydrolase (PARG). While the aberrant removal of post-translation modifications including phosphorylation and methylation has known tumorigenic effects, deregulation of PARylation has not been widely studied. Increased hydrolysis of PARylation chains facilitates cancer growth through enhancing estrogen receptor (ER)-driven proliferation, but oncogenic transformation has not been linked to increased PARG expression. In this study, we find that elevated PARG levels are associated with a poor prognosis in breast cancers, especially in HER2-positive and triple-negative subtypes. Using both in vitro and in vivo models, we demonstrate that heightened expression of catalytically active PARG facilitates cell transformation and invasion of normal mammary epithelial cells. Catalytically inactive PARG mutants did not recapitulate these phenotypes. Consistent with clinical data showing elevated PARG predicts poor outcomes in HER2+ patients, we observed that PARG acts in synergy with HER2 to promote neoplastic growth of immortalized mammary cells. In contrast, PARG depletion significantly impairs the growth and metastasis of triple-negative breast tumors. Mechanistically, we find that PARG interacts with SMAD2/3 and significantly decreases their PARylation in non-transformed cells, leading to enhanced expression of SMAD target genes. Further linking SMAD-mediated transcription to the oncogenicity of PARG, we show that PARG-mediated anchorage-independent growth and invasion are dependent, at least in part, on SMAD expression. Overall, our study underscores the oncogenic impact of aberrant protein PARylation and highlights the therapeutic potential of PARG inhibition in breast cancer.
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Affiliation(s)
- Maud Marques
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Maika Jangal
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Li-Chun Wang
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Anna Kazanets
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Sabrina Daniela da Silva
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada.,Department of Otolaryngology/Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Tiejun Zhao
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Amanda Lovato
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Henry Yu
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Su Jie
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Sonia Del Rincon
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - John Mackey
- Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Sambasivarao Damaraju
- Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Moulay Alaoui-Jamali
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Michael Witcher
- Departments of Oncology and Experimental Medicine, The Lady Davis Institute of the Jewish General Hospital, McGill University, Montreal, QC, Canada.
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48
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Wang Y, Chu J, Yi P, Dong W, Saultz J, Wang Y, Wang H, Scoville S, Zhang J, Wu LC, Deng Y, He X, Mundy-Bosse B, Freud AG, Wang LS, Caligiuri MA, Yu J. SMAD4 promotes TGF-β-independent NK cell homeostasis and maturation and antitumor immunity. J Clin Invest 2018; 128:5123-5136. [PMID: 30183689 DOI: 10.1172/jci121227] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022] Open
Abstract
SMAD4 is the only common SMAD in TGF-β signaling that usually impedes immune cell activation in the tumor microenvironment. However, we demonstrated here that selective deletion of Smad4 in NK cells actually led to dramatically reduced tumor cell rejection and augmented tumor cell metastases, reduced murine CMV clearance, as well as impeded NK cell homeostasis and maturation. This was associated with a downregulation of granzyme B (Gzmb), Kit, and Prdm1 in Smad4-deficient NK cells. We further unveiled the mechanism by which SMAD4 promotes Gzmb expression. Gzmb was identified as a direct target of a transcriptional complex formed by SMAD4 and JUNB. A JUNB binding site distinct from that for SMAD4 in the proximal Gzmb promoter was required for transcriptional activation by the SMAD4-JUNB complex. In a Tgfbr2 and Smad4 NK cell-specific double-conditional KO model, SMAD4-mediated events were found to be independent of canonical TGF-β signaling. Our study identifies and mechanistically characterizes unusual functions and pathways for SMAD4 in governing innate immune responses to cancer and viral infection, as well as NK cell development.
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Affiliation(s)
- Youwei Wang
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.,The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Jianhong Chu
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Ping Yi
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.,Third Affiliated Hospital, Third Military Medical University, Chongqing, China
| | - Wenjuan Dong
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Jennifer Saultz
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Yufeng Wang
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Hongwei Wang
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Steven Scoville
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | | | - Lai-Chu Wu
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Youcai Deng
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | | | | | - Aharon G Freud
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.,Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Li-Shu Wang
- Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, California, USA
| | - Jianhua Yu
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.,The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.,Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, California, USA
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49
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Huang F, Shi Q, Li Y, Xu L, Xu C, Chen F, Wang H, Liao H, Chang Z, Liu F, Zhang XHF, Feng XH, Han JDJ, Luo S, Chen YG. HER2/EGFR-AKT Signaling Switches TGFβ from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer. Cancer Res 2018; 78:6073-6085. [PMID: 30171053 DOI: 10.1158/0008-5472.can-18-0136] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/15/2018] [Accepted: 08/28/2018] [Indexed: 11/16/2022]
Abstract
TGFβ signaling inhibits cell proliferation to block cancer initiation, yet it also enhances metastasis to promote malignancy during breast cancer development. The mechanisms underlying these differential effects are still unclear. Here, we report that HER2/EGFR signaling switches TGFβ function in breast cancer cells from antiproliferation to cancer promotion. Inhibition of HER2/EGFR activity attenuated TGFβ-induced epithelial-mesenchymal transition and migration but enhanced the antiproliferative activity of TGFβ. Activation of HER2/EGFR induced phosphorylation of Smad3 at Ser208 of the linker region through AKT, which promoted the nuclear accumulation of Smad3 and subsequent expression of the genes related to EMT and cell migration. In contrast, HER2/EGFR signaling had no effects on the nuclear localization of Smad2. Knockdown of Smad3, but not Smad2, blocked TGFβ-induced breast cancer cell migration. We observed a positive correlation between the nuclear localization of Smad3 and HER2 activation in advanced human breast cancers. Our results demonstrate a key role for HER2/EGFR in differential regulation of Smad3 activity to shift TGFβ function from antitumorigenic to protumorigenic during breast cancer development.Significance: TGFβ signaling can shift from inhibiting to promoting breast cancer development via HER2/EGFR AKT-mediated phosphorylation of Smad3 at S208, enhancing its nuclear accumulation and upregulation of EMT-related genes.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6073/F1.large.jpg Cancer Res; 78(21); 6073-85. ©2018 AACR.
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Affiliation(s)
- Fei Huang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Qiaoni Shi
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yuzhen Li
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Linlin Xu
- The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Chi Xu
- Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fenfang Chen
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hai Wang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Hongwei Liao
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Zai Chang
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Fang Liu
- Center for Advanced Biotechnology and Medicine, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas
| | - Xin-Hua Feng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jing-Dong J Han
- Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shiwen Luo
- The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
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50
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Tivari S, Lu H, Dasgupta T, De Lorenzo MS, Wieder R. Reawakening of dormant estrogen-dependent human breast cancer cells by bone marrow stroma secretory senescence. Cell Commun Signal 2018; 16:48. [PMID: 30119678 PMCID: PMC6098600 DOI: 10.1186/s12964-018-0259-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/09/2018] [Indexed: 12/16/2022] Open
Abstract
Background Dormant estrogen receptor positive (ER+) breast cancer micrometastases in the bone marrow survive adjuvant chemotherapy and recur stochastically for more than 20 years. We hypothesized that inflammatory cytokines produced by stromal injury can re-awaken dormant breast cancer cells. Methods We used an established in vitro dormancy model of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells incubated at clonogenic density on fibronectin-coated plates to determine the effects of inflammatory cytokines on reactivation of dormant ER+ breast cancer cells. We measured induction of a mesenchymal phenotype, motility and the capacity to re-enter dormancy. We induced secretory senescence in murine stromal monolayers by oxidation, hypoxia and estrogen deprivation with hydrogen peroxide (H2O2), carbonyl-cyanide m-chlorophenylhydrazzone (CCCP) and Fulvestrant (ICI 182780), respectively, and determined the effects on growth of co-cultivated breast cancer cells. Results Exogenous recombinant human (rh) interleukin (IL)-6, IL-8 or transforming growth factor β1 (TGFβ1) induced regrowth of dormant MCF-7 cells on fibronectin-coated plates. Dormant cells had decreased expression of E-cadherin and estrogen receptor α (ERα) and increased expression of N-cadherin and SNAI2 (SLUG). Cytokine or TGFβ1 treatment of dormant clones induced formation of growing clones, a mesenchymal appearance, increased motility and an impaired capacity to re-enter dormancy. Stromal injury induced secretion of IL-6, IL-8, upregulated tumor necrosis factor alpha (TNFα), activated TGFβ and stimulated the growth of co-cultivated MCF-7 cells. MCF-7 cells induced secretion of IL-6 and IL-8 by stroma in co-culture. Conclusions Dormant ER+ breast cancer cells have activated epithelial mesenchymal transition (EMT) gene expression programs and downregulated ERα but maintain a dormant epithelial phenotype. Stromal inflammation reactivates these cells, induces growth and a mesenchymal phenotype. Reactivated, growing cells have an impaired ability to re-enter dormancy. In turn, breast cancer cells co-cultured with stroma induce secretion of IL-6 and IL-8 by the stroma, creating a positive feedback loop.
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Affiliation(s)
- Samir Tivari
- Department of Medicine, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, 205 South Orange Avenue, Cancer Center H1216, Newark, NJ, 07103, USA
| | - Haiyan Lu
- Department of Medicine, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, 205 South Orange Avenue, Cancer Center H1216, Newark, NJ, 07103, USA
| | - Tanya Dasgupta
- Department of Medicine, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, 205 South Orange Avenue, Cancer Center H1216, Newark, NJ, 07103, USA
| | - Mariana S De Lorenzo
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
| | - Robert Wieder
- Department of Medicine, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, 205 South Orange Avenue, Cancer Center H1216, Newark, NJ, 07103, USA.
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