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1
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Silveira FM, Schuch LF, Pereira-Prado V, Molina-Frechero N, Lopez-Verdin S, Gómez Palacio-Gastélum M, Arocena M, Niklander S, Sicco E, Bologna-Molina R. Hypoxia-inducible factor-1α at the invasive tumor front in oral squamous cell carcinoma. World J Exp Med 2025; 15:102175. [DOI: 10.5493/wjem.v15.i2.102175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition, leading to aggressive tumor progression.
AIM To characterize the expression of hypoxia-inducible factor 1-alpha (HIF-1α) at the invasive tumor front (ITF) in comparison to tumor islands (TI) in oral squamous cell carcinoma (OSCC) and to explore its relationship with E-cadherin and Vimentin expression.
METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa (NOM) were included in this study. The ITF was identified based on the region and immune expression of AE1/AE3. Immunohistochemistry was performed to assess the expression of HIF-1α, Vimentin, and E-cadherin. The immunostaining was analyzed using an immunoreactive score, and the results were illustrated using immunofluorescence.
RESULTS HIF-1α expression was significantly higher in the TI region compared to the ITF region (P = 0.0134). Additionally, a significant difference was observed between TI and NOM (P = 0.0115). In the ITF regions, HIF-1α expression showed a significant correlation with Vimentin expression, with higher levels of HIF-1α associated with increased Vimentin expression (P = 0.017).
CONCLUSION Based on the results of this study, HIF-1α appears to play a distinct role in OSCC tumor progression, underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC. Further research is needed to better understand their impact on OSCC prognosis.
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Affiliation(s)
- Felipe Martins Silveira
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Lauren Frenzel Schuch
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Vanesa Pereira-Prado
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Nelly Molina-Frechero
- Division of Biological and Health Sciences, Autonomous Metropolitan University, Coyoacan 04960, Mexico
| | - Sandra Lopez-Verdin
- Health Science Center, Research Institute of Dentistry, Universidad de Guadalajara, Guadalajara 44100, Jalisco, Mexico
| | | | - Miguel Arocena
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, Montevideo 11600, Uruguay
| | - Sven Niklander
- Unit of Oral Pathology and Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar 2520000, Chile
| | - Estefania Sicco
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Ronell Bologna-Molina
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
- Department of Research, Universidad Juarez del Estado de Durango, Durango 34000, Mexico
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Aquino A, Franzese O. Reciprocal Modulation of Tumour and Immune Cell Motility: Uncovering Dynamic Interplays and Therapeutic Approaches. Cancers (Basel) 2025; 17:1547. [PMID: 40361472 PMCID: PMC12072109 DOI: 10.3390/cancers17091547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.
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Affiliation(s)
| | - Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
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3
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Rapanotti MC, Cugini E, Scioli MG, Cenci T, Anzillotti S, Puzzuoli M, Terrinoni A, Ferlosio A, De Luca A, Orlandi A. The Clinical Relevance of Epithelial-to-Mesenchymal Transition Hallmarks: A Cut-Off-Based Approach in Healthy and Cancerous Cell Lines. Int J Mol Sci 2025; 26:3617. [PMID: 40332096 PMCID: PMC12026647 DOI: 10.3390/ijms26083617] [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: 02/24/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
The atypical activation of the epithelial-to-mesenchymal transition represents one of the main mechanisms driving cancer cell dissemination. It enables epithelial cancer cells to detach from the primary tumor mass and gain survival advantages in the bloodstream, significantly contributing to the spread of circulating tumor cells. Notably, epithelial-to-mesenchymal transition is not a binary process but rather leads to the formation of a wide range of cell subpopulations characterized by the simultaneous expression of both epithelial and mesenchymal markers. Therefore, analyzing the modulation of EMT hallmarks during the conversion from healthy cells to metastatic cancer cells, which acquire stem mesenchymal characteristics, is of particular interest. This study investigates the expression of a panel of epithelial-to-mesenchymal transition-related genes in healthy cells, primary and metastatic cancer cells, and in mesenchymal cell lines, derived from various tissues, including the lung, colon, pancreas, skin, and neuro-ectoderm, with the aim of identifying potential cut-off values for assessing cancer aggressiveness. Interestingly, we found that the expression levels of CDH1, which encodes the epithelial marker E-cadherin, CDH5, encoding vascular endothelial cadherin, and the epithelial-to-mesenchymal transition-transcription factor ZEB1, effectively distinguished primary from metastatic cancer cells. Additionally, our data suggest a tissue-specific signature in the modulation of epithelial-to-mesenchymal transition markers during cancer progression. Overall, our results underscore the importance of investigating epithelial-to-mesenchymal transition as a tissue-specific process to identify the most suitable markers acting as potential indicators of disease aggressiveness and therapeutic responsiveness.
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Affiliation(s)
- Maria Cristina Rapanotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Elisa Cugini
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
- Department of Laboratory Medicine, Tor Vergata University Hospital, 00133 Rome, Italy;
| | - Maria Giovanna Scioli
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Tonia Cenci
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Silvia Anzillotti
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Martina Puzzuoli
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Alessandro Terrinoni
- Department of Laboratory Medicine, Tor Vergata University Hospital, 00133 Rome, Italy;
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Amedeo Ferlosio
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
| | - Anastasia De Luca
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Augusto Orlandi
- Anatomic Pathology, Department of Integrated Care Processes, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy (M.G.S.); (T.C.); (S.A.); (M.P.); (A.F.); (A.O.)
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4
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Greene G, Zonfa I, Ravasz Regan E. A Boolean network model of hypoxia, mechanosensing and TGF-β signaling captures the role of phenotypic plasticity and mutations in tumor metastasis. PLoS Comput Biol 2025; 21:e1012735. [PMID: 40238833 PMCID: PMC12061430 DOI: 10.1371/journal.pcbi.1012735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 05/08/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
The tumor microenvironment aids cancer progression by promoting several cancer hallmarks, independent of cancer-related mutations. Biophysical properties of this environment, such as the stiffness of the matrix cells adhere to and local cell density, impact proliferation, apoptosis, and the epithelial to mesenchymal transition (EMT). The latter is a rate-limiting step for invasion and metastasis, enhanced in hypoxic tumor environments but hindered by soft matrices and/or high cell densities. As these influences are often studied in isolation, the crosstalk between hypoxia, biomechanical signals, and the classic EMT driver TGF-β is not well mapped, limiting our ability to predict and anticipate cancer cell behaviors in changing tumor environments. To address this, we built a Boolean regulatory network model that integrates hypoxic signaling with a mechanosensitive model of EMT, which includes the EMT-promoting crosstalk of mitogens and biomechanical signals, cell cycle control, and apoptosis. Our model reproduces the requirement of Hif-1α for proliferation, the anti-proliferative effects of strong Hif-1α stabilization during hypoxia, hypoxic protection from anoikis, and hypoxia-driven mechanosensitive EMT. We offer experimentally testable predictions about the effect of VHL loss on cancer hallmarks, with or without secondary oncogene activation. Taken together, our model serves as a predictive framework to synthesize the signaling responses associated with tumor progression and metastasis in healthy vs. mutant cells. Our single-cell model is a key step towards more extensive regulatory network models that cover damage-response and senescence, integrating most cell-autonomous cancer hallmarks into a single model that can, in turn, control the behavior of in silico cells within a tissue model of epithelial homeostasis and carcinoma.
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Affiliation(s)
- Grant Greene
- Biochemistry and Molecular Biology, College of Wooster, Wooster, Ohio, United States of America
| | - Ian Zonfa
- Biochemistry and Molecular Biology, College of Wooster, Wooster, Ohio, United States of America
| | - Erzsébet Ravasz Regan
- Biochemistry and Molecular Biology, College of Wooster, Wooster, Ohio, United States of America
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5
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Avcu Altiparmak E, Özen Eroğlu G, Özdemir N, Erdem Kuruca S, Bal Demirci T. Synthesis, cytotoxicities, structural properties and comparison of dihalogeno-substituted-thiosemicarbazone ligands and mixed-ligand Ni(II) complexes. Dalton Trans 2025; 54:1454-1467. [PMID: 39632740 DOI: 10.1039/d4dt02774d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
Three novel mixed-ligand Ni(ıı) complexes were synthesized from a 3,5-dihalogenosalicylaldehyde-S-methyl isothiosemicarbazone ligand (3,5-dichloro for Complex I, 3,5-dibromo for Complex II, and 3,5-diiodo for Complex III) and diethanolamine. The synthesized compounds were characterized by elemental analysis, FT-IR, UV-Vis and 1H-NMR spectroscopy. Solid-state structures of Complex I and Complex II were determined by the single-crystal X-ray diffraction technique. Both the complexes were found to have a distorted square planar geometry, with coordination of azomethine nitrogen, phenolate oxygen, terminal amine of the thiosemicarbazone ligand and amine nitrogen of diethanolamine. The cytotoxic effects of the ligands and the complexes were evaluated against two different types of cancer cells (THP-1 human leukaemia monocytic cell line and MDA-MB-231 aggressive breast cancer cell line) and healthy cells (HUVEC human umbilical vein endothelial cell line) by using the MTT method. The findings demonstrated that the chloro-derivatives exhibited better efficacy compared to cisplatin in targeting the monocytic leukemia cell line while displaying reduced toxicity towards healthy cells.
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Affiliation(s)
- Elif Avcu Altiparmak
- Department of Chemistry, Engineering Faculty, Inorganic Chemistry Department, Istanbul University-Cerrahpasa, 34320, Istanbul, Turkiye.
| | - Güneş Özen Eroğlu
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093, Istanbul, Turkiye
| | - Namık Özdemir
- Department of Physics, Faculty of Art and Science, Ondokuz Mayis University, 55139, Samsun, Turkiye
| | - Serap Erdem Kuruca
- Department of Physiology, Faculty of Medicine, Istanbul University, 34390, Istanbul, Turkiye
- Department of Physiology, Faculty of Medicine, Istanbul Atlas University, 34408, Istanbul, Turkiye
| | - Tülay Bal Demirci
- Department of Chemistry, Engineering Faculty, Inorganic Chemistry Department, Istanbul University-Cerrahpasa, 34320, Istanbul, Turkiye.
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6
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [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: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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7
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Shoda C, Lee D, Miwa Y, Yamagami S, Nakashizuka H, Nimura K, Okamoto K, Kawagishi H, Negishi K, Kurihara T. Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis. FASEB J 2024; 38:e23792. [PMID: 38953555 DOI: 10.1096/fj.202400540rrr] [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: 03/10/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/04/2024]
Abstract
Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial-mesenchymal transition of retinal pigment epithelium (RPE) cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel-Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specific Hif1a/Hif2a- and Hif1a-cKO mice. Promotive effects were observed in RPE-specific Vhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products' extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.
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Affiliation(s)
- Chiho Shoda
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
- Ophthalmology, Nihon University School of Medicine, Tokyo, Japan
| | - Deokho Lee
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Yukihiro Miwa
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
- Aichi Animal Eye Clinic, Nagoya, Aichi, Japan
| | - Satoru Yamagami
- Ophthalmology, Nihon University School of Medicine, Tokyo, Japan
| | | | - Kazumi Nimura
- Shizuoka Prefectural Research Institute of Fishery and Ocean, Shizuoka, Japan
| | - Kazutoshi Okamoto
- Shizuoka Prefectural Research Institute of Fishery and Ocean, Shizuoka, Japan
- Marine Open Innovation Institute, Shizuoka, Japan
| | - Hirokazu Kawagishi
- Faculty of Agriculture, Shizuoka University, Shizuoka, Japan
- Research Institute for Mushroom Science, Shizuoka University, Shizuoka, Japan
| | - Kazuno Negishi
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Toshihide Kurihara
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
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8
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De Paolis L, Armando F, Montemurro V, Petrizzi L, Straticò P, Mecocci S, Guarnieri C, Pezzolato M, Fruscione F, Passeri B, Marruchella G, Razzuoli E. Epithelial-mesenchymal transition in an EcPV2-positive vulvar squamous cell carcinoma of a mare. Equine Vet J 2024; 56:768-775. [PMID: 37395141 DOI: 10.1111/evj.13965] [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: 02/27/2023] [Accepted: 05/29/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND Vulvar squamous cell carcinoma (VSCC) has been recently associated with Equus caballus papillomavirus type 2 (EcPV2) infection. Still, few reports concerning this disease are present in the literature. OBJECTIVE To describe a case of naturally occurring EcPV2-induced VSCC, by investigating tumour ability in undergoing the epithelial-to-mesenchymal transition (EMT). STUDY DESIGN Case report. METHODS A 13-year-old Haflinger mare was referred for a rapidly growing vulvar mass. After surgical excision, the mass was submitted to histopathology and molecular analysis. Histopathological diagnosis was consistent with a VSCC. Real-time qPCR, real-time reverse transcriptase (RT)-qPCR and RNAscope were carried out to detect EcPV2 infection and to evaluate E6/E7 oncogenes expression. To highlight the EMT, immunohistochemistry (IHC) was performed. Expression of EMT-related and innate immunity-related genes was investigated through RT-qPCR. RESULTS Real-time qPCR, RT-qPCR and RNAscope confirmed EcPV2 DNA presence and expression of EcPV2 oncoproteins (E6 and E7) within the neoplastic vulvar lesion. IHC highlighted a cadherin switch together with the expression of the EMT-related transcription factor HIF1α. With RT-qPCR, significantly increased gene expression of EBI3 (45.0 ± 1.62, p < 0.01), CDH2 (2445.3 ± 0.39, p < 0.001), CXCL8 (288.7 ± 0.40, p < 0.001) and decreased gene expression of CDH1 (0.3 ± 0.57, p < 0.05), IL12A (0.04 ± 1.06, p < 0.01) and IL17 (0.2 ± 0.64, p < 0.05) were detected. MAIN LIMITATIONS Lack of ability to generalise and danger of over-interpretation. CONCLUSION The results obtained were suggestive of an EMT event occurring within the neoplastic lesion.
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Affiliation(s)
- Livia De Paolis
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Genova, Italy
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Vittoria Montemurro
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Histopathology and Applied Technology Laboratory, Torino, Italy
| | - Lucio Petrizzi
- Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
| | - Paola Straticò
- Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
| | - Samanta Mecocci
- Department of Veterinary Science, University of Perugia, Perugia, Italy
| | - Chiara Guarnieri
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Marzia Pezzolato
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Histopathology and Applied Technology Laboratory, Torino, Italy
| | - Floriana Fruscione
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Genova, Italy
| | | | | | - Elisabetta Razzuoli
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, National Reference Center of Veterinary and Comparative Oncology (CEROVEC), Genova, Italy
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9
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Huang A, Sun Z, Hong H, Yang Y, Chen J, Gao Z, Gu J. Novel hypoxia- and lactate metabolism-related molecular subtyping and prognostic signature for colorectal cancer. J Transl Med 2024; 22:587. [PMID: 38902737 PMCID: PMC11191174 DOI: 10.1186/s12967-024-05391-5] [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: 04/03/2024] [Accepted: 06/12/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a serious global health burden because of its high morbidity and mortality rates. Hypoxia and massive lactate production are hallmarks of the CRC microenvironment. However, the effects of hypoxia and lactate metabolism on CRC have not been fully elucidated. This study aimed to develop a novel molecular subtyping based on hypoxia-related genes (HRGs) and lactate metabolism-related genes (LMRGs) and construct a signature to predict the prognosis of patients with CRC and treatment efficacy. METHODS Bulk and single-cell RNA-sequencing and clinical data of CRC were downloaded from the TCGA and GEO databases. HRGs and LMRGs were obtained from the Molecular Signatures Database. The R software package DESeq2 was used to perform differential expression analysis. Molecular subtyping was performed using unsupervised clustering. A predictive signature was developed using univariate Cox regression, random forest model, LASSO, and multivariate Cox regression analyses. Finally, the sensitivity of tumor cells to chemotherapeutic agents before and after hypoxia was verified using in vitro experiments. RESULTS We classified 575 patients with CRC into three molecular subtypes and were able to distinguish their prognoses clearly. The C1 subtype, which exhibits high levels of hypoxia, has a low proportion of CD8 + T cells and a high proportion of macrophages. The expression of immune checkpoint genes is generally elevated in C1 patients with severe immune dysfunction. Subsequently, we constructed a predictive model, the HLM score, which effectively predicts the prognosis of patients with CRC and the efficacy of immunotherapy. The HLM score was validated in GSE39582, GSE106584, GSE17536, and IMvigor210 datasets. Patients with high HLM scores exhibit high infiltration of CD8 + exhausted T cells (Tex), especially terminal Tex, and oxidative phosphorylation (OXPHOS)-Tex in the immune microenvironment. Finally, in vitro experiments confirmed that CRC cell lines were less sensitive to 5-fluorouracil, oxaliplatin, and irinotecan under hypoxic conditions. CONCLUSION We constructed novel hypoxia- and lactate metabolism-related molecular subtypes and revealed their immunological and genetic characteristics. We also developed an HLM scoring system that could be used to predict the prognosis and efficacy of immunotherapy in patients with CRC.
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Affiliation(s)
- An Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, China
| | - Zhuang Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, China
| | - Haopeng Hong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, China
| | - Yong Yang
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, 100144, China
| | - Jiajia Chen
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, 100144, China
| | - Zhaoya Gao
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, 100144, China
- Department of General Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Jin Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Haidian District, Beijing, 100142, China.
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, 100144, China.
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10
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Shah KA, Rawal RM. A novel algorithm to differentiate between primary lung tumors and distant liver metastasis in lung cancers using an exosome based multi gene biomarker panel. Sci Rep 2024; 14:13769. [PMID: 38877052 PMCID: PMC11178885 DOI: 10.1038/s41598-024-63252-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: 02/07/2024] [Accepted: 05/27/2024] [Indexed: 06/16/2024] Open
Abstract
The lack of non-invasive methods for detection of early metastasis is a crucial reason for the poor prognosis of lung cancer (LC) liver metastasis (LM) patients. In this study, the goal was to identify circulating biomarkers based on a biomarker model for the early diagnosis and monitoring of patients with LCLM. An 8-gene panel identified in our previous study was validated in CTC, cfRNA and exosomes isolated from primary lung cancer with & without metastasis. Further multivariate analysis including PCA & ROC was performed to determine the sensitivity and specificity of the biomarker panel. Model validation cohort (n = 79) was used to verify the stability of the constructed predictive model. Further, clinic-pathological factors, survival analysis and immune infiltration correlations were also performed. In comparison to our previous tissue data, exosomes demonstrated a good discriminative value with an AUC of 0.7247, specificity (72.48%) and sensitivity (96.87%) for the 8-gene panel. Further individual gene patterns led us to a 5- gene panel that showed an AUC of 0.9488 (p = < 0.001) and 0.9924 (p = < 0.001) respectively for tissue and exosomes. Additionally, on validating the model in a larger cohort a risk score was obtained (RS > 0.2) for prediction of liver metastasis with an accuracy of 95%. Survival analysis and immune filtration markers suggested that four exosomal markers were independently associated with poor overall survival. We report a novel blood-based exosomal biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with LCLM.
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Affiliation(s)
- Kanisha A Shah
- Division of Biological and Life Science, Ahmedabad University, Ahmedabad, Gujarat, India
| | - Rakesh M Rawal
- Department of Life Science, School of Sciences, Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India.
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11
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Villareal LB, Falcon DM, Xie L, Xue X. Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis. Br J Cancer 2024; 130:1904-1915. [PMID: 38693428 PMCID: PMC11183190 DOI: 10.1038/s41416-024-02699-3] [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: 05/30/2023] [Revised: 04/14/2024] [Accepted: 04/16/2024] [Indexed: 05/03/2024] Open
Abstract
BACKGROUND/OBJECTIVES Hypoxia-inducible factor (HIF)-3α1's role in colorectal cancer (CRC) cells, especially its effects on epithelial-mesenchymal transition (EMT), zinc finger E-box binding homeobox 2 (ZEB2) gene expression, and iron metabolism, remains largely unstudied. This research sought to elucidate these relationships. METHODS RNA-seq was conducted to investigate the impact of HIF-3α1 overexpression in CRC cells. Dual-luciferase reporter assays assessed the direct targeting of ZEB2 by HIF-3α1. Scratch assays measured changes in cell migration following HIF-3α1 overexpression and ZEB2 knockdown. The effects of HIF-3α1 overexpression on colon tumour growth and liver metastasis were examined in vivo. Iron chelation was used to explore the role of iron metabolism in HIF-3α1-mediated EMT and tumour growth. RESULTS HIF-3α1 overexpression induced EMT and upregulated ZEB2 expression, enhancing cancer cell migration. ZEB2 knockdown reduced mesenchymal markers and cell migration. HIF-3α1 promoted colon tumour growth and liver metastasis, increased transferrin receptor (TFRC) expression and cellular iron levels, and downregulated HIF-1α, HIF-2α, and NDRG1. Iron chelation mitigated HIF-3α1-mediated EMT, tumour growth, and survival. CONCLUSIONS HIF-3α1 plays a critical role in colon cancer progression by promoting EMT, iron accumulation, and metastasis through ZEB2 and TFRC regulation, suggesting potential therapeutic targets in CRC.
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Affiliation(s)
- Luke B Villareal
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, USA
| | - Daniel M Falcon
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, USA
| | - Liwei Xie
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, USA.
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12
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DeFrates KG, Tong E, Cheng J, Heber‐Katz E, Messersmith PB. A Pro-Regenerative Supramolecular Prodrug Protects Against and Repairs Colon Damage in Experimental Colitis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304716. [PMID: 38247203 PMCID: PMC10987129 DOI: 10.1002/advs.202304716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/13/2023] [Indexed: 01/23/2024]
Abstract
Structural repair of the intestinal epithelium is strongly correlated with disease remission in inflammatory bowel disease (IBD); however, ulcer healing is not addressed by existing therapies. To address this need, this study reports the use of a small molecule prolyl hydroxylase (PHD) inhibitor (DPCA) to upregulate hypoxia-inducible factor one-alpha (HIF-1α) and induce mammalian regeneration. Sustained delivery of DPCA is achieved through subcutaneous injections of a supramolecular hydrogel, formed through the self-assembly of PEG-DPCA conjugates. Pre-treatment of mice with PEG-DPCA is shown to protect mice from epithelial erosion and symptoms of dextran sodium sulfate (DSS)-induced colitis. Surprisingly, a single subcutaneous dose of PEG-DPCA, administered after disease onset, leads to accelerated weight gain and complete restoration of healthy tissue architecture in colitic mice. Rapid DPCA-induced restoration of the intestinal barrier is likely orchestrated by increased expression of HIF-1α and associated targets leading to an epithelial-to-mesenchymal transition. Further investigation of DPCA as a potential adjunctive or stand-alone restorative treatment to combat active IBD is warranted.
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Affiliation(s)
- Kelsey G. DeFrates
- Department of BioengineeringUniversity of California, BerkeleyBerkeleyCA94720USA
| | - Elaine Tong
- Department of BioengineeringUniversity of California, BerkeleyBerkeleyCA94720USA
| | - Jing Cheng
- Department of BioengineeringUniversity of California, BerkeleyBerkeleyCA94720USA
| | | | - Phillip B. Messersmith
- Department of BioengineeringUniversity of California, BerkeleyBerkeleyCA94720USA
- Department of Materials Science and EngineeringUniversity of California, BerkeleyBerkeleyCA94720USA
- Materials Sciences DivisionLawrence Berkeley National LaboratoryBerkeleyCA94720USA
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13
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Khalafizadeh A, Hashemizadegan SD, Shokri F, Bakhshinejad B, Jabbari K, Motavaf M, Babashah S. Competitive endogenous RNA networks: Decoding the role of long non-coding RNAs and circular RNAs in colorectal cancer chemoresistance. J Cell Mol Med 2024; 28:e18197. [PMID: 38506091 PMCID: PMC10951891 DOI: 10.1111/jcmm.18197] [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: 06/08/2023] [Revised: 11/17/2023] [Accepted: 02/04/2024] [Indexed: 03/21/2024] Open
Abstract
Colorectal cancer (CRC) is recognized as one of the most common gastrointestinal malignancies across the globe. Despite significant progress in designing novel treatments for CRC, there is a pressing need for more effective therapeutic approaches. Unfortunately, many patients undergoing chemotherapy develop drug resistance, posing a significant challenge for cancer treatment. Non-coding RNAs (ncRNAs) have been found to play crucial roles in CRC development and its response to chemotherapy. However, there are still gaps in our understanding of interactions among various ncRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs). These ncRNAs can act as either oncogenes or tumour suppressors, affecting numerous biological functions in different cancers including CRC. A class of ncRNA molecules known as competitive endogenous RNAs (ceRNAs) has emerged as a key player in various cellular processes. These molecules form networks through lncRNA/miRNA/mRNA and circRNA/miRNA/mRNA interactions. In CRC, dysregulation of ceRNA networks has been observed across various cellular processes, including proliferation, apoptosis and angiogenesis. These dysregulations are believed to play a significant role in the progression of CRC and, in certain instances, may contribute to the development of chemoresistance. Enriching our knowledge of these dysregulations holds promise for advancing the field of diagnostic and therapeutic modalities for CRC. In this review, we discuss lncRNA- and circRNA-associated ceRNA networks implicated in the emergence and advancement of drug resistance in colorectal carcinogenesis.
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Affiliation(s)
- Ali Khalafizadeh
- Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | | | - Fatemeh Shokri
- Research and Development Center of BiotechnologyTarbiat Modares UniversityTehranIran
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Keyvan Jabbari
- Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Mahsa Motavaf
- Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
- Research and Development Center of BiotechnologyTarbiat Modares UniversityTehranIran
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14
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Feng S, Ding B, Dai Z, Yin H, Ding Y, Liu S, Zhang K, Lin H, Xiao Z, Shen Y. Cancer-associated fibroblast-secreted FGF7 as an ovarian cancer progression promoter. J Transl Med 2024; 22:280. [PMID: 38491511 PMCID: PMC10941588 DOI: 10.1186/s12967-024-05085-y] [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: 11/02/2023] [Accepted: 03/10/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Ovarian cancer (OC) is distinguished by its aggressive nature and the limited efficacy of current treatment strategies. Recent studies have emphasized the significant role of cancer-associated fibroblasts (CAFs) in OC development and progression. METHODS Employing sophisticated machine learning techniques on bulk transcriptomic datasets, we identified fibroblast growth factor 7 (FGF7), derived from CAFs, as a potential oncogenic factor. We investigated the relationship between FGF7 expression and various clinical parameters. A series of in vitro experiments were undertaken to evaluate the effect of CAFs-derived FGF7 on OC cell activities, such as proliferation, migration, and invasion. Single-cell transcriptomic analysis was also conducted to elucidate the interaction between FGF7 and its receptor. Detailed mechanistic investigations sought to clarify the pathways through which FGF7 fosters OC progression. RESULTS Our findings indicate that higher FGF7 levels correlate with advanced tumor stages, increased vascular invasion, and poorer prognosis. CAFs-derived FGF7 significantly enhanced OC cell proliferation, migration, and invasion. Single-cell analysis and in vitro studies revealed that CAFs-derived FGF7 inhibits the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF-1α) via FGFR2 interaction. Activation of the FGF7/HIF-1α pathway resulted in the upregulation of mesenchymal markers and downregulation of epithelial markers. Importantly, in vivo treatment with neutralizing antibodies targeting CAFs-derived FGF7 substantially reduced tumor growth. CONCLUSION Neutralizing FGF7 in the medium or inhibiting HIF-1α signaling reversed the effects of FGF7-mediated EMT, emphasizing the dependence of FGF7-mediated EMT on HIF-1α activation. These findings suggest that targeting the FGF7/HIF-1α/EMT axis may offer new therapeutic opportunities to intervene in OC progression.
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Affiliation(s)
- Songwei Feng
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Bo Ding
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhu Dai
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Han Yin
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yue Ding
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Sicong Liu
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ke Zhang
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hao Lin
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
| | - Zhongdang Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
| | - Yang Shen
- Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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15
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Bae T, Hallis SP, Kwak MK. Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer. Exp Mol Med 2024; 56:501-514. [PMID: 38424190 PMCID: PMC10985007 DOI: 10.1038/s12276-024-01180-8] [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: 11/14/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 03/02/2024] Open
Abstract
Oxygen is crucial for life and acts as the final electron acceptor in mitochondrial energy production. Cells adapt to varying oxygen levels through intricate response systems. Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response, activating genes to increase the oxygen supply and reduce expenditure. Under conditions of excess oxygen and resulting oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) activates hundreds of genes for oxidant removal and adaptive cell survival. Hypoxia and oxidative stress are core hallmarks of solid tumors and activated HIFs and NRF2 play pivotal roles in tumor growth and progression. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of intricacy to the HIF and NRF2 signaling systems. This review aimed to elucidate the dynamic changes and functions of the HIF and NRF2 signaling pathways in response to conditions of hypoxia and oxidative stress, emphasizing their implications within the tumor milieu. Additionally, this review explored the elaborate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies.
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Affiliation(s)
- Taegeun Bae
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea
| | - Steffanus Pranoto Hallis
- Department of Pharmacy, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea
| | - Mi-Kyoung Kwak
- Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
- Department of Pharmacy, Graduate School of The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi‑do, 14662, Republic of Korea.
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Strippoli R, Niayesh-Mehr R, Adelipour M, Khosravi A, Cordani M, Zarrabi A, Allameh A. Contribution of Autophagy to Epithelial Mesenchymal Transition Induction during Cancer Progression. Cancers (Basel) 2024; 16:807. [PMID: 38398197 PMCID: PMC10886827 DOI: 10.3390/cancers16040807] [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: 12/15/2023] [Revised: 02/13/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Epithelial Mesenchymal Transition (EMT) is a dedifferentiation process implicated in many physio-pathological conditions including tumor transformation. EMT is regulated by several extracellular mediators and under certain conditions it can be reversible. Autophagy is a conserved catabolic process in which intracellular components such as protein/DNA aggregates and abnormal organelles are degraded in specific lysosomes. In cancer, autophagy plays a controversial role, acting in different conditions as both a tumor suppressor and a tumor-promoting mechanism. Experimental evidence shows that deep interrelations exist between EMT and autophagy-related pathways. Although this interplay has already been analyzed in previous studies, understanding mechanisms and the translational implications of autophagy/EMT need further study. The role of autophagy in EMT is not limited to morphological changes, but activation of autophagy could be important to DNA repair/damage system, cell adhesion molecules, and cell proliferation and differentiation processes. Based on this, both autophagy and EMT and related pathways are now considered as targets for cancer therapy. In this review article, the contribution of autophagy to EMT and progression of cancer is discussed. This article also describes the multiple connections between EMT and autophagy and their implication in cancer treatment.
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Affiliation(s)
- Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- National Institute for Infectious Diseases “Lazzaro Spallanzani”, I.R.C.C.S., 00149 Rome, Italy
| | - Reyhaneh Niayesh-Mehr
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran P.O. Box 14115-331, Iran;
| | - Maryam Adelipour
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran;
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Türkiye;
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain;
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye;
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran P.O. Box 14115-331, Iran;
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Musleh Ud Din S, Streit SG, Huynh BT, Hana C, Abraham AN, Hussein A. Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer. Int J Mol Sci 2024; 25:2060. [PMID: 38396737 PMCID: PMC10888675 DOI: 10.3390/ijms25042060] [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: 12/26/2023] [Revised: 02/07/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.
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Affiliation(s)
- Saba Musleh Ud Din
- Department of Internal Medicine, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA
| | - Spencer G. Streit
- Department of Hematology and Oncology, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA; (S.G.S.); (C.H.); (A.-N.A.); (A.H.)
| | - Bao Tran Huynh
- Department of Pharmacy, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA
| | - Caroline Hana
- Department of Hematology and Oncology, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA; (S.G.S.); (C.H.); (A.-N.A.); (A.H.)
| | - Anna-Ninny Abraham
- Department of Hematology and Oncology, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA; (S.G.S.); (C.H.); (A.-N.A.); (A.H.)
| | - Atif Hussein
- Department of Hematology and Oncology, Memorial Healthcare System, 703 North Flamingo Road, Pembroke Pines, FL 33028, USA; (S.G.S.); (C.H.); (A.-N.A.); (A.H.)
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18
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Nakamichi K, Yamamoto Y, Semba K, Nakayama J. Metastatic potentials classified with hypoxia-inducible factor 1 downstream genes in pan-cancer cell lines. Genes Cells 2024; 29:169-177. [PMID: 38158708 DOI: 10.1111/gtc.13092] [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: 06/20/2023] [Revised: 12/17/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Hypoxia-inducible factor 1 (HIF1) is a transcription factor that is stabilized under hypoxia conditions via post-translational modifications. HIF1 regulates tumor malignancy and metastasis by gene transcriptions, such as Warburg effect and angiogenesis-related genes, in cancer cells. However, the HIF1 downstream genes show varied expressional patterns in different cancer types. Herein, we performed the hierarchical clustering based on the HIF1 downstream gene expression patterns using 1406 cancer cell lines crossing 30 types of cancer to understand the relationship between HIF1 downstream genes and the metastatic potential of cancer cell lines. Two types of cancers, including bone and breast cancers, were classified based on HIF1 downstream genes with significantly altered metastatic potentials. Furthermore, different HIF1 downstream gene subsets were extracted to discriminate each subtype for these cancer types. HIF1 downstream subtyping classification will help to understand the novel insight into tumor malignancy and metastasis in each cancer type.
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Affiliation(s)
- Kazuya Nakamichi
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kentaro Semba
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
- Translational Research Center, Fukushima Medical University, Fukushima, Japan
| | - Jun Nakayama
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
- Department of Oncogenesis and growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan
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19
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Everest‐Dass A, Nersisyan S, Maar H, Novosad V, Schröder‐Schwarz J, Freytag V, Stuke JL, Beine MC, Schiecke A, Haider M, Kriegs M, Elakad O, Bohnenberger H, Conradi L, Raygorodskaya M, Krause L, von Itzstein M, Tonevitsky A, Schumacher U, Maltseva D, Wicklein D, Lange T. Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer. Mol Oncol 2024; 18:62-90. [PMID: 37849446 PMCID: PMC10766209 DOI: 10.1002/1878-0261.13535] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 08/10/2023] [Accepted: 10/12/2023] [Indexed: 10/19/2023] Open
Abstract
Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial-mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia-inducible factor-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.
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Affiliation(s)
- Arun Everest‐Dass
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Stepan Nersisyan
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Institute of Molecular BiologyThe National Academy of Sciences of the Republic of ArmeniaYerevanArmenia
- Armenian Bioinformatics Institute (ABI)YerevanArmenia
- Present address:
Computational Medicine CenterThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Hanna Maar
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Victor Novosad
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
| | | | - Vera Freytag
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Johanna L. Stuke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mia C. Beine
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Alina Schiecke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Marie‐Therese Haider
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Malte Kriegs
- Department of Radiobiology and Radiation OncologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Omar Elakad
- Institute of PathologyUniversity Medical Center GöttingenGermany
| | | | - Lena‐Christin Conradi
- Clinic for General, Visceral and Pediatric SurgeryUniversity Medical Center GöttingenGermany
| | | | - Linda Krause
- Institute of Medical Biometry and EpidemiologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mark von Itzstein
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Alexander Tonevitsky
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
- Art Photonics GmbHBerlinGermany
| | - Udo Schumacher
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Medical School BerlinGermany
| | - Diana Maltseva
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
| | - Daniel Wicklein
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Department of Anatomy and Cell BiologyUniversity of MarburgGermany
| | - Tobias Lange
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Institute of Anatomy IJena University HospitalGermany
- Comprehensive Cancer Center Central Germany (CCCG)Jena and LeipzigGermany
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20
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Fan P, Zhang N, Candi E, Agostini M, Piacentini M, Shi Y, Huang Y, Melino G. Alleviating hypoxia to improve cancer immunotherapy. Oncogene 2023; 42:3591-3604. [PMID: 37884747 DOI: 10.1038/s41388-023-02869-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/07/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023]
Abstract
Tumor hypoxia resulting from abnormal and dysfunctional tumor vascular network poses a substantial obstacle to immunotherapy. In fact, hypoxia creates an immunosuppressive tumor microenvironment (TME) through promoting angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition (EMT), p53 inactivation, and immune evasion. Vascular normalization, a strategy aimed at restoring the structure and function of tumor blood vessels, has been shown to improve oxygen delivery and reverse hypoxia-induced signaling pathways, thus alleviates hypoxia and potentiates cancer immunotherapy. In this review, we discuss the mechanisms of tumor tissue hypoxia and its impacts on immune cells and cancer immunotherapy, as well as the approaches to induce tumor vascular normalization. We also summarize the evidence supporting the use of vascular normalization in combination with cancer immunotherapy, and highlight the challenges and future directions of this overlooked important field. By targeting the fundamental problem of tumor hypoxia, vascular normalization proposes a promising strategy to enhance the efficacy of cancer immunotherapy and improve clinical outcomes for cancer patients.
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Affiliation(s)
- Peng Fan
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
- National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, 215123, Suzhou, China
| | - Naidong Zhang
- National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, 215123, Suzhou, China
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Mauro Piacentini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, 215123, Suzhou, China.
| | - Yuhui Huang
- National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, 215123, Suzhou, China.
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
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21
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Nicolazzo C, Francescangeli F, Magri V, Giuliani A, Zeuner A, Gazzaniga P. Is cancer an intelligent species? Cancer Metastasis Rev 2023; 42:1201-1218. [PMID: 37540301 PMCID: PMC10713722 DOI: 10.1007/s10555-023-10123-0] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/26/2023] [Indexed: 08/05/2023]
Abstract
Some relevant emerging properties of intelligent systems are "adaptation to a changing environment," "reaction to unexpected situations," "capacity of problem solving," and "ability to communicate." Single cells have remarkable abilities to adapt, make adequate context-dependent decision, take constructive actions, and communicate, thus theoretically meeting all the above-mentioned requirements. From a biological point of view, cancer can be viewed as an invasive species, composed of cells that move from primary to distant sites, being continuously exposed to changes in the environmental conditions. Blood represents the first hostile habitat that a cancer cell encounters once detached from the primary site, so that cancer cells must rapidly carry out multiple adaptation strategies to survive. The aim of this review was to deepen the adaptation mechanisms of cancer cells in the blood microenvironment, particularly referring to four adaptation strategies typical of animal species (phenotypic adaptation, metabolic adaptation, niche adaptation, and collective adaptation), which together define the broad concept of biological intelligence. We provided evidence that the required adaptations (either structural, metabolic, and related to metastatic niche formation) and "social" behavior are useful principles allowing putting into a coherent frame many features of circulating cancer cells. This interpretative frame is described by the comparison with analog behavioral traits typical of various animal models.
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Affiliation(s)
- Chiara Nicolazzo
- Department of Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Federica Francescangeli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Valentina Magri
- Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161, Rome, Italy
| | - Alessandro Giuliani
- Environment and Health Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Ann Zeuner
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Paola Gazzaniga
- Department of Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.
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22
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Zefferino R, Conese M. A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects. Vaccines (Basel) 2023; 11:1701. [PMID: 38006033 PMCID: PMC10674257 DOI: 10.3390/vaccines11111701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/07/2023] [Accepted: 10/19/2023] [Indexed: 11/26/2023] Open
Abstract
Is it possible to have an available vaccine that eradicates cancer? Starting from this question, this article tries to verify the state of the art, proposing a different approach to the issue. The variety of cancers and different and often unknown causes of cancer impede, except in some cited cases, the creation of a classical vaccine directed at the causative agent. The efforts of the scientific community are oriented toward stimulating the immune systems of patients, thereby preventing immune evasion, and heightening chemotherapeutic agents effects against cancer. However, the results are not decisive, because without any warning signs, metastasis often occurs. The purpose of this paper is to elaborate on a vaccine that must be administered to a patient in order to prevent metastasis; metastasis is an event that leads to death, and thus, preventing it could transform cancer into a chronic disease. We underline the fact that the field has not been studied in depth, and that the complexity of metastatic processes should not be underestimated. Then, with the aim of identifying the target of a cancer vaccine, we draw attention to the presence of the paradoxical actions of different mechanisms, pathways, molecules, and immune and non-immune cells characteristic of the tumor microenvironment at the primary site and pre-metastatic niche in order to exclude possible vaccine candidates that have opposite effects/behaviors; after a meticulous evaluation, we propose possible targets to develop a metastasis-targeting vaccine. We conclude that a change in the current concept of a cancer vaccine is needed, and the efforts of the scientific community should be redirected toward a metastasis-targeting vaccine, with the increasing hope of eradicating cancer.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Massimo Conese
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
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23
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Bedelbaeva K, Cameron B, Latella J, Aslanukov A, Gourevitch D, Davuluri R, Heber-Katz E. Epithelial-mesenchymal transition: an organizing principle of mammalian regeneration. Front Cell Dev Biol 2023; 11:1101480. [PMID: 37965571 PMCID: PMC10641390 DOI: 10.3389/fcell.2023.1101480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 09/27/2023] [Indexed: 11/16/2023] Open
Abstract
Introduction: The MRL mouse strain is one of the few examples of a mammal capable of healing appendage wounds by regeneration, a process that begins with the formation of a blastema, a structure containing de-differentiating mesenchymal cells. HIF-1α expression in the nascent MRL wound site blastema is one of the earliest identified events and is sufficient to initiate the complete regenerative program. However, HIF-1α regulates many cellular processes modulating the expression of hundreds of genes. A later signal event is the absence of a functional G1 checkpoint, leading to G2 cell cycle arrest with increased cellular DNA but little cell division observed in the blastema. This lack of mitosis in MRL blastema cells is also a hallmark of regeneration in classical invertebrate and vertebrate regenerators such as planaria, hydra, and newt. Results and discussion: Here, we explore the cellular events occurring between HIF-1α upregulation and its regulation of the genes involved in G2 arrest (EVI-5, γH3, Wnt5a, and ROR2), and identify epithelial-mesenchymal transition (EMT) (Twist and Slug) and chromatin remodeling (EZH-2 and H3K27me3) as key intermediary processes. The locus of these cellular events is highly regionalized within the blastema, occurring in the same cells as determined by double staining by immunohistochemistry and FACS analysis, and appears as EMT and chromatin remodeling, followed by G2 arrest determined by kinetic expression studies.
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Affiliation(s)
- Kamila Bedelbaeva
- Lankenau Institute for Medical Research (LIMR), Wynnewood, PA, United States
| | - Benjamin Cameron
- Lankenau Institute for Medical Research (LIMR), Wynnewood, PA, United States
| | - John Latella
- Lankenau Institute for Medical Research (LIMR), Wynnewood, PA, United States
| | - Azamat Aslanukov
- Lankenau Institute for Medical Research (LIMR), Wynnewood, PA, United States
| | | | | | - Ellen Heber-Katz
- Lankenau Institute for Medical Research (LIMR), Wynnewood, PA, United States
- The Wistar Institute, Philadelphia, PA, United States
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24
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Rasool S, Ismaeel QAL, Arif SH. CYR61 promotes colorectal carcinoma progression via activating epithelial-mesenchymal transition. Am J Cancer Res 2023; 13:4872-4887. [PMID: 37970355 PMCID: PMC10636662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/26/2023] [Indexed: 11/17/2023] Open
Abstract
Colorectal carcinoma is the third most common type of cancer. Although the role of matricellular proteins and their association with tumor progression is well documented, limited data are available concerning their involvement in colorectal cancer. The current study investigated the expression pattern of matricellular proteins SPARC and CYR61 with epithelial-mesenchymal transition proteins in human CRC tissues and unleashed their association with colorectal cancer progression. The expression of these proteins was associated with advancement in tumor staging, nodal metastasis, and vascular invasion. Elevated CYR61 protein levels were also consistent with higher mesenchymal markers ZEB1 and Vimentin in collected biopsies and CRC cells. Moreover, expression of CYR61 promoted CRC cell migration, invasion, proliferation, and apoptosis. Our findings conclusively revealed the significant involvement of CYR61 in CRC progression through activating epithelial-mesenchymal transition. This discovery holds great promise for advancing therapeutic approaches in the treatment of CRC.
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Affiliation(s)
- Shelan Rasool
- Department of Anatomy, Biology and Histology, College of Medicine, University of DuhokDuhok 42001, Kurdistan Region of Iraq
| | - Qais AL Ismaeel
- Department of Anatomy, Biology and Histology, College of Medicine, University of DuhokDuhok 42001, Kurdistan Region of Iraq
| | - Sardar H Arif
- Department of Surgery, College of Medicine, University of DuhokDuhok 42001, Kurdistan Region of Iraq
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25
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Ildiz ES, Gvozdenovic A, Kovacs WJ, Aceto N. Travelling under pressure - hypoxia and shear stress in the metastatic journey. Clin Exp Metastasis 2023; 40:375-394. [PMID: 37490147 PMCID: PMC10495280 DOI: 10.1007/s10585-023-10224-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/05/2023] [Indexed: 07/26/2023]
Abstract
Cancer cell invasion, intravasation and survival in the bloodstream are early steps of the metastatic process, pivotal to enabling the spread of cancer to distant tissues. Circulating tumor cells (CTCs) represent a highly selected subpopulation of cancer cells that tamed these critical steps, and a better understanding of their biology and driving molecular principles may facilitate the development of novel tools to prevent metastasis. Here, we describe key research advances in this field, aiming at describing early metastasis-related processes such as collective invasion, shedding, and survival of CTCs in the bloodstream, paying particular attention to microenvironmental factors like hypoxia and mechanical stress, considered as important influencers of the metastatic journey.
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Affiliation(s)
- Ece Su Ildiz
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Werner J Kovacs
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland.
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26
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Araldi RP, Delvalle DA, da Costa VR, Alievi AL, Teixeira MR, Dias Pinto JR, Kerkis I. Exosomes as a Nano-Carrier for Chemotherapeutics: A New Era of Oncology. Cells 2023; 12:2144. [PMID: 37681875 PMCID: PMC10486723 DOI: 10.3390/cells12172144] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
Despite the considerable advancements in oncology, cancer remains one of the leading causes of death worldwide. Drug resistance mechanisms acquired by cancer cells and inefficient drug delivery limit the therapeutic efficacy of available chemotherapeutics drugs. However, studies have demonstrated that nano-drug carriers (NDCs) can overcome these limitations. In this sense, exosomes emerge as potential candidates for NDCs. This is because exosomes have better organotropism, homing capacity, cellular uptake, and cargo release ability than synthetic NDCs. In addition, exosomes can serve as NDCs for both hydrophilic and hydrophobic chemotherapeutic drugs. Thus, this review aimed to summarize the latest advances in cell-free therapy, describing how the exosomes can contribute to each step of the carcinogenesis process and discussing how these nanosized vesicles could be explored as nano-drug carriers for chemotherapeutics.
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Affiliation(s)
- Rodrigo Pinheiro Araldi
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
- BioDecision Analytics Ltd.a., São Paulo 13271-650, SP, Brazil;
| | - Denis Adrián Delvalle
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Vitor Rodrigues da Costa
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Anderson Lucas Alievi
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Endocrinology and Metabology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Michelli Ramires Teixeira
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Endocrinology and Metabology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | | | - Irina Kerkis
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
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27
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Davies A, Zoubeidi A, Beltran H, Selth LA. The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity. Cancer Discov 2023; 13:1771-1788. [PMID: 37470668 PMCID: PMC10527883 DOI: 10.1158/2159-8290.cd-23-0225] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 06/09/2023] [Indexed: 07/21/2023]
Abstract
Lineage plasticity, a process whereby cells change their phenotype to take on a different molecular and/or histologic identity, is a key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage plasticity, it is predominantly a dynamic process controlled by transcriptional and epigenetic dysregulation. This review explores the transcriptional and epigenetic regulators of lineage plasticity and their interplay with other features of malignancy, such as dysregulated metabolism, the tumor microenvironment, and immune evasion. We also discuss strategies for the detection and treatment of highly plastic tumors. SIGNIFICANCE Lineage plasticity is a hallmark of cancer and a critical facilitator of other oncogenic features such as metastasis, therapy resistance, dysregulated metabolism, and immune evasion. It is essential that the molecular mechanisms of lineage plasticity are elucidated to enable the development of strategies to effectively target this phenomenon. In this review, we describe key transcriptional and epigenetic regulators of cancer cell plasticity, in the process highlighting therapeutic approaches that may be harnessed for patient benefit.
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Affiliation(s)
- Alastair Davies
- Oncology Research Discovery, Pfizer Worldwide Research and Development, San Diego, CA, USA
| | - Amina Zoubeidi
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Himisha Beltran
- Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Luke A. Selth
- Flinders Health and Medical Research Institute and Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, South Australia, 5042 Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5005 Australia
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28
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Astore S, Baciarello G, Cerbone L, Calabrò F. Primary and acquired resistance to first-line therapy for clear cell renal cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:517-546. [PMID: 37842234 PMCID: PMC10571064 DOI: 10.20517/cdr.2023.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/26/2023] [Accepted: 07/11/2023] [Indexed: 10/17/2023]
Abstract
The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients' treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.
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Affiliation(s)
- Serena Astore
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | | | - Linda Cerbone
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | - Fabio Calabrò
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
- Medical Oncology, IRCSS, National Cancer Institute Regina Elena, Rome 00128, Italy
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29
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Brockmueller A, Girisa S, Motallebi M, Kunnumakkara AB, Shakibaei M. Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration. Front Pharmacol 2023; 14:1203436. [PMID: 37583906 PMCID: PMC10423823 DOI: 10.3389/fphar.2023.1203436] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/14/2023] [Indexed: 08/17/2023] Open
Abstract
Background: Hypoxia-inducible factor-1α (HIF-1α) is one of the major tumor-associated transcription factors modulating numerous tumor properties such as tumor cell metabolism, survival, proliferation, angiogenesis, and metastasis. Calebin A (CA), a compound derived from turmeric, is known for its anti-cancer activity through modulation of the NF-κB pathway. However, its impact on HIF-1α in colorectal cancer (CRC) cell migration is unknown. Methods: Human CRC cells (HCT-116) in 3D alginate and monolayer multicellular TME (fibroblasts/T lymphocytes) were subjected to CA or the HIF-1α inhibitor to explore the efficacy of CA on TME-induced inflammation, migration, and tumor malignancy. Results: CA significantly inhibited TME-promoted proliferation and migration of HCT-116 cells, similar to the HIF-1α inhibitor. Colony formation, toluidine blue staining, and immunolabeling showed that CA inhibited the migration of HCT-116 cells partly by inhibiting HIF-1α, which is critical for CRC cell viability, and these observations were confirmed by electron microscopy. In addition, Western blot analysis confirmed that CA inhibited TME-initiated expression of HIF-1α and biomarkers of metastatic factors (such as NF-κB, β1-integrin, and VEGF), and promoted apoptosis (caspase-3), in a manner comparable to the HIF-1α inhibitor. Finally, TME induced a purposeful pairing between HIF-1α and NF-κB, suggesting that the synergistic interplay between the two tumor-associated transcription factors is essential for CRC cell malignancy and migration and that CA silences these factors in tandem. Conclusion: These results shed light on a novel regulatory modulation of CA signaling in CRC cell migration, partially via HIF-1α/NF-κB with potentially relevant implications for cancer therapy.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Mahzad Motallebi
- Department of Biology, Yadegar-e-Imam Khomeini Shahr-e-Rey Branch, Islamic Azad University, Tehran, Iran
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
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30
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Galindo-Vega A, Maldonado-Lagunas V, Mitre-Aguilar IB, Melendez-Zajgla J. Tumor Microenvironment Role in Pancreatic Cancer Stem Cells. Cells 2023; 12:1560. [PMID: 37371030 DOI: 10.3390/cells12121560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/18/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a majority of patients presenting with unresectable or metastatic disease, resulting in a poor 5-year survival rate. This, in turn, is due to a highly complex tumor microenvironment and the presence of cancer stem cells, both of which induce therapy resistance and tumor relapse. Therefore, understanding and targeting the tumor microenvironment and cancer stem cells may be key strategies for designing effective PDAC therapies. In the present review, we summarized recent advances in the role of tumor microenvironment in pancreatic neoplastic progression.
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Affiliation(s)
- Aaron Galindo-Vega
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 04710, Mexico
| | | | - Irma B Mitre-Aguilar
- Biochemistry Unit, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City 14080, Mexico
| | - Jorge Melendez-Zajgla
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 04710, Mexico
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31
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Turano M, Vicidomini R, Cammarota F, D'Agostino V, Duraturo F, Izzo P, Rosa MD. The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation. Biomedicines 2023; 11:biomedicines11051428. [PMID: 37239099 DOI: 10.3390/biomedicines11051428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Colorectal cancer (CRC) stands as the third most significant contributor to cancer-related mortality worldwide. A major underlying reason is that the detection of CRC usually occurs at an advanced metastatic stage, rendering therapies ineffective. In the progression from the in situ neoplasia stage to the advanced metastatic stage, a critical molecular mechanism involved is the epithelial-to-mesenchymal transition (EMT). This intricate transformation consists of a series of molecular changes, ultimately leading the epithelial cell to relinquish its features and acquire mesenchymal and stem-like cell characteristics. The EMT regulation involves several factors, such as transcription factors, cytokines, micro RNAs and long noncoding RNAs. Nevertheless, recent studies have illuminated an emerging link between metabolic alterations and EMT in various types of cancers, including colorectal cancers. In this review, we delved into the pivotal role played by EMT during CRC progression, with a focus on highlighting the relationship between the alterations of the tricarboxylic acid cycle, specifically those involving the succinate dehydrogenase enzyme, and the activation of the EMT program. In fact, emerging evidence supports the idea that elucidating the metabolic modifications that can either induce or inhibit tumor progression could be of immense significance for shaping new therapeutic approaches and preventative measures. We conclude that an extensive effort must be directed towards research for the standardization of drugs that specifically target proteins such as SDH and SUCNR1, but also TRAP1, PDH, ERK1/2, STAT3 and the HIF1-α catabolism.
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Affiliation(s)
- Mimmo Turano
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Rosario Vicidomini
- Section on Cellular Communication, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Francesca Cammarota
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy
| | - Valeria D'Agostino
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Francesca Duraturo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy
| | - Paola Izzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Marina De Rosa
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy
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32
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Kung H, Yu J. Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study. MedComm (Beijing) 2023; 4:e216. [PMID: 36814688 PMCID: PMC9939368 DOI: 10.1002/mco2.216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 02/21/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5-year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm.
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Affiliation(s)
- Heng‐Chung Kung
- Krieger School of Arts and SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Jun Yu
- Departments of Medicine and OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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33
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The Role of Reprogrammed Glucose Metabolism in Cancer. Metabolites 2023; 13:metabo13030345. [PMID: 36984785 PMCID: PMC10051753 DOI: 10.3390/metabo13030345] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
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34
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Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e203. [PMID: 36703877 PMCID: PMC9870816 DOI: 10.1002/mco2.203] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023] Open
Abstract
Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.
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Affiliation(s)
- Yan Zhuang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Kua Liu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Qinyu He
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Xiaosong Gu
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
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35
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Guo M, Niu Y, Xie M, Liu X, Li X. Notch signaling, hypoxia, and cancer. Front Oncol 2023; 13:1078768. [PMID: 36798826 PMCID: PMC9927648 DOI: 10.3389/fonc.2023.1078768] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
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Affiliation(s)
- Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Niu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Min Xie
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China,*Correspondence: Xiaochen Li,
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36
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Zarin B, Nedaeinia R, Laher I, Manian M, Javanmard SH. The effects of ALK5 inhibition and simultaneous inhibition or activation of HIF-1α in melanoma tumor growth and angiogenesis. Tumour Biol 2023; 45:111-126. [PMID: 37927290 DOI: 10.3233/tub-220020] [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] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Hypoxia is the most common signature of the tumor microenvironment that drives tumorigenesis through the complex crosstalk of a family of transcription factors called hypoxia-inducible factors (HIFs), with other intercellular signaling networks. Hypoxia increases transforming growth factor-beta (TGF-β) expression. TGF-β and HIF-1α play critical roles in several malignancies and their interactions in melanoma progression remain unknown. Therefore, the aim of this study was to assess the impact of inhibiting activin receptor-like kinase-5 (ALK5), a TGF-β receptor, on the response to HIF-1α activation or inhibition in melanoma tumor progression. MATERIALS AND METHODS Tumors were induced in C57BL/6J mice by subcutaneous inoculation with B16F10 melanoma cells. Mice were divided into HIF-1α inhibitor, ALK5 inhibitor (1 mg/kg) and HIF-1α inhibitor (100 mg/kg), ALK5 inhibitor, HIF-1α activator (1000 mg/kg), HIF-1α activator and ALK5 inhibitor, and control groups to receive inhibitors and activators through intraperitoneal injection. The expression of E-cadherin was evaluated by RT-qPCR. Vessel density and platelet-derived growth factor receptor beta (PDGFR)-β+ cells around the vessels were investigated using immunohistochemistry. RESULTS The groups receiving HIF-1α inhibitor and activator showed lower and higher tumor growth compared to the control group, respectively. E-cadherin expression decreased in all groups compared to the control group, illustrating the dual function of E-cadherin in the tumor microenvironment. Vascular density was reduced in the groups given HIF-1α inhibitor, ALK5 inhibitor, and ALK5 and HIF-1α inhibitor simultaneously. The percentage of PDGFR-β+ cells was reduced in the presence of HIF-1α inhibitor, ALK5 inhibitor, HIF-1α and ALK5 inhibitors, and upon simultaneous treatment with HIF-1α activator and ALK5 inhibitor. CONCLUSION Despite increased expression and interaction between TGF-β and HIF-1α pathways in some cancers, in melanoma, inhibition of either pathway alone may have a stronger effect on tumor inhibition than simultaneous inhibition of both pathways. The synergistic effects may be context-dependent and should be further evaluated in different cancer types.
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Affiliation(s)
- Bahareh Zarin
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ismail Laher
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
| | - Mostafa Manian
- Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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Abstract
Metastasis is the leading cause of mortality in most patients with cancer. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain poorly understood. Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature. In this review, we describe the roles of hypoxia and hypoxia-inducible factor (HIF) signaling in the metastatic cascade, with an emphasis on recent biological insights from in vivo studies.
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Affiliation(s)
- Kyoung Eun Lee
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan.,Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
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38
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Poonaki E, Kahlert UD, Meuth SG, Gorji A. The role of the ZEB1–neuroinflammation axis in CNS disorders. J Neuroinflammation 2022; 19:275. [PMCID: PMC9675144 DOI: 10.1186/s12974-022-02636-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 11/21/2022] Open
Abstract
Zinc finger E-box binding homeobox 1 (ZEB1) is a master modulator of the epithelial–mesenchymal transition (EMT), a process whereby epithelial cells undergo a series of molecular changes and express certain characteristics of mesenchymal cells. ZEB1, in association with other EMT transcription factors, promotes neuroinflammation through changes in the production of inflammatory mediators, the morphology and function of immune cells, and multiple signaling pathways that mediate the inflammatory response. The ZEB1–neuroinflammation axis plays a pivotal role in the pathogenesis of different CNS disorders, such as brain tumors, multiple sclerosis, cerebrovascular diseases, and neuropathic pain, by promoting tumor cell proliferation and invasiveness, formation of the hostile inflammatory micromilieu surrounding neuronal tissues, dysfunction of microglia and astrocytes, impairment of angiogenesis, and dysfunction of the blood–brain barrier. Future studies are needed to elucidate whether the ZEB1–neuroinflammation axis could serve as a diagnostic, prognostic, and/or therapeutic target for CNS disorders.
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Affiliation(s)
- Elham Poonaki
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany ,grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany
| | - Ulf Dietrich Kahlert
- grid.5807.a0000 0001 1018 4307Molecular and Experimental Surgery, Faculty of Medicine, University Clinic for General-, Visceral-, Vascular- and Transplantation Surgery, Otto-Von-Guericke-University, Magdeburg, Germany
| | - Sven G. Meuth
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ali Gorji
- grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany ,grid.512981.60000 0004 0612 1380Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran ,grid.411583.a0000 0001 2198 6209Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications. J Hematol Oncol 2022; 15:160. [PMID: 36319992 PMCID: PMC9628128 DOI: 10.1186/s13045-022-01358-5] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/26/2022] [Indexed: 11/07/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.
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40
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Tiwari A, Trivedi R, Lin SY. Tumor microenvironment: barrier or opportunity towards effective cancer therapy. J Biomed Sci 2022; 29:83. [PMID: 36253762 PMCID: PMC9575280 DOI: 10.1186/s12929-022-00866-3] [Citation(s) in RCA: 170] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 10/01/2022] [Indexed: 12/24/2022] Open
Abstract
Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis of tumor. With the advent of 3D culture and advanced bioinformatic methodologies, it is now possible to study TME’s individual components and their interplay at higher resolution. Deeper understanding of the immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction of TMEs has provided the opportunity to explore the spatial and temporal regulation of immune therapeutic interventions. The variation of TME composition among patients plays an important role in determining responders and non-responders towards cancer immunotherapy. Therefore, there could be a possibility of reprogramming of TME components to overcome the widely prevailing issue of immunotherapeutic resistance. The focus of the present review is to understand the complexity of TME and comprehending future perspective of its components as potential therapeutic targets. The later part of the review describes the sophisticated 3D models emerging as valuable means to study TME components and an extensive account of advanced bioinformatic tools to profile TME components and predict neoantigens. Overall, this review provides a comprehensive account of the current knowledge available to target TME.
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Affiliation(s)
- Aadhya Tiwari
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Rakesh Trivedi
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shiaw-Yih Lin
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Bahadory S, Sadraei J, Zibaei M, Pirestani M, Dalimi A. In vitro anti-gastrointestinal cancer activity of Toxocara canis-derived peptide: Analyzing the expression level of factors related to cell proliferation and tumor growth. Front Pharmacol 2022; 13:878724. [PMID: 36204226 PMCID: PMC9530354 DOI: 10.3389/fphar.2022.878724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Recently, a hypothesis about the negative relationship between cancers and parasites has been proposed and investigated; some parasitic worms and their products can affect the cancer cell proliferation. Due to the potential anti-cancer effect of helminthic parasites, in the present study, the excretory–secretory protein of Toxocara canis (T. canis) parasite was used to evaluate the possible anti-cancer properties and their effect on gastrointestinal and liver cancer cell proliferation-related genes in laboratory conditions. Methods and materials: The selected synthesized peptide fraction from the T. canis excretory–secretory Troponin protein peptide (ES TPP) was exposed at 32, 64, 128, and 256 μg/ml concentrations to three gastrointestinal cancer cell lines AGS, HT-29, and Caco 2, as well as HDF cells as normal cell lines. We used the MTT assay to evaluate cellular changes and cell viability (CV). Variations in gene (Bcl-2, APAF1, ZEB1, VEGF, cyclin-D1, and caspase-3) expression were analyzed by real-time RT-PCR. Results: After 24 h of exposure to pept1ides and cell lines, a decrease in CV was observed at a concentration of 64 μg/ml and compared to the control group. Then, after 48 h, a significant decrease in the CV of Caco 2 cells was observed at a concentration of 32 μg/ml; in the other cancer cell lines, concentrations above 32 μg/ml were effective. The peptide was able to significantly alter the expression of the studied genes at a concentration of 100 μg/ml. Conclusion: Although the studied peptide at high concentrations could have a statistically significant effect on cancer cells, it is still far from the standard drug and can be optimized and promising in future studies.
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Affiliation(s)
- Saeed Bahadory
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javid Sadraei
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- *Correspondence: Javid Sadraei,
| | - Mohammad Zibaei
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Evidence-Based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Pirestani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abdolhossein Dalimi
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy. Cells 2022; 11:cells11182811. [PMID: 36139386 PMCID: PMC9496732 DOI: 10.3390/cells11182811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/27/2022] [Accepted: 09/05/2022] [Indexed: 12/05/2022] Open
Abstract
Previous studies have shown that tumors under a hypoxic environment can induce an important hypoxia-responsive element, hypoxia-induced factor-1α (HIF-1α), which can increase tumor migration, invasion, and metastatic ability by promoting epithelial-to-mesenchymal transition (EMT) in tumor cells. Currently, with the deeper knowledge of long noncoding RNAs (lncRNAs), more and more functions of lncRNAs have been discovered. HIF-1α can regulate hypoxia-responsive lncRNAs under hypoxic conditions, and changes in the expression level of lncRNAs can regulate the production of EMT transcription factors and signaling pathway transduction, thus promoting EMT progress. In conclusion, this review summarizes the regulation of the EMT process by HIF-1α and lncRNAs and discusses their relationship with tumorigenesis. Since HIF-1α plays an important role in tumor progression, we also summarize the current drugs that inhibit tumor progression by modulating HIF-1α.
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Guo Y, Wang M, Zou Y, Jin L, Zhao Z, Liu Q, Wang S, Li J. Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer. J Nanobiotechnology 2022; 20:371. [PMID: 35953863 PMCID: PMC9367166 DOI: 10.1186/s12951-022-01586-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/04/2022] [Indexed: 11/10/2022] Open
Abstract
Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.
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Affiliation(s)
- Yu Guo
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Min Wang
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Yongbo Zou
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Longhai Jin
- Department of Radiology, Jilin University Second Hospital, Changchun, 130000, China
| | - Zeyun Zhao
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Qi Liu
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Shuang Wang
- Department of the Dermatology, Jilin University Second Hospital, Changchun, 130000, China.
| | - Jiannan Li
- Department of the General Surgery, Jilin University Second Hospital, Changchun, 130000, China.
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Comprehensive and Integrated Analysis Identifies ZEB1 as a Key Novel Gene in Oral Squamous Cell Carcinoma. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:4486104. [PMID: 36034202 PMCID: PMC9381230 DOI: 10.1155/2022/4486104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/23/2022] [Indexed: 11/18/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer with a poor prognosis. Therefore, it is crucial to explore molecular prognostic biomarkers for OSCC. ZEB1 (also known as δEF1) is a member of the zinc finger E-box binding protein family of transcription factors involved in various biological processes, including tumorigenesis, progression, and metastasis. Recent evidence suggests that ZEB1 has a role in the tumorigenicity of oral epithelial cells, although its mode of action needs to be investigated further. To better understand the relationship between ZEB1 and OSCC, we transfected the ZEB1-overexpressing oral squamous cell lines SCC9 and SCC25 with lentivirus and then extracted RNA from the cells for gene expression analysis. Furthermore, the GSE30784 dataset was downloaded from the Gene Expression Omnibus (GEO) database to identify potential biomarkers of OSCC and to assess the potential mechanisms. The criteria for identification of their DEGs were |logFC| > 1 and
< 0.05. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses were also carried out. Integrating the data from the PPI network and survival analysis identified that ZEB1 might be an independent prognostic biomarker in OSCC. In conclusion, integrated bioinformatics and microarray analysis identified the critical gene ZEB1 linked to the overall survival (OS) of patients with OSCC. ZEB1 could be applied as a prognostic biomarker to forecast the survival of patients with OSCC and might indicate innovative therapeutic indicators for OSCC.
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Weng X, Liu H, Ruan J, Du M, Wang L, Mao J, Cai Y, Lu X, Chen W, Huang Y, Zhi X, Shan J. HOTAIR/miR-1277-5p/ZEB1 axis mediates hypoxia-induced oxaliplatin resistance via regulating epithelial-mesenchymal transition in colorectal cancer. Cell Death Discov 2022; 8:310. [PMID: 35798695 PMCID: PMC9263107 DOI: 10.1038/s41420-022-01096-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/03/2022] [Accepted: 06/20/2022] [Indexed: 01/19/2023] Open
Abstract
The hypoxic microenvironment contributes to the chemoresistance of many malignant tumors including colorectal cancer (CRC). Accumulating studies have indicated that long non-coding RNAs (lncRNAs) play important roles in chemotherapy resistance. In this study, we aimed to determine the effect of lncRNAs in hypoxia-mediated resistance in CRC and its potential mechanism. Here, we discovered that hypoxia-induced oxaliplatin resistance and HOX transcript antisense RNA (HOTAIR) expression was increased in hypoxia-treated CRC cell lines and CRC tumors. Knockdown of HOTAIR by siRNA reduced the viability and proliferation of CRC cells treated with oxaliplatin and reversed hypoxia-induced resistance. Mechanically, we found that HOTAIR modulates zinc finger E-box binding homeobox 1 (ZEB1) expression by negative regulations of miR-1277-5p. When miR-1277-5p was silenced, knockdown of HOTAIR was unable to reduce the oxaliplatin resistance in CRC cells. In mouse models of CRC, HOTAIR knockdown markedly inhibited the tumor growth when treated with oxaliplatin. Thus, HOTAIR/miR-1277-5p/ZEB1 axis appears a promising therapeutic target for improving the oxaliplatin efficacy in CRC.
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Affiliation(s)
- Xingyue Weng
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Hao Liu
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Miaoyan Du
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Lingjie Wang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiayan Mao
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Ying Cai
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Xuemei Lu
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, Zhejiang, China
| | - Yaqing Huang
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Zhejiang Provincial Peoples Hospital, Affiliated Peoples Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Xiao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
| | - Jianzhen Shan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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Singh V, Singh R, Kushwaha R, Verma SP, Tripathi AK, Mahdi AA. The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia. Front Oncol 2022; 12:912942. [PMID: 35847841 PMCID: PMC9279726 DOI: 10.3389/fonc.2022.912942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic myeloid leukemia (CML) is potentially fatal blood cancer, but there is an unmet need to discover novel molecular biomarkers. The hypothesis of this study aimed to elucidate the relationship of HIF1α with the redox system, Krebs cycles, notch1, and other regulatory proteins to better understand the pathophysiology and clinical relevance in chronic myeloid leukemia (CML) patients, as the molecular mechanism of this axis is still not clear. This study included CML patient samples (n = 60; 60: blood; 10: bone marrow tissues) and compared them with healthy controls (n = 20; blood). Clinical diagnosis confirmed on bone marrow aspiration, marrow trephine biopsy, and BCR/ABL1 translocation. Cases were subclassified into chronic, accelerated, and blast crises as per WHO guidelines. Molecular experiments included redox parameters, DNA fragmentation, Krebs cycle metabolites, and gene expression by RT-PCR/Western blot/LC-MS, PPI (STRING), Pearson correlation, and ROC curve analysis. Here, our findings show that p210/p190BCR/ABL1 translocation is common in all blast crisis phases of CML. Redox factor/Krebs oncometabolite concentrations were high, leading to upregulation and stabilization of HIF1α. HIF1α leads to the pathogenesis in CML cells by upregulating their downstream genes (Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53, etc.). Whereas, downregulated ubiquitin proteasomal and apoptotic factors in CML pateints, can trigger degradation of HIF1α through proline hydroxylation. However, HIF1α showed a negative corelation with the notch1 pathway. Notch1 plays a tumor-suppressive role in CML and might have the potential to be used as a diagnostic marker along with other factors in CML patients. The outcome also revealed that oxidant treatment could not be effective in augmentation with conventional therapy because CML cells can enhance the levels of antioxidants for their survival. HIF1α might be a novel therapeutic target other than BCR/ABL1 translocation.
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Affiliation(s)
- Vivek Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, India
| | - Ranjana Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, India
- *Correspondence: Ranjana Singh, ;
| | - Rashmi Kushwaha
- Department of Pathology, King George’s Medical University, Lucknow, India
| | | | - Anil Kumar Tripathi
- Department of Clinical Hematology, King George’s Medical University, Lucknow, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George’s Medical University, Lucknow, India
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Coronel-Hernández J, Delgado-Waldo I, Cantú de León D, López-Camarillo C, Jacobo-Herrera N, Ramos-Payán R, Pérez-Plasencia C. HypoxaMIRs: Key Regulators of Hallmarks of Colorectal Cancer. Cells 2022; 11:1895. [PMID: 35741024 PMCID: PMC9221210 DOI: 10.3390/cells11121895] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 01/27/2023] Open
Abstract
Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to death by necrosis in cells, there is an exquisitely regulated mechanism that rescues hypoxic cells from their fatal fate. The accumulation in the cytoplasm of the transcription factor HIF-1α, which, under normoxic conditions, is marked for degradation by a group of oxygen-sensing proteins known as prolyl hydroxylases (PHDs) in association with the von Hippel-Lindau anti-oncogene (VHL) is critical for the cell, as it regulates different mechanisms through the genes it induces. A group of microRNAs whose expression is regulated by HIF, collectively called hypoxaMIRs, have been recognized. In this review, we deal with the hypoxaMIRs that have been shown to be expressed in colorectal cancer. Subsequently, using data mining, we analyze a panel of hypoxaMIRs expressed in both normal and tumor tissues obtained from TCGA. Finally, we assess the impact of these hypoxaMIRs on cancer hallmarks through their target genes.
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Affiliation(s)
- Jossimar Coronel-Hernández
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
| | - Izamary Delgado-Waldo
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - David Cantú de León
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City 03100, Mexico;
| | - Nadia Jacobo-Herrera
- Biochemistry Unit, Institute of Medical Sciences and Nutrition, Salvador Zubirán, Tlalpan, Mexico City 14080, Mexico;
| | - Rosalío Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacan City 80030, Mexico;
| | - Carlos Pérez-Plasencia
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
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Sirtuins and Hypoxia in EMT Control. Pharmaceuticals (Basel) 2022; 15:ph15060737. [PMID: 35745656 PMCID: PMC9228842 DOI: 10.3390/ph15060737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 05/25/2022] [Accepted: 06/08/2022] [Indexed: 02/06/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach.
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Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest 2022; 132:159839. [PMID: 35642641 PMCID: PMC9151701 DOI: 10.1172/jci159839] [Citation(s) in RCA: 291] [Impact Index Per Article: 97.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
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Affiliation(s)
| | - Gregg L Semenza
- Department of Genetic Medicine.,Institute for Cell Engineering, and.,Stanley Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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50
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Huang Z, Zhang Z, Zhou C, Liu L, Huang C. Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm (Beijing) 2022; 3:e144. [PMID: 35601657 PMCID: PMC9115588 DOI: 10.1002/mco2.144] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/05/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.
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Affiliation(s)
- Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
| | - Chengwei Zhou
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Lin Liu
- Department of Thoracic Surgery the Affiliated Hospital of Medical School of Ningbo University Ningbo China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 China
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