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Li D, Wang J, Li X, Wang Z, Yu Q, Koh SB, Wu R, Ye L, Guo Y, Okoli U, Pati-Alam A, Mota E, Wei W, Yoo KH, Cho WC, Feng D, Heavey S. Interactions between radiotherapy resistance mechanisms and the tumor microenvironment. Crit Rev Oncol Hematol 2025; 210:104705. [PMID: 40107436 DOI: 10.1016/j.critrevonc.2025.104705] [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: 01/31/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Resistance to radiotherapy (RT) presents a significant clinical challenge in management of cancer. Recent evidence points to specific mechanisms of resistance within the tumor microenvironment (TME), which we aim to discuss, with the aim of overcoming the clinical challenge. METHODS We performed the narrative review using PubMed and Web of Science databases to identify studies that reported the regulative network and treatments of RT resistance from TME perspectives. RESULTS RT significantly changes the immune TME of cancers, which is closely appearing to play a key role in RT resistance (RTR) by modulating immune cell infiltration and function. Various phenotypes are involved in the development of RTR, such as autophagy, senescence, oxidative stress, cell polarization, ceramide metabolism, and angiogenesis in the TME. Key genes and pathways are also implicated in RTR, including immune and inflammatory cytokines, TGF-β, P53, the NF-κB pathway, the cGAS/STING pathway, the ERK and AKT pathway, and the STAT pathway. Based on the mechanism of RTR in the TME, many proposed routes to overcome RTR, several specifically target the TME including targeting fibroblast activation protein, exosomes management, nanomedicine, and immunotherapy. Many challenges in RT resistance still need to be further explored with emerging investigative methods, such as artificial intelligence, genetic technologies, and bioengineering. CONCLUSIONS The complex interactions between RT and TME significantly affect the efficiency of RT. Novel approaches to overcome this clinical difficulty are promising, which needs future work to further explore and identify better treatment strategies.
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Affiliation(s)
- Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinrui Li
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Zhipeng Wang
- Department of Urology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Qingxin Yu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, China
| | - Siang Boon Koh
- Faculty of Health and Life Sciences, University of Bristol, Bristol, BS8 1TD, UK
| | - Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Luxia Ye
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yiqing Guo
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Uzoamaka Okoli
- Division of Surgery & Interventional Science, University College London, London, UK; Basic and Translational Cancer Research Group, Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Eastern part of Nigeria, Nsukka, Enugu, Nigeria
| | - Alisha Pati-Alam
- Division of Surgery & Interventional Science, University College London, London, UK
| | - Eduardo Mota
- Division of Surgery & Interventional Science, University College London, London, UK
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Koo Han Yoo
- Department of Urology, Kyung Hee University, South Korea
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region of China.
| | - Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China; Division of Surgery & Interventional Science, University College London, London, UK.
| | - Susan Heavey
- Division of Surgery & Interventional Science, University College London, London, UK.
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 424] [Impact Index Per Article: 424.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Ge R, Huang GM. Targeting transforming growth factor beta signaling in metastatic osteosarcoma. J Bone Oncol 2023; 43:100513. [PMID: 38021074 PMCID: PMC10666000 DOI: 10.1016/j.jbo.2023.100513] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/28/2023] [Accepted: 11/07/2023] [Indexed: 12/01/2023] Open
Abstract
Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling. TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.
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Affiliation(s)
- Rongrong Ge
- Hillman Cancer Center at Central Pennsylvania, University of Pittsburg Medical Center, Harrisburg, PA, 17109, USA
| | - Gavin M. Huang
- Harrisburg Academy School, 10 Erford Rd, Wormleysburg, PA, 17043, USA
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Yu YC, Shi TM, Gu SL, Li YH, Yang XM, Fan Q, Wang YD. A novel cervix carcinoma biomarker: Pathological-epigenomics, integrated analysis of MethylMix algorithm and pathology for predicting response to cancer immunotherapy. Front Oncol 2022; 12:1053800. [PMID: 36408176 PMCID: PMC9667097 DOI: 10.3389/fonc.2022.1053800] [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: 09/26/2022] [Accepted: 10/21/2022] [Indexed: 11/05/2022] Open
Abstract
Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future.
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Affiliation(s)
- Yu-Chong Yu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian-Ming Shi
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Lan Gu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Hong Li
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Ming Yang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiong Fan
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yu-Dong Wang, ; Qiong Fan,
| | - Yu-Dong Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yu-Dong Wang, ; Qiong Fan,
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Hachana S, Larrivée B. TGF-β Superfamily Signaling in the Eye: Implications for Ocular Pathologies. Cells 2022; 11:2336. [PMID: 35954181 PMCID: PMC9367584 DOI: 10.3390/cells11152336] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 02/06/2023] Open
Abstract
The TGF-β signaling pathway plays a crucial role in several key aspects of development and tissue homeostasis. TGF-β ligands and their mediators have been shown to be important regulators of ocular physiology and their dysregulation has been described in several eye pathologies. TGF-β signaling participates in regulating several key developmental processes in the eye, including angiogenesis and neurogenesis. Inadequate TGF-β signaling has been associated with defective angiogenesis, vascular barrier function, unfavorable inflammatory responses, and tissue fibrosis. In addition, experimental models of corneal neovascularization, diabetic retinopathy, proliferative vitreoretinopathy, glaucoma, or corneal injury suggest that aberrant TGF-β signaling may contribute to the pathological features of these conditions, showing the potential of modulating TGF-β signaling to treat eye diseases. This review highlights the key roles of TGF-β family members in ocular physiology and in eye diseases, and reviews approaches targeting the TGF-β signaling as potential treatment options.
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Affiliation(s)
- Soumaya Hachana
- Maisonneuve-Rosemont Hospital Research Center, Montreal, QC H1T 2M4, Canada
- Department of Ophthalmology, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Bruno Larrivée
- Maisonneuve-Rosemont Hospital Research Center, Montreal, QC H1T 2M4, Canada
- Department of Ophthalmology, Université de Montréal, Montreal, QC H3C 3J7, Canada
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Krzyżanowska N, Wojas-Krawczyk K, Milanowski J, Krawczyk P. Future Prospects of Immunotherapy in Non-Small-Cell Lung Cancer Patients: Is There Hope in Other Immune Checkpoints Targeting Molecules? Int J Mol Sci 2022; 23:3087. [PMID: 35328510 PMCID: PMC8950480 DOI: 10.3390/ijms23063087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
Currently, one of the leading treatments for non-small-cell lung cancer is immunotherapy involving immune checkpoint inhibitors. These monoclonal antibodies restore the anti-tumour immune response altered by negative immune checkpoint interactions. The most commonly used immunotherapeutics in monotherapy are anti-PD-1 and anti-PD-L1 antibodies. The effectiveness of both groups of antibodies has been proven in many clinical trials, which have translated into positive immunotherapeutic registrations for cancer patients worldwide. These antibodies are generally well tolerated, and certain patients achieve durable responses. However, given the resistance of some patients to this form of therapy, along with its other drawbacks, such as adverse events, alternatives are constantly being sought. Specifically, new drugs targeting already known molecules are being tested, and new potential targets are being explored. The aim of this paper is to provide an overview of the latest developments in this area.
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Affiliation(s)
- Natalia Krzyżanowska
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland; (K.W.-K.); (J.M.); (P.K.)
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Dzobo K, Dandara C. Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 24:314-339. [PMID: 32496970 DOI: 10.1089/omi.2020.0023] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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Huang J, Zhang L, Wan D, Zhou L, Zheng S, Lin S, Qiao Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct Target Ther 2021; 6:153. [PMID: 33888679 PMCID: PMC8062524 DOI: 10.1038/s41392-021-00544-0] [Citation(s) in RCA: 442] [Impact Index Per Article: 110.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/17/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.
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Affiliation(s)
- Jiacheng Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Lele Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Dalong Wan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China
| | - Shengzhang Lin
- School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, 310000, China.
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, 310003, China.
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003, China.
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AHMED AMIRABEN, ZIDI SABRINA, ALMAWI WASSIM, GHAZOUANI EZZEDDINE, MEZLINI AMEL, LOUESLATI BESMAYACOUBI, STAYOUSSEF MOUNA. Single nucleotide polymorphism of transforming growth factor-β1 and interleukin-6 as risk factors for ovarian cancer. Cent Eur J Immunol 2020; 45:267-275. [PMID: 33437178 PMCID: PMC7790009 DOI: 10.5114/ceji.2020.101242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 01/02/2018] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION We investigated the association between common variants in TGF-β1, IL-6 and the risk of ovarian cancer (OC) in Tunisian patients and control women. MATERIAL METHODS AND RESULTS Study subjects comprised 71 OC cases and 74 control women. Genotyping of TGF-β1 and IL-6 SNPs was done by real-time PCR. No differences were noted in the minor allele frequencies of the three TGF-β1 SNPs between OC patients and controls. However, marked differences in the distribution of TGF-β1 rs1800469 genotypes were seen between OC cases and controls (p < 0.001), with TGF-β1 rs1800469 heterozygous (C/T) genotype being negatively associated with OC (OR [95% CI] = 0.24 [0.15-0.58]). The allelic and genotypic distributions at IL-6 polymorphisms showed a positive association between minor allele (G) at IL-6 rs1880242 variant (p = 0.0275; R [95% CI] = 1.88 [1.03-3.46]) and the occurrence of OC. In fact, the presence of T allele [G/T + T/T] decrease the risk of OC (p = 0.021; OR [95% CI] = 0.38 [0.17-0.88]). In addition, the Haploview analysis demonstrated high linkage disequilibrium (LD) between IL-6 SNPs and eight-locus haplotype analysis identified that GGAGGGGA and GGAGGGTA haplotypes are positively associated with OC risk. A negative association was shown between IL-6 haplotype (TGGGCCTA) and OC occurrence. CONCLUSIONS Our results suggest that TGF-β1 rs1800469, IL-6 rs1880242 variants and IL-6 haplotype (TGGGCCTA) have protective roles of OC risk. IL-6 haplotypes (GGAGGGGA and GGAGGGTA) increase OC susceptibility among Tunisian women.
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Affiliation(s)
- AMIRA BEN AHMED
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, El Manar University, Tunis, Tunisia
| | - SABRINA ZIDI
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, El Manar University, Tunis, Tunisia
| | - WASSIM ALMAWI
- College of Health Sciences, Abu Dhabi University, United Arab Emirates
| | | | | | - BESMA YACOUBI LOUESLATI
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, El Manar University, Tunis, Tunisia
| | - MOUNA STAYOUSSEF
- Department of Biology, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, El Manar University, Tunis, Tunisia
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10
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Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect). Cancers (Basel) 2019; 11:cancers11070966. [PMID: 31324057 PMCID: PMC6678894 DOI: 10.3390/cancers11070966] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 07/04/2019] [Accepted: 07/05/2019] [Indexed: 12/30/2022] Open
Abstract
Pancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning as a major physical barrier against permeation and penetration. In the case of cell-based immunotherapeutics, there are several other bottlenecks preventing translation into clinical use due to their biological nature; for example, poor availability of cell therapeutic in a readily usable form due to difficulties in production, handling, shipping, and storage. To address these challenges, we have isolated allogeneic natural killer (NK) cells from healthy donors and expanded them in vitro to generate cryopreserved stocks. These cryopreserved NK cells were thawed to evaluate their therapeutic efficacy against desmoplastic pancreatic tumors, ultimately aiming to develop a readily accessible and mass-producible off-the-shelf cell-based immunotherapeutic. The cultured NK cells post-thawing retained highly pure populations of activated NK cells that expressed various activating receptors and a chemokine receptor. Furthermore, systemic administration of NK cells induced greater in vivo tumor growth suppression when compared with gemcitabine, which is the standard chemotherapeutic used for pancreatic cancer treatment. The potent antitumor effect of NK cells was mediated by efficient tumor-homing ability and infiltration into desmoplastic tumor tissues. Moreover, the infiltration of NK cells led to strong induction of apoptosis, elevated expression of the antitumor cytokine interferon (IFN)-γ, and inhibited expression of the immunosuppressive transforming growth factor (TGF)-β in tumor tissues. Expanded and cryopreserved NK cells are strong candidates for future cell-mediated systemic immunotherapy against pancreatic cancer.
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11
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Miura R, Yokoi A, Matsumoto T, Oguri Y, Hashimura M, Tochimoto M, Kajita S, Saegusa M. Nodal induces apoptosis and inhibits proliferation in ovarian endometriosis-clear cell carcinoma lesions. BMC Cancer 2019; 19:308. [PMID: 30943930 PMCID: PMC6448249 DOI: 10.1186/s12885-019-5539-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 03/28/2019] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Expression of Nodal, a member of the TGF-β superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy. However, little is known about its involvement in ovarian tumorigenesis. Herein, we focused on the functional roles of Nodal in ovarian endometriosis-carcinoma lesions. METHODS Regulation and function of Nodal and its associated molecules, including Smad2, GSK-3β, and several cell kinetics-related molecules, were assessed using clinical samples consisting of 108 ovarian carcinomas and 33 endometriotic lesions, as well as ES-2 (ovarian clear cell carcinoma; OCCCa) and Ishikawa (endometrial carcinoma) cell lines. RESULTS Nodal expression was significantly higher in endometriosis and OCCCa lesions as compared to that of non-OCCCas, with positive correlations to phosphorylated forms of both Smad2 (pSmad2) and GSK-3β. When compared to endometriotic lesions, the expression of Nodal and pSmad2 was significantly decreased in OCCCa. Treatment of Ishikawa cells with TGF-β1 resulted in transcriptional upregulation of Nodal, along with increased pSmad2 expression, while inhibition of GSK-3β also induced an increase in Nodal expression at the posttranslational level. Both ES-2 and Ishikawa cells stably overexpressing Nodal had increased susceptibility to apoptosis in response to treatment with cisplatin and doxorubicin, respectively, together with higher cleaved caspase-3 expression and decreased Bcl2/Bax ratio. Moreover, the stable Nodal-overexpressing cells showed reduced cell proliferation, along with increased expression of p27kip1 and p21waf1. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in Nodal-positive as compared to Nodal-negative OCCCa. CONCLUSIONS These findings suggest that Nodal is a multifunctional cytokine involved in the modulation of cell kinetics in ovarian endometriosis-OCCCa lesions.
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Affiliation(s)
- Rinako Miura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Toshihide Matsumoto
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Masataka Tochimoto
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Sabine Kajita
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
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12
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Kaur A, Riaz MS, Singh SK, Kishore U. Human Surfactant Protein D Suppresses Epithelial-to-Mesenchymal Transition in Pancreatic Cancer Cells by Downregulating TGF-β. Front Immunol 2018; 9:1844. [PMID: 30158928 PMCID: PMC6104167 DOI: 10.3389/fimmu.2018.01844] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
Human surfactant protein-D (SP-D), an innate immune pattern recognition soluble factor, is known to modulate a range of cytokines and chemokines, such as TNF-α and TGF-β at mucosal surfaces during infection, allergy, and inflammation. A recent study has shown that treatment with a recombinant fragment of human SP-D (rfhSP-D) for 48 h induces apoptosis in pancreatic cancer cells. Our hypothesis is that at earlier time points, SP-D can also influence key cytokines as a part of its putative role in the immune surveillance against pancreatic cancer, where the inflammatory tumor microenvironment contributes to the epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. Here, we provide the first evidence that rfhSP-D can suppress the invasive-mesenchymal properties of highly aggressive pancreatic cancer cells. Mechanistically, rfhSP-D inhibited TGF-β expression in a range of pancreatic cancer cell lines, Panc-1, MiaPaCa-2, and Capan-2, thereby reducing their invasive potential. Smad2/3 expression diminished in the cytoplasm of rfhSP-D-treated cells as compared to the untreated control, suggesting that an interrupted signal transduction negatively affected the transcription of key mesenchymal genes. Thus, expressions of Vimentin, Zeb1, and Snail were found to be downregulated upon rfhSP-D treatment in the pancreatic cancer cell lines. Furthermore, blocking TGF-β with neutralizing antibody showed similar downregulation of mesenchymal markers as seen with rfhSP-D treatment. This study highlights yet another novel innate immune surveillance role of SP-D where it interferes with EMT induction by attenuating TGF-β pathway in pancreatic cancer.
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Affiliation(s)
- Anuvinder Kaur
- Biosciences Division, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Muhammad Suleman Riaz
- Biosciences Division, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Shiv K Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, Gottingen, Germany
| | - Uday Kishore
- Biosciences Division, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
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13
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Liu Y, Wang JX, Huang D, Wang B, Li LL, Li XX, Ni P, Dong XL, Xia W, Yu CX, Xu WL, Chu WF, Zhao D. PMLIV overexpression promotes TGF-β-associated epithelial-mesenchymal transition and migration in MCF-7 cancer cells. J Cell Physiol 2018; 233:9575-9583. [PMID: 29943817 DOI: 10.1002/jcp.26862] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/22/2018] [Indexed: 11/10/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is a key event associated with metastasis and dissemination in breast tumor pathogenesis. Promyelocytic leukemia (PML) gene produces several isoforms due to alternative splicing; however, the biological function of each specific isoform has yet to be identified. In this study, we report a previously unknown role for PMLIV, the most intensely studied nuclear isoform, in transforming growth factor-β (TGF-β) signaling-associated EMT and migration in breast cancer. This study demonstrates that PMLIV overexpression promotes a more aggressive mesenchymal phenotype and increases the migration of MCF-7 cancer cells. This event is associated with activation of the TGF-β canonical signaling pathway through the induction of Smad2/3 phosphorylation and the translocation of phospho-Smad2/3 to the nucleus. In this study, we report a previously unknown role for PMLIV in TGF-β signaling-induced regulation of breast cancer-associated EMT and migration. Targeting this pathway may be therapeutically beneficial.
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Affiliation(s)
- Yu Liu
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jia-Xin Wang
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Di Huang
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Bing Wang
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Liang-Liang Li
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Xiu-Xian Li
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Ping Ni
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Xing-Li Dong
- Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Wei Xia
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Chun-Xiao Yu
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Wan-Lu Xu
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Wen-Feng Chu
- Department of Pharmacology, University at Harbin College of Pharmacy, Harbin Medical University, Harbin, China
| | - Dan Zhao
- Department of Clinical Pharmacy, The 2nd Affiliated Hospital, Harbin Medical University at Harbin, Harbin, China
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14
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Zhou C, Li J, Lin L, Shu R, Dong B, Cao D, Li Q, Wang Z. A targeted transforming growth factor-beta (TGF-β) blocker, TTB, inhibits tumor growth and metastasis. Oncotarget 2018; 9:23102-23113. [PMID: 29796175 PMCID: PMC5955403 DOI: 10.18632/oncotarget.24562] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/13/2017] [Indexed: 12/14/2022] Open
Abstract
Transforming growth factor beta (TGF-β) promotes cancer growth in late stage cancers. To inhibit the TGF-β pathway, we investigated a tumor-targeting TGF-β receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-β receptor II, the endoglin domain of TGF-β receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted TTB exhibited potent TGF-β neutralization activities, and inhibited cancer cell migration and invasion as well as colony formation. In xenograft models, the TTB had potent tumor inhibition activities. The TTB also attenuated the TGF-β1-induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-β blocker with a potential for blocking excessive TGF-β induced pathogenesis in vivo.
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Affiliation(s)
- Changhua Zhou
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.,Center for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Jing Li
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.,Center for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Limin Lin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.,Center for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Rui Shu
- Ying Rui Inc., Guangzhou, Guangdong, 510009, China
| | - Bin Dong
- School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510009, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China
| | - Qing Li
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.,Center for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Zhong Wang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.,Center for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, 510006, China
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15
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El-Deeb NM, Yassin AM, Al-Madboly LA, El-Hawiet A. A novel purified Lactobacillus acidophilus 20079 exopolysaccharide, LA-EPS-20079, molecularly regulates both apoptotic and NF-κB inflammatory pathways in human colon cancer. Microb Cell Fact 2018; 17:29. [PMID: 29466981 PMCID: PMC5820793 DOI: 10.1186/s12934-018-0877-z] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 02/12/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The direct link between inflammatory bowel diseases and colorectal cancer is well documented. Previous studies have reported that some lactic acid bacterial strains could inhibit colon cancer progression however; the exact molecules involved have not yet been identified. So, in the current study, we illustrated the tumor suppressive effects of the newly identified Lactobacillus acidophilus DSMZ 20079 cell-free pentasaccharide against colon cancer cells. The chemical structure of the purified pentasaccharide was investigated by MALDI-TOF mass spectrum, 1D and 2D Nuclear Magnetic Resonance (NMR). The anticancer potentiality of the purified pentasaccharide against both Human colon cancer (CaCo-2) and Human breast cancer (MCF7) cell lines with its safety usage pattern were evaluated using cytotoxicity, annexin V quantification and BrdU incorporation assays. Also, the immunomodulatory effects of the identified compound were quantified on both LPS-induced PBMC cell model and cancer cells with monitoring the immunophenotyping of T and dendritic cell surface marker. At molecular level, the alteration in gene expression of both inflammatory and apoptotic pathways were quantified upon pentasaccharide-cellular treatment by RTqPCR. RESULTS The obtained data of the spectroscopic analysis, confirmed the structure of the newly extracted pentasaccharide; (LA-EPS-20079) to be: α-D-Glc (1→2)][α-L-Fuc(1→4)] α-D-GlcA(1→2) α-D-GlcA(1→2) α-D-GlcA. This pentasaccharide, recorded safe dose on normal mammalian cells ranged from 2 to 5 mg/ml with cancer cells selectivity index, ranged of 1.96-51.3. Upon CaCo-2 cell treatment with the non-toxic dose of LA-EPS-20079, the inhibition percentage in CaCo-2 cellular viability, reached 80.65 with an increase in the ratio of the apoptotic cells in sub-G0/G1 cell cycle phase. Also, this pentasaccharide showed potentialities to up-regulate the expression of IKbα, P53 and TGF genes. CONCLUSION The anticancer potentialities of LA-EPS-20079 oligosaccharides against human colon cancer represented through its regulatory effects on both apoptotic and NF-κB inflammatory pathways.
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Affiliation(s)
- Nehal M El-Deeb
- Biopharmacetical Product Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technology Applications, New Borg El-Arab City, 21934, Alexandria, Egypt.
| | - Abdelrahman M Yassin
- Biopharmacetical Product Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technology Applications, New Borg El-Arab City, 21934, Alexandria, Egypt
| | - Lamiaa A Al-Madboly
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.
| | - Amr El-Hawiet
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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16
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Akiya M, Yamazaki M, Matsumoto T, Kawashima Y, Oguri Y, Kajita S, Kijima D, Chiba R, Yokoi A, Takahashi H, Kodera Y, Saegusa M. Identification of LEFTY as a molecular marker for ovarian clear cell carcinoma. Oncotarget 2017; 8:63646-63664. [PMID: 28969018 PMCID: PMC5609950 DOI: 10.18632/oncotarget.18882] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 06/11/2017] [Indexed: 01/16/2023] Open
Abstract
To identify proteins involved in ovarian clear cell carcinoma (OCCCa), shotgun proteomics analysis was applied using formalin-fixed and paraffin-embedded samples of ovarian carcinoma. Analysis of 1521 proteins revealed that 52 were differentially expressed between four OCCCa and 12 non-OCCCa samples. Of the highly expressed proteins in OCCCa, we focused on left-right determination factor (LEFTY), a novel member of the transforming growth factor-β superfamily. In 143 cases of ovarian epithelial carcinoma including 99 OCCCas and 44 non-OCCCas, LEFTY expression at both mRNA and protein levels was significantly higher in OCCCas compared with non-OCCCas, with the mRNA expression of LEFTY1 being predominant compared to that of LEFTY2. OCCCa cells stably overexpressing LEFTY1 showed reduced cell proliferation, along with decreased pSmad2 expression, and also either displayed an activated p53/p21waf1 pathway or increased p27kip1 expression, directly or indirectly. Moreover, the treatment of stable cell lines with cisplatin led to increased apoptotic cells, together with the inhibition of protein expression of a pSmad2-mediated X-linked inhibitor of apoptosis and a decreased bcl2/bax ratio. Blocking LEFTY1 expression with a specific short hairpin RNA inhibited cisplatin-induced apoptosis, probably through the increased expression of both XIAP and bcl2, but not bax. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in OCCCas with a high LEFTY score relative to those with a low score. These findings suggest that LEFTY may be an excellent OCCCa-specific molecular marker, which has anti-tumor effects in altering cell proliferation and cellular susceptibility to apoptosis.
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Affiliation(s)
- Masashi Akiya
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Masaaki Yamazaki
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Toshihide Matsumoto
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Yusuke Kawashima
- Center for Disease Proteomics, School of Science, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Sabine Kajita
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Daiki Kijima
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Risako Chiba
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
| | - Yoshio Kodera
- Center for Disease Proteomics, School of Science, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan
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17
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Moqattash S, Lutton JD. Leukemia Cells and the Cytokine Network: Therapeutic Prospects. Exp Biol Med (Maywood) 2016; 229:121-37. [PMID: 14734791 DOI: 10.1177/153537020422900201] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The network and balance of cytokines is of major importance in maintaining proper homeostasis of hematopoiesis. Abnormalities in this network may result in a variety of blood disorders; however, the role of this network is not clear in leukemia. The use of antineoplastic agents has improved the survival rate of some types of leukemia, and adjunctive therapy with cytokines may be helpful. Chemotherapeutic approaches are no longer the best choice because cytotoxicity may affect normal and leukemic cells, and leukemic cells may develop resistance to the chemotherapeutic agent. Induction of differentiation to a mature phenotype and the control of apoptotic-gene expression have provided other possible alternative therapies. Combined effects of cytokines and vitamin derivatives such as retinoic acid (RA) and 1, 25 dihydroxyvitamin D3 (VD3) were found more beneficial than any of these agents individually. These agents exhibit cooperative effects, potentiate each other's effects, or both. Therefore, understanding the hematopoietic actions of these agents, their interactions with their receptors, and their differentiation signaling pathways may result In the design of new therapies. However, the role of cytokines in apoptosis is controversial because in some cases they were found to increase tumor cell resistance to apoptosis-inducing agents. Recent studies in the molecular biology of gene regulation, transcription factors, and repressors have led to new possible approaches such as differentiation therapy for the treatment of leukemia. In addition, the development of drugs that act on the molecular level such as imatinib is just the beginning of a new era in molecular targeted therapy in which the drug acts specifically on the leukemic cell. There are many possible combinations of cytokines, retinoids, and VD3, and perhaps the best therapeutic combination is yet to be described. This minireview is an update on the role of cytokines and the therapeutic potential of combinations with agents such as RA, VD3, and other chemotherapeutic agents.
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Affiliation(s)
- Satei Moqattash
- Department of Human and Clinical Anatomy, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman.
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18
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Transforming growth factor β type II receptor as a marker in diffuse large B cell lymphoma. Tumour Biol 2015; 36:9903-8. [PMID: 26168957 DOI: 10.1007/s13277-015-3700-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 06/22/2015] [Indexed: 12/22/2022] Open
Abstract
The objective of this study was to investigate the expression and significance of the transforming growth factor β type II receptor (TGFβRII) in diffuse large B cell lymphoma. All patients were enrolled at the First Affiliated Hospital of Liaoning Medical University between 2001 and 2007. The median follow-up period was 53.3 months. Of the 338 patients studied, 131 (38.76 %) had TGFβRII positive expression on immunohistochemistry. The 5 year survival rate was significantly higher in patients with TGFβRII expression than in those without TGFβRII expression (40.3 vs. 31.6 %, P = 0.041). Multivariate analysis identified TGFβRII expression as an independent predictive parameter for survival, in addition to lactate dehydrogenase, clinical stage, and histologic subtype. TGFβRII expression may be considered a new prognostic factor of diffuse large B cell lymphoma.
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19
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Bahhnassy A, Mohanad M, Shaarawy S, Ismail MF, El-Bastawisy A, Ashmawy AM, Zekri AR. Transforming growth factor-β, insulin-like growth factor I/insulin-like growth factor I receptor and vascular endothelial growth factor-A: prognostic and predictive markers in triple-negative and non-triple-negative breast cancer. Mol Med Rep 2015; 12:851-64. [PMID: 25824321 PMCID: PMC4438878 DOI: 10.3892/mmr.2015.3560] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 01/15/2015] [Indexed: 12/20/2022] Open
Abstract
In the current study, the prognostic and predictive values of serum transforming growth factor-β1 (TGF-β1), insulin-like growth factor I (IGF-I)/IGF-I receptor (IGF-IR) and vascular endothelial growth factor-A (VEGF-A) were evaluated in triple-negative and non-triple-negative breast cancer (TNBC and non-TNBC). The aim was to identify a group of serological biomarkers and to identify possible candidates for targeted therapy in patients with TNBC and non-TNBC. Protein levels of TGF-β1, IGF-I/IGF-IR and VEGF-A in the serum were measured in 43 TNBC, 53 non-TNBC and 20 normal control participants using quantitative ELISA assays. Results were correlated against standard prognostic factors, response to treatment and survival. TNBC was identified to be associated with poor prognosis and serum levels of VEGF-A and IGF/IGF-IR were significantly higher in the TNBC group compared with the non-TNBC group. IGF-IR and VEGF-A overexpression was observed to be correlated with TGF-β1 expression and all of the markers investigated were associated with metastasis and disease progression. In the multivariate analysis, VEGF-A, IGF-I and IGF-IR were observed to be independent predictors for overall survival, whereas TGF-β1 and lymph node status were identified as independent predictors for disease-free survival. The overall response rate was significantly lower in patients with TNBC and those with high levels of TGF-β1, IGF-I/IGF-IR and VEGF-A. In view of the present results, it was concluded that TGF-β1, IGF-I/IGF-IR and VEGF-A overexpression is associated with the presence of aggressive tumors, which exhibit an increased probability of metastasis, a poor response to treatment and reduced survival rate. This indicates that VEGF-A, IGF-IR and IGF-I have the potential to be used as surrogate biomarkers and are promising candidates for targeted therapy, particularly in patients with TNBC.
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Affiliation(s)
- Abeer Bahhnassy
- Molecular Pathology Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Marwa Mohanad
- Department of Biochemistry, Faculty of Pharmacy, Misr University for Science and Technology, Cairo 11796, Egypt
| | - Sabry Shaarawy
- Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Manal F Ismail
- Faculty of Pharmacy, Cairo University, Cairo 11796, Egypt
| | - Ahmed El-Bastawisy
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Abeer M Ashmawy
- Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Abdel-Rahman Zekri
- Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
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20
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Wang H, Pan JQ, Luo L, Ning XJ, Ye ZP, Yu Z, Li WS. NF-κB induces miR-148a to sustain TGF-β/Smad signaling activation in glioblastoma. Mol Cancer 2015; 14:2. [PMID: 25971746 PMCID: PMC4429406 DOI: 10.1186/1476-4598-14-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 12/02/2014] [Indexed: 01/08/2023] Open
Abstract
Background Inflammatory cytokines and transforming growth factor-β (TGF-β) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-β signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-β signaling. Methods We determined NF-κB and TGF-β/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase–associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice. Results QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-β/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-β/Smad signaling in a cohort of human glioblastoma specimens. Conclusions These findings uncover a plausible mechanism for NF-κB–sustained TGF-β/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-14-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hui Wang
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tian He Road, Tian He District, Guangzhou, Guangdong, 510630, China.
| | - Jian-Qing Pan
- Department of Neurosurgery, The Affiliated Shenzhen Nanshan Hospital, Guangdong Medical College, Shenzhen, 518052, China. .,Guangzhou Biocare Cancer Institute, Guangzhou, 510663, China.
| | - Lun Luo
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tian He Road, Tian He District, Guangzhou, Guangdong, 510630, China.
| | - Xin-Jie Ning
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tian He Road, Tian He District, Guangzhou, Guangdong, 510630, China.
| | - Zhuo-Peng Ye
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tian He Road, Tian He District, Guangzhou, Guangdong, 510630, China.
| | - Zhe Yu
- Guangzhou Biocare Cancer Institute, Guangzhou, 510663, China.
| | - Wen-Sheng Li
- Department of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tian He Road, Tian He District, Guangzhou, Guangdong, 510630, China.
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Tsai MM, Wang CS, Tsai CY, Chi HC, Tseng YH, Lin KH. Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. World J Gastroenterol 2014; 20:13791-13803. [PMID: 25320517 PMCID: PMC4194563 DOI: 10.3748/wjg.v20.i38.13791] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/18/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers.
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Lee C, Lee SH, Kim DS, Jeon YS, Lee NK, Lee SE. Growth inhibition after exposure to transforming growth factor-β1 in human bladder cancer cell lines. Korean J Urol 2014; 55:487-92. [PMID: 25045449 PMCID: PMC4101120 DOI: 10.4111/kju.2014.55.7.487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 05/12/2014] [Indexed: 11/26/2022] Open
Abstract
Purpose Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells. Materials and Methods The role of TGF-β1 in bladder cancer cells was examined by observing cell viability by using the tetrazolium dye (MTT) assay after treating the bladder cancer cell lines 253J, 5637, T24, J82, HT1197, and HT1376 with TGF-β1. Among these cell lines, the 253J and T24 cell lines were coincubated with TGF-β1 and the pan anti-TGF-β antibody. Fluorescence-activated cell sorter (FACS) analysis was performed to determine the mechanism involved after TGF-β1 treatment in 253J cells. Results All six cell lines showed inhibited cellular growth after TGF-β1 treatment. Although the T24 and J82 cell lines also showed inhibited cellular growth, the growth inhibition was less than that observed in the other 4 cell lines. The addition of pan anti-TGF-β antibodies to the culture media restored the growth properties that had been inhibited by TGF-β1. FACS analysis was performed in the 253J cells and the 253J cells with TGF-β1. There were no significant differences in the cell cycle between the two treatments. However, there were more apoptotic cells in the TGF-β1-treated 253J cells. Conclusions TGF-β1 did not stimulate cellular proliferation but was a growth inhibitory factor in bladder cancer cells. However, the pattern of its effects depended on the cell line. TGF-β1 achieved growth inhibition by enhancing the level of apoptosis.
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Affiliation(s)
- Changho Lee
- Department of Urology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea. ; Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Sang-Han Lee
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Doo Sang Kim
- Department of Urology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yun Soo Jeon
- Department of Urology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Nam Kyu Lee
- Department of Urology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Eun Lee
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea. ; Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
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Pattern of TGFbeta receptor 1 expression differs between kras-mutated keratoacanthomas and squamous cell carcinomas of the skin. Pathol Res Pract 2014; 210:596-602. [PMID: 24954139 DOI: 10.1016/j.prp.2014.05.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 04/26/2014] [Accepted: 05/15/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Increasing evidence indicates that TGFbeta- and EGFR-signaling is involved in the pathogenesis of keratoacanthoma (KA) and squamous cell carcinoma (SCC) of the skin. We analyzed the expression pattern of TGFbeta-signaling components and screened for mutations in tgfbetaR1, egfr, kras and braf in KAs and SCCs. METHODS Immunohistochemical analysis of TGFbeta1, TGFbetaR1, TGFbetaR2 and phospho-SMAD2/3 was performed on skin tumors (29 KAs, 30 well and 31 moderately differentiated SCCs). Mutation screening in hotspot regions of tgfbetaR1, egfr, kras and braf was performed through pyrosequencing of tumor DNA. FINDINGS Expression of TGFbeta1, TGFbetaR1 and p-SMAD2/3 was increased in tumors as compared to surrounding skin. In KAs characteristic strong discontinuous membranous TGFbetaR1 expression pattern frequently associated with kras mutation was noted. SCCs showed continuous TGFbetaR1 expression, stronger p-SMAD2/3 expression and less frequent kras mutations. In tumors at sun-exposed sites stronger TGFbetaR1 expression was noted. One SCC showed tgfbetaR1 mutation, but no other mutations were found. CONCLUSION Although tgfbetaR1 germline mutations cause inherited KAs and our finding of strong discontinuous membranous expression in KAs suggests accumulation of functionally altered protein, we found no tgfbetaR1 mutations or influence on TGFbeta-signaling, but frequent kras mutations in this subgroup of KAs. Characteristic TGFbetaR1 expression pattern in KA can facilitate histopathologic distinction from SCC.
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Pooja S, Francis A, Rajender S, Tamang R, Rajkumar R, Saini KS, Megu K, Goel MM, Surekha D, Rao DR, Rao L, Ramachandra L, Kumar S, Kumar S, Vishnupriya S, Satyamoorthy K, Negi MPS, Thangaraj K, Konwar R. Strong impact of TGF-β1 gene polymorphisms on breast cancer risk in Indian women: a case-control and population-based study. PLoS One 2013; 8:e75979. [PMID: 24146803 PMCID: PMC3798290 DOI: 10.1371/journal.pone.0075979] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 08/19/2013] [Indexed: 11/28/2022] Open
Abstract
Introduction TGF-β1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-β1 signaling in breast cancer progression is well documented. Some TGF-β1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear. Methods We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-β1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-β1 were measured by ELISA. Results c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (p = 0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-β1 was significantly elevated in patients in comparison to controls (p<0.001). Conclusion c.29C>T and c.74G>C polymorphisms in the TGF-β1 gene significantly affect breast cancer risk, which correlates with elevated TGF-β1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.
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Affiliation(s)
- Singh Pooja
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Department of Pathology, King George's Medical University, Lucknow, India
| | | | - Singh Rajender
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rakesh Tamang
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
- Department of Genetics, Osmania University, Hyderabad, India
| | - Raja Rajkumar
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Karan Singh Saini
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Kaling Megu
- Department of Surgery, King George's Medical University, Lucknow, India
| | - Madhu Mati Goel
- Department of Pathology, King George's Medical University, Lucknow, India
| | | | | | - Lakshmi Rao
- Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India
| | | | - Sandeep Kumar
- Department of Surgery, King George's Medical University, Lucknow, India
- All India Institute of Medical Sciences, Bhopal, India
| | - Surender Kumar
- Department of Surgery, King George's Medical University, Lucknow, India
| | | | | | | | - Kumarasamy Thangaraj
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
- * E-mail: (RK); (KT)
| | - Rituraj Konwar
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- * E-mail: (RK); (KT)
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Pfeiffer H, Sowik T, Schatzschneider U. Bioorthogonal oxime ligation of a Mo(CO)4(N–N) CO-releasing molecule (CORM) to a TGF β-binding peptide. J Organomet Chem 2013. [DOI: 10.1016/j.jorganchem.2012.09.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Sengupta S, Kundu S, Bhattacharyya A. Attenuation of Smad2 activity shows resistance to TGF-β signalling in mammary adenocarcinoma (MCF-7) cells. Cell Biol Int 2013; 37:449-57. [DOI: 10.1002/cbin.10061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 01/16/2013] [Indexed: 11/08/2022]
Affiliation(s)
| | | | - Arindam Bhattacharyya
- Immunology Lab, Department of Zoology; University of Calcutta; Kolkata, West Bengal; 700019; India
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Wilson S, Levy D. A mathematical model of the enhancement of tumor vaccine efficacy by immunotherapy. Bull Math Biol 2012; 74:1485-500. [PMID: 22438084 DOI: 10.1007/s11538-012-9722-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Accepted: 03/01/2012] [Indexed: 11/28/2022]
Abstract
TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.
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Affiliation(s)
- Shelby Wilson
- Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM), University of Maryland, College Park, MD 20742, USA.
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28
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Capietto AH, Martinet L, Fournié JJ. How tumors might withstand γδ T-cell attack. Cell Mol Life Sci 2011; 68:2433-42. [PMID: 21547501 PMCID: PMC11115001 DOI: 10.1007/s00018-011-0705-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 04/19/2011] [Accepted: 04/20/2011] [Indexed: 01/13/2023]
Abstract
Several clinical trials are currently assessing the therapeutic activity of human TCRVγ9Vδ2(+) lymphocytes in cancer. Growing tumors usually follow a triphasic "Elimination, Equilibrium, Escape" evolution in patients. Thus, at diagnostic, most tumors have already developed some means to escape to immune protection. We review here the conventional immunoescape mechanisms which might also protect against cytolytic TCRVγ9Vδ2(+) lymphocytes activated by phosphoantigens. Neutralization of these deleterious processes might prove highly valuable to improve the efficacy of ongoing γδ cell-based cancer immunotherapies.
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Affiliation(s)
- Aude-Hélène Capietto
- INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France
- CNRS ERL5294, BP3028, CHU Purpan, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
- Present Address: Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Ludovic Martinet
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
- Institut De Pharmacologie et de Biologie Structurale, Unité Mixte de Recherches (UMR) 5089, 31077 Toulouse, France
| | - Jean-Jacques Fournié
- INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France
- CNRS ERL5294, BP3028, CHU Purpan, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31300 Toulouse, France
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Penafuerte C, Bautista-Lopez N, Bouchentouf M, Birman E, Forner K, Galipeau J. Novel TGF-β Antagonist Inhibits Tumor Growth and Angiogenesis by Inducing IL-2 Receptor-Driven STAT1 Activation. THE JOURNAL OF IMMUNOLOGY 2011; 186:6933-44. [DOI: 10.4049/jimmunol.1003816] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 2011; 102:1193-200. [PMID: 21366804 DOI: 10.1111/j.1349-7006.2011.01917.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive human cancers with a 5-year survival rate of <5%. Overexpression of transforming growth factor-beta 2 (TGF-β2) in pancreatic malignancies is suggested to be a pivotal factor for malignant progression by inducing immunosuppression, metastasis, angiogenesis and proliferation. Trabedersen (AP 12009) is a phosphorothioate antisense oligodeoxynucleotide specific for human TGF-β2 mRNA and was successfully tested in a randomized, active-controlled phase IIb clinical study in patients with high-grade glioma. Here, we report on the antitumor activity of trabedersen in human pancreatic cancer cells and in an orthotopic xenograft mouse model of human metastatic pancreatic cancer. Trabedersen reduced TGF-β2 secretion in human pancreatic cell lines with an IC50 in the low μM range without transfection reagent, clearly inhibited cell proliferation, and completely blocked migration of pancreatic cancer cells. Additionally, trabedersen reversed TGF-β2-mediated immunosuppression of pancreatic cancer cells targeted by lymphokine activated killer (LAK) cells, resulting in considerably increased LAK cell-mediated cytotoxicity. Moreover, in an orthotopic mouse model of metastatic pancreatic cancer, intraperitoneal (i.p.) treatment with trabedersen significantly reduced tumor growth, lymph node metastasis and angiogenesis. These promising results warrant further clinical development of trabedersen.
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Ali NA, McKay MJ, Molloy MP. Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. MOLECULAR BIOSYSTEMS 2010; 6:2332-8. [PMID: 20862427 DOI: 10.1039/c0mb00016g] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
TGF-β signalling can play a paradoxical cell type specific role in cancer progression. Smad4 is a key mediator of the TGF-β pathway, and is mutated and/or deleted in many cancers. To investigate Smad4 regulated TGF-β signalling in colon cancer we conducted an iTRAQ mass spectrometry quantitative screen using wild type SW480 (Smad4 negative) colon carcinoma cells and stably restored Smad4 positive SW480 cells. In cells possessing a restored canonical TGF-β signalling pathway, 48 h TGF-β stimulation induced the expression of 15 proteins and repressed 1 protein, while in Smad4 wild type cells, TGF-β induced 7 proteins and repressed 2 proteins. The expression of several S100 protein family members (A2, A4, A10, and A11), transgelin-2 and AKAP12, amongst others, were shown to be regulated by TGF-β in a Smad4 dependent manner. We observed that S100 A4 could be repressed by TGF-β, independently of Smad4 expression, while other Smad4 independent TGF-β responses were restricted to induction of ribosomes and cytoskeletal proteins. Our proteomic screen has identified new Smad4 dependent and independent TGF-β responses in colon carcinoma cells.
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Affiliation(s)
- Naveid Ahmad Ali
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, Australia
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Tandon A, Tovey JCK, Sharma A, Gupta R, Mohan RR. Role of transforming growth factor Beta in corneal function, biology and pathology. Curr Mol Med 2010; 10:565-78. [PMID: 20642439 PMCID: PMC3048459 DOI: 10.2174/1566524011009060565] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Accepted: 05/04/2010] [Indexed: 12/20/2022]
Abstract
Transforming growth factor-beta (TGFbeta) is a pleiotropic multifunctional cytokine that regulates several essential cellular processes in many parts of the body including the cornea. Three isoforms of TGFbeta are known in mammals and the human cornea expresses all of them. TGFbeta1 has been shown to play a central role in scar formation in adult corneas whereas TGFbeta2 and TGFbeta3 have been implicated to play a critical role in corneal development and scarless wound healing during embryogenesis. The biological effects of TGFbeta in the cornea have been shown to follow Smad dependent as well as Smad-independent signaling pathways depending upon cellular responses and microenvironment. Corneal TGFbeta expression is necessary for maintaining corneal integrity and corneal wound healing. On the other hand, TGFbeta is perhaps the most important cytokine in the pathogenesis of fibrotic disease in the cornea. Although the transformation of keratocytes to myofibroblasts induced by TGFbeta is largely believed to cause corneal fibrosis or scarring, the precise molecular mechanism(s) involved in this process is still unknown. Currently no drugs are available to treat corneal scarring effectively without causing significant side effects. Many approaches to treat TGFbeta-mediated corneal scarring are under investigation. These include blocking of TGFbeta, TGFbeta receptor, TGFbeta function and/or TGFbeta maturation. Other strategies such as modulating keratocyte proliferation, apoptosis, transcription and DNA condensation are also being investigated. The potential of gene therapy to neutralize the pathologic effects of TGFbeta has also been demonstrated recently.
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Affiliation(s)
- Ashish Tandon
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Jonathan C. K. Tovey
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Ajay Sharma
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Rangan Gupta
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Rajiv R. Mohan
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65212, USA
- Department of Ophthalmology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65212, USA
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Nagaraj NS, Datta PK. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs 2010; 19:77-91. [PMID: 20001556 DOI: 10.1517/13543780903382609] [Citation(s) in RCA: 213] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The transforming growth factor-ss (TGF-beta) signaling pathway plays a pivotal role in diverse cellular processes. TGF-beta switches its role from a tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that the Smad-dependent pathway is involved in TGF-beta tumor-suppressive functions, whereas activation of Smad-independent pathways, coupled with the loss of tumor-suppressor functions of TGF-beta, is important for its pro-oncogenic functions. TGF-beta signaling has been considered a useful therapeutic target. The discovery of oncogenic actions of TGF-beta has generated a great deal of enthusiasm for developing TGF-beta signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-beta-induced tumor suppressor functions but also responsive to the tumor-promoting effects of TGF-beta. TGF-beta pathway inhibitors, including small and large molecules, have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here, we focus on the mechanisms of signaling and specific targets of the TGF-beta pathway that are critical effectors of tumor progression and invasion. This report also examines the therapeutic intervention of TGF-ss signaling in human cancers.
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Affiliation(s)
- Nagathihalli S Nagaraj
- Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Department of Surgery, Nashville, TN 37232, USA
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Healy J, Dionne J, Bélanger H, Larivière M, Beaulieu P, Labuda D, Sinnett D. Functional impact of sequence variation in the promoter region of TGFB1. Int J Cancer 2009; 125:1483-9. [PMID: 19536820 DOI: 10.1002/ijc.24526] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Pathological deregulation of the transforming growth factor, beta 1 (TGFB1) pathway has been implicated in the development of several major diseases, including cancers. Regulatory variation in the TGFB1 gene may lead to altered TGFB1 expression and activity, and thus, modulate an individual's susceptibility to disease. Here, we performed a study of the functional relevance of cis-acting regulatory variation in the proximal promoter region of the TGFB1 gene. In a previous study, 9 promoter polymorphisms were identified in the 2kb region upstream of the transcription start site and 9 distinct promoter haplotypes were inferred from a panel of individuals from 5 distinct continental population groups. Following experimental validation, we found that the 2 major haplotypes significantly influenced TGFB1 transcriptional activity in an allele-specific manner and that 3 of the SNPs (-1886G>A, -509C>T and -1550DEL/AGG) altered DNA-protein complex formation. Though the biological relevance of these findings remains to be verified, our study suggests that polymorphisms in the TGFB1 promoter could indeed influence gene expression and potentially contribute to the pathogenesis of TGFB1 related diseases.
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Affiliation(s)
- Jasmine Healy
- Division of Hematology-Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
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Flanders KC, Wakefield LM. Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression. J Mammary Gland Biol Neoplasia 2009; 14:131-44. [PMID: 19396528 PMCID: PMC2797127 DOI: 10.1007/s10911-009-9122-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 04/15/2009] [Indexed: 01/07/2023] Open
Abstract
During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.
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Affiliation(s)
- Kathleen C Flanders
- Laboratory of Cancer Biology & Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
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36
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Tan AR, Alexe G, Reiss M. Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat 2009; 115:453-95. [PMID: 18841463 PMCID: PMC2693232 DOI: 10.1007/s10549-008-0184-1] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 09/02/2008] [Indexed: 12/24/2022]
Abstract
In most human breast cancers, lowering of TGFbeta receptor- or Smad gene expression combined with increased levels of TGFbetas in the tumor microenvironment is sufficient to abrogate TGFbetas tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFbeta signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFbeta tumor suppression. In mouse models of "triple-negative" or basal-like breast cancer, treatment with TGFbeta neutralizing antibodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFbeta antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFbeta target genes upregulation in human breast cancers suggest that TGFbeta may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFbeta appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFbeta because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFbeta, while antiestrogens act by upregulating TGFbeta. This model predicts that inhibiting TGFbeta signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFbeta antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These predictions need to be addressed prospectively in clinical trials and should inform the selection of patient populations most likely to benefit from this novel anti-metastatic therapeutic approach.
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Affiliation(s)
- Antoinette R Tan
- Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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37
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Martinet L, Poupot R, Fournié JJ. Pitfalls on the roadmap to γδ T cell-based cancer immunotherapies. Immunol Lett 2009; 124:1-8. [DOI: 10.1016/j.imlet.2009.03.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 03/02/2009] [Accepted: 03/04/2009] [Indexed: 12/29/2022]
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38
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Yoneda M, Suzuki T, Nakamura T, Ajima R, Yoshida Y, Kakuta S, Katsuko S, Iwakura Y, Shibutani M, Mitsumori K, Yokota J, Yamamoto T. Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma. Cancer Sci 2009; 100:225-32. [PMID: 19068083 PMCID: PMC11159387 DOI: 10.1111/j.1349-7006.2008.01030.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The abundant in neuroepithelium area (ana) gene was originally identified as a member of the tob/btg family of antiproliferative genes. Like the other family members, Ana inhibits growth of NIH3T3 cells when overexpressed. However, whether or not Ana is involved in tumor progression has been elusive. Here, we show that expression of ana is relatively high in the lung, the expression being restricted in type II alveolar epithelial cells. We further show that ana expression is reduced in 97% of the human lung cancer cell lines examined (61/63) and 86% of clinical samples from lung adenocarcinoma patients (36/42). Long-term observation of ana-deficient (ana−/–) mice reveals that 8% of them develop lung tumors (5/66) by 21 months after birth, while 0% of wild-type mice (0/35) develop the same type of tumors. We also show that exogenously expressed ana gene product suppresses the levels of matrix metalloproteinase-2 (MMP-2) and plasminogen activator inhibitor-1 (PAI-1) expression in lung cancer cells. Taken together, we propose that ana functions as a tumor suppressor and that its product inhibits tumor progression as well by suppressing angiogenesis, invasion, and metastasis.
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Affiliation(s)
- Mitsuhiro Yoneda
- Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan
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Dancea HC, Shareef MM, Ahmed MM. Role of Radiation-induced TGF-beta Signaling in Cancer Therapy. MOLECULAR AND CELLULAR PHARMACOLOGY 2009; 1:44-56. [PMID: 20336170 PMCID: PMC2844640 DOI: 10.4255/mcpharmacol.09.06] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
TGF-β signaling regulates several different biological processes involving cell-growth, differentiation, apoptosis, motility, angiogenesis, epithelial mesenchymal transition and extracellular matrix production that affects embryonic development and pathogenesis of various diseases, including cancer, its effects depending on the cellular context and physiological environment. Growth suppression mediated by TGF-β signaling often associated with inhibition of c-myc, cdks and induction of p15, p27, Bax and p21. Despite its growth inhibitory effect, in certain conditions TGF-β may act as a promoter of cell proliferation and invasion. Loss of responsiveness to growth suppression by TGF-β due to mutation or loss of TGF-beta type II receptor (TβRII) and Smad4 in several different cancer cells are reported. In addition, TGF-β binding to its receptor activates many non-canonical signaling pathways. Radiation induced TGF-β is primarily involved in normal tissue injury and fibrosis. Seminal studies from our group have used radio-adjuvant therapies, involving classical components of the pathway such as TβRII and SMAD4 to overcome the growth promoting effects of TGF-β. The main impediment in the radiation-induced TGF-β signaling is the induction of SMAD7 that blocks TGF-β signaling in a negative feedback manner. It is well demonstrated from our studies that the use of neutralizing antibodies against TGF- β can render a robust radio-resistant effect. Thus, understanding the functional interactions of TGF-β signaling components of the pathway with other molecules may help tailor appropriate adjuvant radio-therapeutic strategies for treatment of solid tumors.
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Affiliation(s)
- Horatiu C Dancea
- Department of General Surgery, Geisinger Clinic, Danville, Pennsylvania
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40
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Godman CA, Joshi R, Tierney BR, Greenspan E, Rasmussen TP, Wang HW, Shin DG, Rosenberg DW, Giardina C. HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. Cancer Biol Ther 2008; 7:1570-80. [PMID: 18769117 PMCID: PMC2614677 DOI: 10.4161/cbt.7.10.6561] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Histone deacetylase 3 (HDAC3) is overexpressed in approximately half of all colon adenocarcinomas. We took an RNAi approach to determine how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APC(Min) tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both positive and negative effects observed. However, long-term knockdown of HDAC3 suppressed beta-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
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Affiliation(s)
- Cassandra A Godman
- Department of Molecular & Cell Biology, University of Connecticut, Storrs, CT 06269, USA
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41
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TGF-beta1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival. Br J Cancer 2008; 99:1357-63. [PMID: 18827819 PMCID: PMC2570529 DOI: 10.1038/sj.bjc.6604689] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Transforming growth factor-beta (TGF-beta)-mediated signals play complicated roles in the development and progression of breast tumour. The purposes of this study were to analyse the genotype of TGF-beta1 at T29C and TGF-beta1 phenotype in breast tumours, and to evaluate their associations with IGFs and clinical characteristics of breast cancer. Fresh tumour samples were collected from 348 breast cancer patients. TGF-beta1 genotype and phenotype were analysed with TaqMan and ELISA, respectively. Members of the IGF family in tumour tissue were measured with ELISA. Cox proportional hazards regression analysis was performed to assess the association of TGF-beta1 and disease outcomes. Patients with the T/T (29%) genotype at T29C had the highest TGF-beta1, 707.9 pg mg(-1), followed by the T/C (49%), 657.8 pg mg(-1), and C/C (22%) genotypes, 640.8 pg mg(-1), (P=0.210, T/T vs C/C and C/T). TGF-beta1 concentrations were positively correlated with levels of oestrogen receptor, IGF-I, IGF-II and IGFBP-3. Survival analysis showed TGF-beta1 associated with disease progression, but the association differed by disease stage. For early-stage disease, patients with the T/T genotype or high TGF-beta1 had shorter overall survival compared to those without T/T or with low TGF-beta1; the hazard ratios (HR) were 3.54 (95% CI: 1.21-10.40) for genotype and 2.54 (95% CI: 1.10-5.89) for phenotype after adjusting for age, grade, histotype and receptor status. For late-stage disease, however, the association was different. The T/T genotype was associated with lower risk of disease recurrence (HR=0.13, 95% CI: 0.02-1.00), whereas no association was found between TGF-beta1 phenotype and survival outcomes. The study suggests a complex role of TGF-beta1 in breast cancer progression, which supports the finding of in vitro studies that TGF-beta1 has conflicting effects on tumour growth and metastasis.
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42
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Verona EV, Tang Y, Millstead TK, Hinck AP, Agyin JK, Sun LZ. Expression, purification and characterization of BG(E)RII: a novel pan-TGFbeta inhibitor. Protein Eng Des Sel 2008; 21:463-73. [PMID: 18499679 PMCID: PMC2575055 DOI: 10.1093/protein/gzn023] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 04/01/2008] [Accepted: 04/03/2008] [Indexed: 11/13/2022] Open
Abstract
Transforming growth factor beta (TGFbeta) isoforms are known to be upregulated during the progression of some diseases. They have been shown to stimulate invasion and metastasis during carcinogenesis and promote many pathological fibrotic diseases when overstimulated. This involvement in late-stage carcinoma and pathological fibrosis makes TGFbeta isoforms prime targets for therapeutic intervention. Although soluble ectodomains of TGFbeta type II (RII) and betaglycan (BG) have been utilized as TGFbeta inhibitors, their antagonistic potency against different TGFbeta isoforms varies considerably because RII does not appreciably bind to TGFbeta2 whereas BG binds weakly to TGFbeta1 and TGFbeta3. In this study, we have successfully constructed and expressed a recombinant fusion protein containing the endoglin domain of BG (BG(E)) and the extracellular domain of RII. The fusion protein (named BG(E)RII) was purified from bacterial inclusion bodies by immobilized metal ion chromatography, refolded and characterized. It bound with higher affinity to TGFbeta1 and TGFbeta3 than a commercially available soluble RII and to TGFbeta2 than a commercially available soluble BG. More significantly, whereas BG(E) or RII alone showed no antagonistic activity towards TGFbeta2, BG(E)RII inhibited the signaling of both TGFbeta1 and TGFbeta2 in cell-based assays including TGFbeta-induced phosphorylation of Smad2 and Smad3, and transcription from a TGFbeta-responsive promoter more effectively than equimolar concentrations of either RII or BG. After further purification by gel filtration chromatography, BG(E)RII was found to have greater activity than other potent TGFbeta inhibitors in blocking the signaling of TGFbeta1 and TGFbeta3. Thus, BG(E)RII is a potent pan-TGFbeta inhibitor in vitro and has potential for blocking TGFbeta-induced pathogenesis in vivo.
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Affiliation(s)
| | - Yuping Tang
- Departments of Cellular and Structural Biology
| | - Thomas K. Millstead
- Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Andrew P. Hinck
- Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | | | - Lu-Zhe Sun
- Departments of Cellular and Structural Biology
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43
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Faria PC, Saba K, Neves AF, Cordeiro ER, Marangoni K, Freitas DG, Goulart LR. Transforming growth factor-beta 1 gene polymorphisms and expression in the blood of prostate cancer patients. Cancer Invest 2007; 25:726-32. [PMID: 18058470 DOI: 10.1080/07357900701600921] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The transforming growth factor beta 1 (TGF-beta1) is a multifunctional cytokine with several regulatory activities in tumor cells affecting growth, differentiation, and function. Alterations in gene expression, secretion, and regulation of TGF-beta1 may lead to a favorable environment for tumor development by angiogenesis stimulation and immune system suppression. We evaluated the influence of the TGFB1 polymorphisms by ARMS-PCR, Leu10Pro, and Arg25Pro, on prostate cancer (PCa) and benign prostatic hyperplasia (BPH). We assessed TGFB1 polymorphisms and their relation to mRNA levels (semi-quantitative RT-PCR) in blood samples as well as the implications in disease occurrence and progression. Peripheral blood samples from 175 patients were analyzed as to 92 BPH and 83 PCa. Samples obtained from 132 healthy males were used as negative controls. PCa patients with a Gleason score greater than 7 presented a higher frequency of the C allele (Leu10Pro). This allele was associated with a higher risk of developing PCa and BPH compared to the population (2.6 and 3.6 times higher, respectively). Patients with TGFB1 transcript levels equal to or more than 70% higher than control levels presented a 5.34 and 2.14-fold higher risk of having PCa and BPH, respectively, relative to the population. No association was detected between polymorphisms and mRNA levels. The C allele of the Leu10Pro polymorphism may predispose men to a more rapid cancer progression. Additionally, higher mRNA levels in the peripheral blood of PCa patients suggest that tumor cells may be disseminated in the circulation and could be used as a biomarker for extra-capsular invasion.
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Affiliation(s)
- Paula Cristina Faria
- Federal University of Uberlândia, Institute of Genetics and Biochemistry, Molecular Genetics Laboratory, Uberlândia, MG, Brazil
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44
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Yates B, Zetterberg C, Rajeev V, Reiss M, Rittling SR. Promoter-independent regulation of vimentin expression in mammary epithelial cells by val(12)ras and TGFbeta. Exp Cell Res 2007; 313:3718-28. [PMID: 17719575 PMCID: PMC2097954 DOI: 10.1016/j.yexcr.2007.07.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2007] [Revised: 06/20/2007] [Accepted: 07/16/2007] [Indexed: 12/25/2022]
Abstract
The 1,029 series of mammary epithelial cell lines (D6, GP+E, r3 and r3T) are progressively more transformed: the latter two by val(12)ras. These cell lines respond to TGFbeta by undergoing early events of epithelial-mesenchymal transition (EMT), including morphological changes and redistribution of E-cadherin. Tumors formed by r3T cells in the choroid of the eye express vimentin, a late marker of EMT, possibly in response to TGFbeta. In vitro, vimentin expression is induced in all the cell lines by TGFbeta treatment, whereas cytokeratin expression is only slightly affected. Surprisingly, ras transformation results in a 10-fold suppression of vimentin expression. Neither suppression of vimentin by ras transformation nor induction by TGFbeta is mediated by the vimentin promoter in r3T cells. In transient transfection assays, several human vimentin promoter constructs are more active in the low-expressing r3T cell line than in the vimentin-expressing mesenchymal cell line NIH3T3. In the r3T cells, there is no effect of TGFbeta treatment for 9 days on the activity of either promoter. Azacytidine treatment does not affect vimentin expression in either NIH3T3 or r3T, suggesting that promoter methylation is not the mechanism of suppression by ras. Finally, the half-life of the vimentin mRNA is similar in both the r3T cells and NIH3T3 cells. We conclude that the suppression of vimentin expression by ras, and the relief of this suppression by TGFbeta, occurs in a promoter-independent fashion, possibly through sequences in the first or second intron.
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Affiliation(s)
- Bradley Yates
- The Forsyth Institute 140 The Fenway, Boston, MA 02115
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45
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Pisati F, Belicchi M, Acerbi F, Marchesi C, Giussani C, Gavina M, Javerzat S, Hagedorn M, Carrabba G, Lucini V, Gaini SM, Bresolin N, Bello L, Bikfalvi A, Torrente Y. Effect of Human Skin-Derived Stem Cells on Vessel Architecture, Tumor Growth, and Tumor Invasion in Brain Tumor Animal Models. Cancer Res 2007; 67:3054-63. [PMID: 17409412 DOI: 10.1158/0008-5472.can-06-1384] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation.
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Affiliation(s)
- Federica Pisati
- Stem Cell Laboratory, Department of Neurological Science, Centro Dino Ferrari, University of Milan, Milan, Italy
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Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-beta are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-beta is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-beta. Loss of autocrine TGF-beta activity and/or responsiveness to exogenous TGF-beta appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-beta in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-beta inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-beta due to inactivation of the TGF-beta signaling pathway or aberrant regulation of the cell cycle, the role of TGF-beta becomes one of tumor promotion. Resistance to TGF-beta-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-beta signaling and cell cycle pathways. TGF-beta can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-beta to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-beta as a tumor suppressor and pro-oncogenic factor, members of the TGF-beta signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.
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Affiliation(s)
- Sonia B Jakowlew
- National Cancer Institute, Cell and Cancer Biology Branch, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA.
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47
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Abstract
The autoimmune disease scleroderma (systemic sclerosis (SSc)) is characterized by extensive tissue fibrosis, causing significant morbidity. There is no therapy for the fibrosis observed in SSc; indeed, the underlying cause of the scarring observed in this disease is unknown. Transforming growth factor-β (TGFβ) has long been hypothesized to be a major contributor to pathological fibrotic diseases, including SSc. Recently, the signaling pathways through which TGFβ activates a fibrotic program have been elucidated and, as a consequence, several possible points for anti-fibrotic drug intervention in SSc have emerged.
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Affiliation(s)
- Andrew Leask
- Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London, ON N6A 5C1, Canada.
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48
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Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, Schreiner G, Barnard N, Reiss M. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res 2007; 12:4315-30. [PMID: 16857807 DOI: 10.1158/1078-0432.ccr-06-0162] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Transforming growth factor-beta (TGF-beta) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-beta, they often constitutively overexpress and activate TGF-beta, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-beta pathway antagonists. EXPERIMENTAL DESIGN We examined the effects of selective TGF-beta type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo. RESULTS Both agents blocked TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-beta. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis. CONCLUSION TGF-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.
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Affiliation(s)
- Rongrong Ge
- Department of Internal Medicine, The Cancer Institute of New Jersey, New Jersey 08903, USA
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49
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Lu SL, Herrington H, Wang XJ. Mouse models for human head and neck squamous cell carcinomas. Head Neck 2007; 28:945-54. [PMID: 16721744 DOI: 10.1002/hed.20397] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mouse models of human cancer play an important role in understanding the mechanisms of carcinogenesis and have accelerated the search for finding new molecular targets for cancer therapy. However, genetically engineered mouse models for head and neck squamous cell carcinoma (HNSCC) have only recently overcome major technical obstacles and begun to be explored. Here we review the current progress in the development of mouse models for human HNSCC, with emphasis on conditional transgenic and knockout mouse models. These new models faithfully recapitulate human HNSCC at both the pathologic and molecular levels. These animal models will not only be useful to define the roles of specific genes in HNSCC development and progression but will also provide a unique tool for developing and testing new therapeutic approaches.
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MESH Headings
- 9,10-Dimethyl-1,2-benzanthracene
- Animals
- Carcinoma, Squamous Cell/chemically induced
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/therapy
- Disease Models, Animal
- ErbB Receptors/physiology
- Genes, Tumor Suppressor/physiology
- Head and Neck Neoplasms/chemically induced
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/pathology
- Head and Neck Neoplasms/therapy
- Humans
- Mice
- Mice, Knockout
- Mice, Transgenic
- Neoplasm Transplantation
- Transforming Growth Factor beta/physiology
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Affiliation(s)
- Shi-Long Lu
- Department of Otolaryngology, Oregon Health & Science University, PVMC Building 103-F221, R&D 46, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
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50
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Farmer JT, Weigent DA. Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone. Brain Behav Immun 2007; 21:79-85. [PMID: 16631346 DOI: 10.1016/j.bbi.2006.02.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2005] [Revised: 02/15/2006] [Accepted: 02/24/2006] [Indexed: 11/18/2022] Open
Abstract
In the present study, we report the upregulation of functional IGF-2Rs in cells overexpressing growth hormone (GH). EL4 lymphoma cells stably transfected with an rGH cDNA overexpression vector (GHo) exhibited an increase in the binding of (125)I-IGF-2 with no change in the binding affinity compared to vector alone controls. An increase in the expression of the insulin-like growth factor-2 receptor (IGF-2R) in cells overexpressing GH was confirmed by Western blot analysis and IGF-2R promoter luciferase assays. EL4 cells produce insulin-like growth factor-2 (IGF-2) as detected by the reverse transcription-polymerase chain reaction (RT-PCR); however, no IGF-2 protein was detected by Western analysis. The increase in the expression of the IGF-2R resulted in greater levels of IGF-2 uptake in GHo cells compared to vector alone controls. The data suggest that one of the consequences of the overexpression of GH is an increase in the expression of the IGF-2R.
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Affiliation(s)
- John T Farmer
- Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA
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