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1
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Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals (Basel) 2024; 17:533. [PMID: 38675493 PMCID: PMC11054419 DOI: 10.3390/ph17040533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs' pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.
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Affiliation(s)
- David Danielpour
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH 44106, USA; ; Tel.: +1-216-368-5670; Fax: +1-216-368-8919
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
- Institute of Urology, University Hospitals, Cleveland, OH 44106, USA
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2
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Sun DZ, Wei PK, Yue XQ. Xiaotan Sanjie decoction normalizes tumor permissive microenvironment in gastric cancer (Review). Oncol Rep 2023; 49:74. [PMID: 36866751 DOI: 10.3892/or.2023.8511] [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: 07/27/2022] [Accepted: 01/20/2023] [Indexed: 03/04/2023] Open
Abstract
Gastric cancer (GC) develops in a complex tissue environment, the tumor microenvironment (TME), which it relies on for persistent proliferation, migration, invasion and metastasis. Non‑malignant stromal cell types within the TME are regarded as a clinical meaningful target with the lower risk of resistance and tumor relapse. Studies have revealed that the Xiaotan Sanjie decoction, which is formulated on the basis of the theory of phlegm syndrome, a Traditional Chinese Medicine concept, modulates released factors such as transforming growth factor‑β from tumor cells, immune cells, cancer‑associated fibroblasts, extracellular matrix, as well as vascular endothelial growth factor involved in the process of angiogenesis within the TME. Clinical studies have also shown that the Xiaotan Sanjie decoction is associated with favorable survival and quality of life. The present review aimed to interpret the hypothesis that Xiaotan Sanjie decoction has the ability to normalize the GC tumor cells by influencing functions of stromal cells within the TME. The possible association between phlegm syndrome and the TME in GC was discussed in the present review. Overall, Xiaotan Sanjie decoction may be suitable to be added to tumor cell‑directed agents or emerging immunotherapies becoming a desirable modality in the management of GC and acquire improved outcomes for patients with GC.
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Affiliation(s)
- Da-Zhi Sun
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, P.R. China
| | - Pin-Kang Wei
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, P.R. China
| | - Xiao-Qiang Yue
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, P.R. China
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3
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Yang MH, Baek SH, Hwang ST, Um JY, Ahn KS. Corilagin exhibits differential anticancer effects through the modulation of STAT3/5 and MAPKs in human gastric cancer cells. Phytother Res 2022; 36:2449-2462. [PMID: 35234310 DOI: 10.1002/ptr.7419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 01/28/2022] [Accepted: 01/29/2022] [Indexed: 12/24/2022]
Abstract
Corilagin (CLG) is a hydrolyzable tannin and possesses various pharmacological activities. Here, we investigated the impact of CLG as an anti-tumor agent against human gastric tumor cells. We observed that CLG could cause negative regulation of JAKs-Src-STAT3/5 signaling axis in SNU-1 cells, but did not affect these pathways in SNU-16 cells. Interestingly, CLG promoted the induction of mitogen-activated protein kinases (MAPKs) signaling pathways in only SNU-16 cells, but not in the SNU-1 cells. CLG exhibited apoptotic effects that caused an increased accumulation of the cells in sub-G1 phase and caspase-3 activation in both SNU-1 and SNU-16 cell lines. We also noticed that CLG and docetaxel co-treatment could exhibit significantly enhanced apoptotic effects against SNU-1 cells. Moreover, the combinations treatment of CLG and docetaxel markedly inhibited cell growth, phosphorylation of JAK-Src-STAT3 and induced substantial apoptosis. Additionally, pharmacological inhibition of JNK, p38, and ERK substantially blocked CLG-induced activation of MAPKs, cell viability, and apoptosis, thereby implicating the pivotal role of MAPKs in the observed anti-cancer effects of CLG. Taken together, our data suggest that CLG could effectively block constitutive STAT3/5 activation in SNU-1 cells but induce sustained MAPKs activation in SNU-16 cells.
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Affiliation(s)
- Min Hee Yang
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.,Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seung Ho Baek
- College of Korean Medicine, Dongguk University, Goyang-si, South Korea
| | - Sun Tae Hwang
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Kwang Seok Ahn
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.,Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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4
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Molecular Genetics and the Role of Molecularly Targeted Agents in Metastatic Colorectal Carcinoma. J Gastrointest Cancer 2021; 51:387-400. [PMID: 31273629 DOI: 10.1007/s12029-019-00272-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is the third most common malignancy and fourth leading cancer-related deaths worldwide. In the USA, CRC is the third most commonly diagnosed cancer in both men and women. It is caused by genetic components and potential environmental factors such as consumption of processed meat, red meat, animal fats, low fiber intake, and obesity. Despite the utilization of effective screening modalities and guidelines in the USA, a significant number of patients are diagnosed with advanced, metastatic disease at the time of presentation to the physician. Recent advances in the understanding of molecular medicine with subsequent development and incorporation of newer therapeutic agents into current chemotherapeutic regimens have improved outcomes; however, the management of metastatic CRC remains challenging, particularly for the treating oncologists. METHODS We conducted a literature search on CRC mainly related to molecular genetics, targeted biologic agents, and published clinical trials. We also searched and reviewed ongoing clinical trials from Clinicaltrials.gov. RESULTS AND CONCLUSIONS Alterations in several oncogenes are associated with CRC, among those RAS, BRAF, and HER2 are of current clinical importance. Chemotherapy drugs, along with vascular endothelial growth factor or epidermal growth factor receptor monoclonal antibodies, are proven to be efficient with manageable toxicity profiles in metastatic CRC. Additional researches on Her-2-directed therapy, BRAF-targeted agents, immunotherapeutic, and newer molecularly targeted agents are needed for further improvement in outcome.
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5
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Juarez I, Gutierrez A, Vaquero‐Yuste C, Molanes‐López EM, López A, Lasa I, Gómez R, Martin‐Villa JM. TGFB1 polymorphisms and TGF-β1 plasma levels identify gastric adenocarcinoma patients with lower survival rate and disseminated disease. J Cell Mol Med 2021; 25:774-783. [PMID: 33274798 PMCID: PMC7812301 DOI: 10.1111/jcmm.16131] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/16/2020] [Accepted: 11/06/2020] [Indexed: 12/09/2022] Open
Abstract
TGF-β1 is involved in tumour growth. Four TGFB1 SNPs and TGF-β1 production by stimulated PBMC were determined in seventy-eight gastric adenocarcinoma patients. In addition, TGF-β1 levels were measured in the plasma of further thirty patients. rs1800471-G/C genotype was prevalent in patients (20.7%) compared to controls (8.4%), as it also was the rs1800468 SNP-G/A genotype in stage IV patients (20.7%) compared to stage I, II and III patients, combined (10.3%). Conversely, the T/T rs1800469 SNP-T/T genotype was absent in the former group and present in 19.0% in the latter. Furthermore, the rs1800469-C/rs1800470-T (CT) haplotype was found in 15.0% of stage IV patients as compared to 3.0% of the remaining patients (3.0%) and also identifies patients with worse five-year life expectancy (P = .03). TGF-β1 synthesis by stimulated PBMCs was significantly lower in patients with the risk SNPs or haplotype, compared to the alternative genotype. Finally, TGF-β1 plasma levels were lower in patients with worse life expectancy. Analysis of TGFB1 SNPs and measurement of plasma TGF-β1 levels serves to identify patients at risk of developing a more aggressive disease.
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Affiliation(s)
- Ignacio Juarez
- Department of Immunology, Ophthalmology and ENTFacultad de MedicinaUniversidad Complutense de Madrid (UCM)MadridSpain
| | | | - Christian Vaquero‐Yuste
- Department of Immunology, Ophthalmology and ENTFacultad de MedicinaUniversidad Complutense de Madrid (UCM)MadridSpain
| | - Elisa M. Molanes‐López
- Department of Statistics and Operations ResearchFacultad de MedicinaUniversidad Complutense de Madrid (UCM)MadridSpain
| | - Adela López
- Hospital Universitario Príncipe de AsturiasMadridSpain
| | | | | | - José Manuel Martin‐Villa
- Department of Immunology, Ophthalmology and ENTFacultad de MedicinaUniversidad Complutense de Madrid (UCM)MadridSpain
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM)MadridSpain
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6
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Choe JH, Williams JZ, Lim WA. Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2020. [DOI: 10.1146/annurev-cancerbio-030419-033657] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
T cells engineered to recognize and kill tumor cells have emerged as powerful agents for combating cancer. Nonetheless, our ability to engineer T cells remains relatively primitive. Aside from CAR T cells for treating B cell malignancies, most T cell therapies are risky, toxic, and often ineffective, especially those that target solid cancers. To fulfill the promise of cell-based therapies, we must transform cell engineering into a systematic and predictable science by applying the principles and tools of synthetic biology. Synthetic biology uses a hierarchical approach—assembling sets of modular molecular parts that can be combined into larger circuits and systems that perform defined target tasks. We outline the toolkit of synthetic modules that are needed to overcome the challenges of solid cancers, progress in building these components, and how these modules could be used to reliably engineer more effective and precise T cell therapies.
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Affiliation(s)
- Joseph H. Choe
- Department of Cellular and Molecular Pharmacology and Cell Design Initiative, University of California, San Francisco, California 94158, USA
| | - Jasper Z. Williams
- Department of Cellular and Molecular Pharmacology and Cell Design Initiative, University of California, San Francisco, California 94158, USA
| | - Wendell A. Lim
- Department of Cellular and Molecular Pharmacology and Cell Design Initiative, University of California, San Francisco, California 94158, USA
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7
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Voisin A, Damon-Soubeyrand C, Bravard S, Saez F, Drevet JR, Guiton R. Differential expression and localisation of TGF-β isoforms and receptors in the murine epididymis. Sci Rep 2020; 10:995. [PMID: 31969637 PMCID: PMC6976608 DOI: 10.1038/s41598-020-57839-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/16/2019] [Indexed: 12/21/2022] Open
Abstract
Testes produce spermatozoa that transit through and are stored in the epididymis where they acquire their fertilising capacities. Spermatozoa appear in the genital tract at puberty, long after the immune system was trained to self-antigens. As a consequence, this organ has to set strategies to tolerate sperm antigens to avoid autoimmune responses that would specifically target and destroy them. A recent study pointed the Transforming Growth Factor-beta (TGF-β) signalling in the dendritic cells as a crucial mechanism for epididymal tolerance to spermatozoa. In the mouse, TGF-β exists under three isoforms, and three distinct receptors have been described. Using RT-qPCR, immunohistochemistry and ELISA techniques, we investigated the expression and spatial distribution of the epididymal TGF-β isoforms and of their receptors in young and adult mice. We showed that both ligands and receptors were produced by immune and non-immune cells in the epididymis, whatever the age mice have. These data bring new clues as to the mechanisms of peripheral tolerance to sperm cells in the murine epididymis and raise potential other implications of the cytokine isoforms.
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Affiliation(s)
- Allison Voisin
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France
| | - Christelle Damon-Soubeyrand
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France
| | - Stéphanie Bravard
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France
| | - Fabrice Saez
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France
| | - Joël R Drevet
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France.
| | - Rachel Guiton
- GReD laboratory, CNRS UMR 6293 - INSERM U1103 - Université Clermont Auvergne, 28 place Henri Dunant, 63001, Clermont-Ferrand Cedex, France.
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8
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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9
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Miah S, Banks CAS, Ogunbolude Y, Bagu ET, Berg JM, Saraf A, Tettey TT, Hattem G, Dayebgadoh G, Kempf CG, Sardiu M, Napper S, Florens L, Lukong KE, Washburn MP. BRK phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG, and metastatic potential. SCIENCE ADVANCES 2019; 5:eaaw3113. [PMID: 31681835 PMCID: PMC6810434 DOI: 10.1126/sciadv.aaw3113] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 09/13/2019] [Indexed: 05/06/2023]
Abstract
The tumor-suppressing function of SMAD4 is frequently subverted during mammary tumorigenesis, leading to cancer growth, invasion, and metastasis. A long-standing concept is that SMAD4 is not regulated by phosphorylation but ubiquitination. Our search for signaling pathways regulated by breast tumor kinase (BRK), a nonreceptor protein tyrosine kinase that is up-regulated in ~80% of invasive ductal breast tumors, led us to find that BRK competitively binds and phosphorylates SMAD4 and regulates transforming growth factor-β/SMAD4 signaling pathway. A constitutively active BRK (BRK-Y447F) phosphorylates SMAD4, resulting in its recognition by the ubiquitin-proteasome system, which accelerates SMAD4 degradation. Activated BRK-mediated degradation of SMAD4 is associated with the repression of tumor suppressor gene FRK and increased expression of mesenchymal markers, SNAIL, and SLUG. Thus, our data suggest that combination therapies targeting activated BRK signaling may have synergized the benefits in the treatment of SMAD4 repressed cancers.
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Affiliation(s)
- S. Miah
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - C. A. S. Banks
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - Y. Ogunbolude
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - E. T. Bagu
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - J. M. Berg
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - A. Saraf
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - T. T. Tettey
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - G. Hattem
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - G. Dayebgadoh
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - C. G. Kempf
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - M. Sardiu
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - S. Napper
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Vaccine and Infectious Disease Organization–International Vaccine Centre, University of Saskatchewan, Saskatoon, SK S7 N 5E3, Canada
| | - L. Florens
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
| | - K. E. Lukong
- Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - M. P. Washburn
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA
- Departments of Pathology and Laboratory Medicine, University of Kansas Medical Centre, Kansas City, KS 66160, USA
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10
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Amerizadeh F, Bahrami A, Khazaei M, Hesari A, Rezayi M, Talebian S, Maftouh M, Moetamani-Ahmadi M, Seifi S, Shahidsales S, Joudi-Mashhad M, Ferns GA, Ghasemi F, Avan A. Current status and future prospects of transforming growth factor-β as a potential prognostic and therapeutic target in the treatment of breast cancer. J Cell Biochem 2019; 120:6962-6971. [PMID: 30672016 DOI: 10.1002/jcb.27831] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 09/14/2018] [Indexed: 01/24/2023]
Abstract
The transforming growth factor-β (TGF-β) signaling pathway is one of the important pathways involved in the cancer cell proliferation, invasion, migration, angiogenesis, apoptosis, as well as in metastasis by agitation or invasion of metastasis-related factors, including matrix metalloproteinase (MMP), epithelial-to-mesenchymal transition (EMT), tumor microenvironment (TME), cancer stem cells (CSCs), and cell adhesion molecules (CAMs). These data suggest its potential value as a therapeutic object in the treatment of malignancies including breast cancer. Several pharmacological approaches have been established to suppress TGF-β pathway; such as vaccines, small molecular inhibitors, antisense oligonucleotides, and monoclonal antibodies. Some of these are now approved by the US Food and Drug Administration for targeting the TGF-β signaling pathway. This study attempts to summarize the current data about the functions of TGF-β in cancer cells, and their probable application in the cancer therapy with a specific emphasis on recent preclinical and clinical research in the treatment of breast cancer and its prognostic value.
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Affiliation(s)
- Forouzan Amerizadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - AmirReza Hesari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Talebian
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Maftouh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sima Seifi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mona Joudi-Mashhad
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
| | - Faezeh Ghasemi
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Furler RL, Nixon DF, Brantner CA, Popratiloff A, Uittenbogaart CH. TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction. Cancers (Basel) 2018; 10:E199. [PMID: 29903994 PMCID: PMC6025279 DOI: 10.3390/cancers10060199] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/12/2018] [Accepted: 06/12/2018] [Indexed: 02/07/2023] Open
Abstract
Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors. Additionally, we discuss the role of TGF-β in the mechanobiology of cancer. Understanding how TGF-β dampens proinflammatory responses and induces pro-survival mechanical signals throughout cancer development is critical for designing therapeutics that inhibit tumor progression while bolstering the immune response.
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Affiliation(s)
- Robert L Furler
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, 413 E 69th St., Belfer Research Building, New York, NY 10021, USA.
| | - Douglas F Nixon
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, 413 E 69th St., Belfer Research Building, New York, NY 10021, USA.
| | - Christine A Brantner
- GW Nanofabrication and Imaging Center, Office of the Vice President for Research, George Washington University, Washington, DC 20052, USA.
| | - Anastas Popratiloff
- GW Nanofabrication and Imaging Center, Office of the Vice President for Research, George Washington University, Washington, DC 20052, USA.
| | - Christel H Uittenbogaart
- Departments of Microbiology, Immunology and Molecular Genetics, Medicine, Pediatrics, UCLA AIDS Institute and the Jonsson Comprehensive Cancer Center, University of California, 615 Charles E. Young Drive South, BSRB2, Los Angeles, CA 90095, USA.
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12
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The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development. Nat Commun 2018; 9:1216. [PMID: 29572483 PMCID: PMC5865211 DOI: 10.1038/s41467-018-03609-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 02/28/2018] [Indexed: 11/28/2022] Open
Abstract
Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFβ-independent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development. Transforming growth factor-β (TGFβ) regulates many cellular processes. Here the authors show that the orphan G-protein coupled receptor GPR50 can activate the TGFβ receptor I, in the absence of TGFβ, by stabilizing its active conformation and show antitumor activity in a mouse model of breast cancer.
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13
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Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, Cao X. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res 2018; 6:2. [PMID: 29423331 PMCID: PMC5802812 DOI: 10.1038/s41413-017-0005-4] [Citation(s) in RCA: 278] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/12/2017] [Accepted: 11/15/2017] [Indexed: 02/05/2023] Open
Abstract
TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
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Affiliation(s)
- Xin Xu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Gehua Zhen
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Janet L. Crane
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD USA
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xu Cao
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA
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14
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Powell AGMT, Hughes DL, Wheat JR, Lewis WG. The 100 most influential manuscripts in gastric cancer: A bibliometric analysis. Int J Surg 2016; 28:83-90. [DOI: 10.1016/j.ijsu.2016.02.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/27/2016] [Accepted: 02/03/2016] [Indexed: 12/22/2022]
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15
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Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines. Oncotarget 2016; 6:11009-22. [PMID: 25826092 PMCID: PMC4484435 DOI: 10.18632/oncotarget.3557] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 02/12/2015] [Indexed: 12/19/2022] Open
Abstract
Leucine-rich α2-glycoprotein (LRG) is an approximately 50-kDa glycoprotein that has been found to be elevated in the sera of patients with several types of cancer. LRG directly binds to transforming growth factor beta 1 (TGFβ1) and modulates TGFβ1 signaling in endothelial cells; however, the precise function of LRG in cancer remains unclear. This study aimed to investigate the role of LRG in cancer. Lewis lung carcinoma (LLC) cells hardly expressed LRG. The growth of LLC tumors allografted in the LRG knockout (KO) mice was significantly increased compared with wild-type (WT) mice. Conversely, overexpression of LRG significantly inhibited the growth of LLC tumors in WT mice. In the presence of LRG, TGFβ1 significantly inhibited the proliferation of LLC cells and human hepatocellular carcinoma Hep3B cells in vitro by inducing apoptosis via the potent activation of smad2 and its downstream signaling pathway. Furthermore, administration of a TGFβR1 inhibitor (SB431542) significantly enhanced the growth of LLC tumors in WT mice compared with LRG KO mice via inhibition of apoptosis. We propose that LRG potentiates the effect of TGFβ1 in cancer cells whose growth is suppressed in the presence of TGFβ1.
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16
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TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. JOURNAL OF ONCOLOGY 2015; 2015:587193. [PMID: 25883652 PMCID: PMC4389829 DOI: 10.1155/2015/587193] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 10/14/2014] [Indexed: 01/07/2023]
Abstract
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.
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17
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Papageorgis P, Stylianopoulos T. Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review). Int J Oncol 2015; 46:933-43. [PMID: 25573346 PMCID: PMC4306018 DOI: 10.3892/ijo.2015.2816] [Citation(s) in RCA: 162] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 10/30/2014] [Indexed: 02/07/2023] Open
Abstract
Deregulation of cell signaling homeostasis is a predominant feature of cancer initiation and progression. Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner. Aberrant activity of TGFβ signaling is well known to play dual roles in cancer, depending on tumor stage and cellular context. The crucial roles of TGFβ in modulating the tumor microenvironment, its contribution to the accumulation of mechanical forces within the solid constituents of a tumor and its effects on the effective delivery of drugs are also becoming increasingly clear. In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs. We also report the implications of tumor mechanics in cancer therapy and the potential usage of anti-TGFβ agents to enhance drug delivery and augment existing therapeutic approaches. These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.
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Affiliation(s)
- Panagiotis Papageorgis
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus
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18
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Chen H, Wang JW, Liu LX, Yan JD, Ren SH, Li Y, Lu Z. Expression and significance of transforming growth factor-β receptor type II and DPC4/Smad4 in non-small cell lung cancer. Exp Ther Med 2014; 9:227-231. [PMID: 25452807 PMCID: PMC4247285 DOI: 10.3892/etm.2014.2065] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 08/15/2014] [Indexed: 11/14/2022] Open
Abstract
The aim of the present study was to investigate the expression levels of transforming growth factor-β (TGF-β) receptor type II (TβRII) and DPC4/Smad4 in the TGF-β signaling pathway and the importance of these expression levels in non-small cell lung cancer (NSCLC). The mRNA and protein expression levels of TβRII and DPC4/Smad4 were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively, in NSCLC and control nonlesional lung tissues of 60 patients. The protein expression levels of DPC4/Smad4 were detected by immunohistochemistry in paraffin-embedded samples of NSCLC. In addition, the correlations among the expression levels of TβRII and DPC4/Smad4 and their association with the clinical and pathological features of NSCLC were analyzed. The expression levels of TβRII and DPC4/Smad4 in NSCLC tissues were significantly lower when compared with the control nonlesional lung tissues (P<0.05). In addition, the expression of TβRII and DPC4/Smad4 in poorly-differentiated NSCLC tissues was significantly lower compared with moderately- or well-differentiated NSCLC tissues (P<0.05). The expression levels of TβRII and DPC4/Smad4 were significantly lower in NSCLC tissues with metastatic lymph nodes compared with tissue without metastatic lymph nodes (P<0.05). Thus, the expression levels were demonstrated to significantly correlate with the clinical and pathological stages, and subsequently were shown to be associated with the occurrence and progression of NSCLC. In conclusion, TβRII and DPC4/Smad4 may play an important role in the tumorigenesis, differentiation and progression of NSCLC via the TGF-β signaling pathway.
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Affiliation(s)
- Hong Chen
- Department of Radiotherapy and Chemotherapy, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Jing-Wei Wang
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Li-Xin Liu
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Ji-Dong Yan
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Shu-Hua Ren
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Yan Li
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Zheng Lu
- Department of Thoracic Surgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
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19
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Li YL, Liu L, Xiao Y, Zeng T, Zeng C. 14-3-3σ is an independent prognostic biomarker for gastric cancer and is associated with apoptosis and proliferation in gastric cancer. Oncol Lett 2014; 9:290-294. [PMID: 25435977 PMCID: PMC4246703 DOI: 10.3892/ol.2014.2676] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 09/26/2014] [Indexed: 11/13/2022] Open
Abstract
14-3-3 proteins participate in various cellular processes, including apoptosis, proliferation and malignant transformation. 14-3-3σ, a member of the 14-3-3 protein family, is important in several types of cancer; however, little is known about the clinical significance and biological roles of 14-3-3σ in gastric cancer. The present study analyzed the expression pattern of 14-3-3σ in gastric cancer and investigated its correlation with the prognosis of gastric cancer patients. Furthermore, the association of 14-3-3σ with Ki-67, Bcl-2 and Bax was evaluated. 14-3-3σ was expressed at higher level in gastric cancer tissue compared with healthy gastric tissue, and 14-3-3σ expression was significantly correlated with tumor size and tumor node metastasis stage (P<0.05). To the best of our knowledge, the present study data are the first to suggest that 14-3-3σ expression has been significantly associated with poor prognosis in gastric cancer. Additionally, 14-3-3σ overexpression was positively correlated with Ki-67 and Bcl-2 expression levels. Thus, 14-3-3σ is a potential prognostic marker for gastric cancer patients, and may be involved in regulating the apoptosis and proliferation of gastric cancer cells.
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Affiliation(s)
- Yi-Liang Li
- Department of Neurology, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan 417000, P.R. China
| | - Lihua Liu
- Department of Respiratory Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yang Xiao
- Department of Orthopaedics, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan 417000, P.R. China
| | - Tao Zeng
- School of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
| | - Chao Zeng
- Department of Pathology, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
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20
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Mahu C, Purcarea AP, Gheorghe CM, Purcarea MR. Molecular events in gastric carcinogenesis. J Med Life 2014; 7:375-8. [PMID: 25408758 PMCID: PMC4233442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 06/29/2014] [Indexed: 11/24/2022] Open
Abstract
Gastric cancer represents an important problem for the public health, being one of the main causes of mortality. At present, it represents the second cause of mortality due to cancer, after the bronchopulmonary cancer in men and the fourth cause of mortality in women. Important progresses have been made in the last couple of years in determining the neoplastic etiopathogenesis, but it cannot be affirmed that the genetic mutations chain, which leads to the appearance of the malignant cell, has been fully understood.
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Affiliation(s)
- C Mahu
- "Prof. Dr. D. Gerota" Ministry of Internal Affairs Emergency Hospital, Bucharest, Romania
| | - A P Purcarea
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - C M Gheorghe
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - M R Purcarea
- "Dr. Carol Davila" Clinical Nephrology Hospital, Bucharest, Romania
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21
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Disruption of interleukin-1β autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One 2014; 9:e99257. [PMID: 24901709 PMCID: PMC4047112 DOI: 10.1371/journal.pone.0099257] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 05/13/2014] [Indexed: 12/22/2022] Open
Abstract
Patients with cystic fibrosis (CF) have elevated concentration of cytokines in sputum and a general inflammatory condition. In addition, CF cells in culture produce diverse cytokines in excess, including IL-1β. We have previously shown that IL-1β, at low doses (∼30 pM), can stimulate the expression of CFTR in T84 colon carcinoma cells, through NF-κB signaling. However, at higher doses (>2.5 ng/ml, ∼150 pM), IL-1β inhibit CFTR mRNA expression. On the other hand, by using differential display, we found two genes with reduced expression in CF cells, corresponding to the mitochondrial proteins CISD1 and MTND4. The last is a key subunit for the activity of mitochondrial Complex I (mCx-I); accordingly, we later found a reduced mCx-I activity in CF cells. Here we found that IB3-1 cells (CF cells), cultured in serum-free media, secrete 323±5 pg/ml of IL-1β in 24 h vs 127±3 pg/ml for S9 cells (CFTR-corrected IB3-1 cells). Externally added IL-1β (5 ng/ml) reduces the mCx-I activity and increases the mitochondrial (MitoSOX probe) and cellular (DCFH-DA probe) ROS levels of S9 (CFTR-corrected IB3-1 CF cells) or Caco-2/pRSctrl cells (shRNA control cells) to values comparable to those of IB3-1 or Caco-2/pRS26 cells (shRNA specific for CFTR). Treatments of IB3-1 or Caco-2/pRS26 cells with either IL-1β blocking antibody, IL-1 receptor antagonist, IKK inhibitor III (NF-κB pathway) or SB203580 (p38 MAPK pathway), restored the mCx-I activity. In addition, in IB3-1 or Caco-2/pRS26 cells, IL-1β blocking antibody, IKK inhibitor III or SB203580 reduced the mitochondrial ROS levels by ∼50% and the cellular ROS levels near to basal values. The AP-1 inhibitors U0126 (MEK1/2) or SP600125 (JNK1/2/3 inhibitor) had no effects. The results suggest that in these cells IL-1β, through an autocrine effect, acts as a bridge connecting the CFTR with the mCx-I activity and the ROS levels.
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22
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Tumors as organs: biologically augmenting radiation therapy by inhibiting transforming growth factor β activity in carcinomas. Semin Radiat Oncol 2014; 23:242-51. [PMID: 24012338 DOI: 10.1016/j.semradonc.2013.05.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Transforming growth factor β (TGFβ) plays critical roles in regulating a plethora of physiological processes in normal organs, including morphogenesis, embryonic development, stem cell differentiation, immune regulation, and wound healing. Though considered a tumor suppressor, TGFβ is a critical mediator of tumor microenvironment, in which it likewise mediates tumor and stromal cell phenotype, recruitment, inflammation, immune function, and angiogenesis. The fact that activation of TGFβ is an early and persistent event in irradiated tissues and that TGFβ signaling controls effective DNA damage response provides a new means to manipulate tumor response to radiation. Here we discuss preclinical studies unraveling TGFβ effects in cancer treatment and review TGFβ biology in lung cancer as an example of the opportunities for TGFβ pathway inhibition as a pharmaceutical approach to augment radiation therapy.
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23
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Shaker O, Hammam O, Wishahi M, Roshdi M. TGF-B1 pathway as biological marker of bladder carcinoma schistosomal and non-schistosomal. Urol Oncol 2013; 31:372-8. [DOI: 10.1016/j.urolonc.2011.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 02/06/2011] [Accepted: 02/07/2011] [Indexed: 11/24/2022]
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24
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Li F, Liu J, Li S. MicorRNA 106b ∼ 25 cluster and gastric cancer. Surg Oncol 2013; 22:e7-10. [PMID: 23510949 DOI: 10.1016/j.suronc.2013.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 01/15/2013] [Accepted: 01/22/2013] [Indexed: 12/19/2022]
Abstract
Conventional strategies for the early diagnosis and treatment of gastric cancer are not yet satisfactory, and it calls for better diagnosis and treatments based on a deeper understanding of the molecular mechanisms. It has been revealed that the number of verified human microRNA (miRNA) expression contribute to the initiation and progression of cancer. Among them, miR-106b ∼ 25 cluster is of particular interest. The miRNA-106b ∼ 25 cluster is composed of the highly conserved miRNA-106b, miRNA-93 and miRNA-25. The miRNA-106b ∼ 25 polycistron exerted potential proliferative, anti-apoptotic and cell cycle-promoting effects on cancer cells. Over-expression of the miRNA-106b ∼ 25 cluster is known to overcome TGF-beta mediated growth suppression via targeting p21 and Bim. This cluster can additionally target the inhibitory Smad7 protein and increase TGF-beta RI which is sufficient to induce epithelial-to-mesenchymal transition (EMT). MiRNA-93 can promote angiogenesis. The tumor suppressor genes RB and PTEN are the direct targets of miRNA-106b ∼ 25. Especially, miRNA-106b ∼ 25 clusters play an important role in oncogenesis of gastric cancer. Focus on the essential role in tumorgenisis and extremely low expression of miRNA-106b ∼ 25 in normal tissues, it maybe an appropriate target of gastric cancer treatment and a novel biomarkers for detecting gastric cancer.
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Affiliation(s)
- Fangxuan Li
- Cancer Prevention Center, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Hexi District, Tianjin 300060, China
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25
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Zhang L, Yu Z, Muranski P, Palmer DC, Restifo NP, Rosenberg SA, Morgan RA. Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther 2012; 20:575-80. [PMID: 22972494 DOI: 10.1038/gt.2012.75] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transforming growth factor β (TGF-β) is a cytokine with complex biological functions that may involve tumor promotion or tumor suppression. It has been reported that multiple types of tumors secrete TGF-β, which can inhibit tumor-specific cellular immunity and may represent a major obstacle to the success of tumor immunotherapy. In this study, we sought to enhance tumor immunotherapy using genetically modified antigen-specific T cells by interfering with TGF-β signaling. We constructed three γ-retroviral vectors, one that expressed TGF-β-dominant-negative receptor II (DNRII) or two that secreted soluble TGF-β receptors: soluble TGF-β receptor II (sRII) and the sRII fused with mouse IgG Fc domain (sRIIFc). We demonstrated that T cells genetically modified with these viral vectors were resistant to exogenous TGF-β-induced smad-2 phosphorylation in vitro. The functionality of antigen-specific T cells engineered to resist TGF-β signaling was further evaluated in vivo using the B16 melanoma tumor model. Antigen-specific CD8+ T cells (pmel-1) or CD4+ T cells (tyrosinase-related protein-1) expressing DNRII dramatically improved tumor treatment efficacy. There was no enhancement in the B16 tumor treatment using cells secreting soluble receptors. Our data support the potential application of the blockade of TGF-β signaling in tumor-specific T cells for cancer immunotherapy.
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Affiliation(s)
- L Zhang
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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26
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Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-β - an excellent servant but a bad master. J Transl Med 2012; 10:183. [PMID: 22943793 PMCID: PMC3494542 DOI: 10.1186/1479-5876-10-183] [Citation(s) in RCA: 387] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 08/28/2012] [Indexed: 12/13/2022] Open
Abstract
The transforming growth factor (TGF-β) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-β signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-β pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however in tumor cells, TGF-β looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-β signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.
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Affiliation(s)
- Lenka Kubiczkova
- Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, 625 00, Czech Republic
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27
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Silencing of the TGF-β1 gene increases the immunogenicity of cells from human ovarian carcinoma. J Immunother 2012; 35:267-75. [PMID: 22421944 DOI: 10.1097/cji.0b013e31824d72ee] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cells from many tumors produce transforming growth factor (TGF)-β which facilitates their escape from control by the immune system. We previously reported that nonimmunogenic cells from either of 2 transplantable mouse tumors became effective as therapeutic tumor vaccines after lentivirus-mediated shRNA interference to "silence" the TGF-β1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-β1 and that this can be prevented by "silencing" the TGF-β1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells in the presence of either mitomycin-treated OvC cells whose TGF-β1 gene was silenced or in vitro matured dendritic cells that had been pulsed with homogenates from OvC cells with silenced TGF-β1 generated a stronger Th1/Tc1 immune response to the respective wild-type OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon-γ and tumor necrosis factor-α-producing CD4+ and CD8+ T cells increased while there were fewer cells expressing markers characteristic for regulatory T cells or myeloid-derived suppressor cells. Similar results were obtained when peripheral blood mononuclear cells from a patient with OvC were sensitized to dendritic cells pulsed with homogenate from autologous TGF-β1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-β1-silenced tumor vaccines for immunotherapy of OvC.
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28
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Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature. J Transl Med 2012; 92:883-95. [PMID: 22411066 PMCID: PMC3584162 DOI: 10.1038/labinvest.2012.47] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
SMAD proteins are downstream effectors of the TGF-β signaling pathway. Smad3-null mice develop colorectal cancer by 6 months of age. In this study, we have examined whether the loss of Smad3 promotes gastric neoplasia in mice. The stomachs of Smad3⁻/⁻ mice were compared with age-matched Smad3 heterozygous and wild-type mice. E-cadherin, Ki-67, phosphoSTAT3, and TFF2/SP expression was analyzed by immunohistochemisty. The short hairpin RNA (ShRNA)-mediated knockdown of Smad3 in AGS and MKN28 cells was also performed. In addition, we examined alterations in DCLK1-expressing cells. Smad3⁻/⁻ mouse stomachs at 6 months of age revealed the presence of exophytic growths along the lesser curvature in the proximal fundus. Six-month-old Smad3⁻/⁻ mouse stomachs showed metaplastic columnar glands initiating from the transition zone junction between the forestomach and the glandular epithelium along the lesser curvature. Ten-month-old Smad3⁻/⁻ mice all exhibited invasive gastric neoplastic changes with increased Ki-67, phosphoSTAT3 expression, and aberrant cytosolic E-cadherin staining in papillary glands within the invading submucosal gland. The shRNA-mediated knockdown of Smad3 in AGS and MKN28 cells promoted the expression of phosphoSTAT3. DCLK1-expressing cells, which also stained for the tuft cell marker acetylated-α-tubulin, were observed in 10-month-old Smad3⁻/⁻ mice within tumors and in fundic invasive lesions. In conclusion, Smad3-null mice develop gastric tumors in the fundus, which arise from the junction between the forestomach and the glandular epithelium and progress to prominent invasive tumors over time. Smad3-null mice represent a novel model of fundic gastric tumor initiated from forestomach/glandular transition zone along the lesser curvature.
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29
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Abstract
Overwhelming experimental evidence accumulated over the past decade indicates that microRNAs (miRNAs) are key regulators of gene expression in animals and plants and play important roles in development, homeostasis, and disease. The miR-17-92 family of miRNA clusters is composed of 3 related, highly conserved, polycistronic miRNA genes that collectively encode for a total of 15 miRNAs. We discuss recent studies demonstrating that these miRNAs are essential for vertebrate development and homeostasis. We also show how their mutation or deregulation contributes to the pathogenesis of a variety of human diseases, including cancer and congenital developmental defects. Finally, we discuss the current evidence suggesting how the different miRNAs encoded by these 3 clusters can functionally cooperate to fine-tune signaling and developmental pathways.
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Affiliation(s)
- Carla P. Concepcion
- Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program 1275 York Avenue, New York, NY, 10065
| | - Ciro Bonetti
- Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program 1275 York Avenue, New York, NY, 10065
| | - Andrea Ventura
- Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program 1275 York Avenue, New York, NY, 10065
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30
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Kang JM, Park S, Kim SJ, Hong HY, Jeong J, Kim HS, Kim SJ. CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling. Oncogene 2012; 31:5123-31. [PMID: 22310290 DOI: 10.1038/onc.2012.18] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-β (TGF-β) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, PAI-I and CDK inhibitors such as p15(INK4b) and p21(Cip1). Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity.
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Affiliation(s)
- J M Kang
- Department of Biomedical Science, CHA University, Seoul, Korea
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Hu S, Zhou G, Zhang L, Jiang H, Xiao M. The Effects of Functional Polymorphisms in the TGFβ1 Gene on Nasopharyngeal Carcinoma Susceptibility. Otolaryngol Head Neck Surg 2012; 146:579-84. [PMID: 22282866 DOI: 10.1177/0194599811434890] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective. Transforming growth factor β1 (TGFβ1) promotes tumor growth and metastasis in the later stage of cancer development. In this study, we explored whether TGFβ1 polymorphisms were associated with increased risk of nasopharyngeal carcinoma (NPC) in a Chinese population. Design. Case-control study. Setting. Hospitals of the Department of Otorhinolaryngology–Head and Neck Surgery. Subjects and Methods. Two single nucleotide polymorphisms of TGFβ1 gene promoter -509C/T (rs1800469) and 869T/C (Leu 10 Pro, rs1800470) at exon 1 were analyzed in 522 NPC patients and 712 age- and sex-matched controls in a Chinese population, using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis. Functional relevance of the polymorphism was determined by biochemical assays. Results. The -509T allele carriers were associated with a significantly reduced risk of NPC as compared with the noncarriers (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.53-0.89 and OR, 0.50; 95% CI, 0.31-0.67, respectively). Moreover, -509C-containing TGFβ1 promoter drove an ~1.7-fold increase in reporter expression, compared with the -509T-containing counterpart in both CNE-1 and CNE-2 cell lines. The TGFβ1 -509 CC genotype carriers had a higher TGFβ1 mRNA level than the TGFβ1 -509TT genotype carriers did ( P < .01). However, no significant association was observed between the 869T/C polymorphism and risk of NPC. Conclusion. These findings indicate that the -509C/T polymorphism in TGFβ1 may play a vital role in mediating individual susceptibility to NPC.
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Affiliation(s)
- Sunhong Hu
- Department of Otorhinolaryngology–Head and Neck Surgery, Sir Run Run Shaw Hospital, Key Laboratory of Biotherapy of Zhejiang province, Zhejiang University, Hangzhou, China
| | - Guojin Zhou
- Department of Otorhinolaryngology–Head and Neck Surgery, Sir Run Run Shaw Hospital, Key Laboratory of Biotherapy of Zhejiang province, Zhejiang University, Hangzhou, China
| | - Lei Zhang
- Department of Otorhinolaryngology–Head and Neck Surgery, Sir Run Run Shaw Hospital, Key Laboratory of Biotherapy of Zhejiang province, Zhejiang University, Hangzhou, China
| | - Huifen Jiang
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mang Xiao
- Department of Otorhinolaryngology–Head and Neck Surgery, Sir Run Run Shaw Hospital, Key Laboratory of Biotherapy of Zhejiang province, Zhejiang University, Hangzhou, China
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Abstract
To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-β (transforming growth factor-β) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-β did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-β-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.
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Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert AW, Abdolmaleky HM, Zhou JR, Thiagalingam S. Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res 2011; 71:998-1008. [PMID: 21245094 DOI: 10.1158/0008-5472.can-09-3269] [Citation(s) in RCA: 157] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFβ signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFβ and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of function of Smad4 and retention of intact TGFβ receptors could synergistically increase the levels of VEGF, a major proangiogenic factor. Pharmacologic inhibition studies suggest that overactivation of the TGFβ-induced MEK-Erk and p38-MAPK (mitogen-activated protein kinase) auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in matrix metalloprotease 9 enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis, and resistance to 5'-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with hypoxia-inducible factor (HIF) 1α under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFβ-induced auxiliary pathways, such as MEK-ERK, and p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention.
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Affiliation(s)
- Panagiotis Papageorgis
- Department of Medicine, Genetics & Genomics Graduate Program, Boston University School of Medicine, Boston, Massachusetts, USA
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Saitoh M. Transforming Growth Factor-β Signaling and Epithelial-Mesenchymal Transition in Cancer Progression. J Oral Biosci 2011. [DOI: 10.1016/s1349-0079(11)80036-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Juárez P, Guise TA. TGF-β in cancer and bone: implications for treatment of bone metastases. Bone 2011; 48:23-9. [PMID: 20699127 DOI: 10.1016/j.bone.2010.08.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 08/03/2010] [Accepted: 08/04/2010] [Indexed: 01/09/2023]
Abstract
Bone metastases are common in patients with advanced breast, prostate and lung cancer. Tumor cells co-opt bone cells to drive a feed-forward cycle which disrupts normal bone remodeling to result in abnormal bone destruction or formation and tumor growth in bone. Transforming growth factor-beta (TGF-β) is a major bone-derived factor, which contributes to this vicious cycle of bone metastasis. TGF-β released from bone matrix during osteoclastic resorption stimulates tumor cells to produce osteolytic factors further increasing bone resorption adjacent to the tumor cells. TGF-β also regulates 1) key components of the metastatic cascade such as epithelial-mesenchymal transition, tumor cell invasion, angiogenesis and immunosuppression as well as 2) normal bone remodeling and coupling of bone resorption and formation. Preclinical models demonstrate that blockade of TGF-β signaling is effective to treat and prevent bone metastases as well as to increase bone mass.
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Affiliation(s)
- Patricia Juárez
- Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA
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36
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Abstract
Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E(2) (PGE(2)) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE(2) pathway in gastric mucosa induces development of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE(2) pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE(2) pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE(2) pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis.
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Affiliation(s)
- Hiroko Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Japan
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37
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Song JH, Lee HS, Yoon JH, Kang YH, Nam SW, Lee JY, Park WS. TGFBR2 frameshift mutation in gastric tumors with microsatellite instability. Mol Cell Toxicol 2010; 6:321-326. [DOI: 10.1007/s13273-010-0043-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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38
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Mamiya T, Yamazaki K, Masugi Y, Mori T, Effendi K, Du W, Hibi T, Tanabe M, Ueda M, Takayama T, Sakamoto M. Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. J Transl Med 2010; 90:1339-45. [PMID: 20531292 DOI: 10.1038/labinvest.2010.105] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-beta (TGF-beta) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-beta signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-beta signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-beta receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-beta. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (P<0.001), poor differentiation (P<0.001), portal vein invasion (P=0.002), intrahepatic metastasis (IM) (P<0.001), and shorter recurrence-free survival (P=0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC.
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Affiliation(s)
- Takao Mamiya
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
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39
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Fibroblast and prostate tumor cell cross-talk: fibroblast differentiation, TGF-β, and extracellular matrix down-regulation. Exp Cell Res 2010; 316:3207-26. [PMID: 20727350 DOI: 10.1016/j.yexcr.2010.08.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 08/12/2010] [Accepted: 08/12/2010] [Indexed: 01/27/2023]
Abstract
Growth and survival of tumors at a site of metastasis involve interactions with stromal cells in the surrounding environment. Stromal cells aid tumor cell growth by producing cytokines as well as by modifying the environment surrounding the tumor through modulation of the extracellular matrix (ECM). Small leucine-rich proteoglycans (SLRPs) are biologically active components of the ECM which can be altered in the stroma surrounding tumors. The influence tumor cells have on stromal cells has been well elucidated. However, little is understood about the effect metastatic cancer cells have on the cell biology and behavior of the local stromal cells. Our data reveal a significant down-regulation in the expression of ECM components such as collagens I, II, III, and IV, and the SLRPs, decorin, biglycan, lumican, and fibromodulin in stromal cells when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145. Interestingly, TGF-β down-regulation was observed in stromal cells, as well as actin depolymerization and increased vimentin and α5β1 integrin expression. MT1-MMP expression was upregulated and localized in stromal cell protrusions which extended into the ECM. Moreover, enhanced stromal cell migration was observed after cross-talk with metastatic prostate tumor cells. Xenografting metastatic prostate cancer cells together with "activated" stromal cells led to increased tumorigenicity of the prostate cancer cells. Our findings suggest that metastatic prostate cancer cells create a metastatic niche by altering the phenotype of local stromal cells, leading to changes in the ECM.
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40
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Jo Y, Han SU, Kim YJ, Kim JH, Kim ST, Kim SJ, Hahm KB. Suppressed Gastric Mucosal TGF-beta1 Increases Susceptibility to H. pylori-Induced Gastric Inflammation and Ulceration: A Stupid Host Defense Response. Gut Liver 2010; 4:43-53. [PMID: 20479912 DOI: 10.5009/gnl.2010.4.1.43] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Accepted: 11/12/2009] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Loss of transforming growth factor beta1 (TGF-beta1) exhibits a similar pathology to that seen in a subset of individuals infected with Helicobacter pylori, including propagated gastric inflammation, oxidative stress, and autoimmune features. We thus hypothesized that gastric mucosal TGF-beta1 levels could be used to determine the outcome after H. pylori infection. METHODS Northern blot for the TGF-beta1 transcript, staining of TGF-beta1 expression, luciferase reporter assay, and enzyme-linked immunosorbent assay for TGF-beta1 levels were performed at different times after H. pylori infection. RESULTS The TGF-beta1 level was markedly lower in patients with H. pylori-induced gastritis than in patients with a similar degree of gastritis induced by nonsteroidal anti-inflammatory drugs. There was a significant negative correlation between the severity of inflammation and gastric mucosal TGF-beta1 levels. SNU-16 cells showing intact TGF-beta signaling exhibited a marked decrease in TGF-beta1 expression, whereas SNU-638 cells defective in TGF-beta signaling exhibited no such decrease after H. pylori infection. The decreased expressions of TGF-beta1 in SNU-16 cells recovered to normal after 24 hr of H. pylori infection, but lasted very spatial times, suggesting that attenuated expression of TGF-beta1 is a host defense mechanism to avoid attachment of H. pylori. CONCLUSIONS H. pylori infection was associated with depressed gastric mucosal TGF-beta1 for up to 24 hr, but this apparent strategy for rescuing cells from H. pylori attachment exacerbated the gastric inflammation.
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Affiliation(s)
- Yunjeong Jo
- Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea
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41
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Significant association of RUNX3 T/A polymorphism at intron 3 (rs760805) with the risk of gastric atrophy in Helicobacter pylori seropositive Japanese. J Gastroenterol 2010; 44:1165-71. [PMID: 19728008 DOI: 10.1007/s00535-009-0118-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2008] [Accepted: 08/02/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to examine the associations of a RUNX3 T/A polymorphism at exon 1 (Asn18Ile) (rs6672420) and another RUNX3 intronic T/A polymorphism (rs760805) with the risk of gastric cancer together with the risk of H. pylori seropositivity and gastric atrophy in Japanese people. METHODS Study subjects were 583 histologically diagnosed gastric cancer patients and age- and sex-frequency-matched 1,742 control outpatients (among whom 1,637 subjects were eligible for the analyses), who visited Aichi Cancer Center Hospital from 2001 to 2005. Serum pepsinogens were measured to evaluate gastric atrophy. RESULTS There was no significant association between the RUNX3 polymorphisms and the seropositivity. Among H. pylori seropositive subjects, we found a significant association between RUNX3 rs760805 polymorphism and the risk of gastric atrophy with the age- and sex-adjusted OR of 1.51 (95% CI 1.11-2.05, P = 0.008) in T/A, 1.59 (95% CI 1.08-2.33, P = 0.019) in A/A, and 1.53 (95% CI 1.14-2.05, P = 0.004) in T/A + A/A, compared with T/T genotype. We found no statistically significant associations between RUNX3 rs6672420 polymorphism and risk of gastric atrophy, nor between these two RUNX3 polymorphisms and the risk of gastric cancer relative to the subjects with gastric atrophy. CONCLUSIONS Our study results revealed that the RUNX3 intronic T/A polymorphism (rs760805) might modulate the risk of gastric atrophy among H. pylori seropositive subjects, and the RUNX3 T/A polymorphism at exon 1 (rs6672420) had little influence on the risks of H. pylori infection, gastric atrophy or gastric cancer in Japanese people. Further investigation is required to verify our findings.
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Chang TL, Ito K, Ko TK, Liu Q, Salto-Tellez M, Yeoh KG, Fukamachi H, Ito Y. Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells. Gastroenterology 2010; 138:255-65.e1-3. [PMID: 19706291 DOI: 10.1053/j.gastro.2009.08.044] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 08/03/2009] [Accepted: 08/10/2009] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The transcription factor RUNX3 is a gastric tumor suppressor. Tumorigenic Runx3(-/-) gastric epithelial cells attach weakly to each other, compared with nontumorigenic Runx3(+/+) cells. We aimed to identify RUNX3 target genes that promote cell-cell contact to improve our understanding of RUNX3's role in suppressing gastric carcinogenesis. METHODS We compared gene expression profiles of Runx3(+/+) and Runx3(-/-) cells and observed down-regulation of genes associated with cell-cell adhesion in Runx3(-/-) cells. Reporter, mobility shift, and chromatin immunoprecipitation assays were used to examine the regulation of these genes by RUNX3. Tumorigenesis assays and immunohistological analyses of human gastric tumors were performed to confirm the role of the candidate genes in gastric tumor development. RESULTS Mobility shift and chromatin immunoprecipitation assays revealed that the promoter activity of the gene that encodes the tight junction protein claudin-1 was up-regulated via the binding of RUNX3 to the RUNX consensus sites. The tumorigenicity of gastric epithelial cells from Runx3(-/-) mice was significantly reduced by restoration of claudin-1 expression, whereas knockdown of claudin-1 increased the tumorigenicity of human gastric cancer cells. Concomitant expression of RUNX3 and claudin-1 was observed in human normal gastric epithelium and cancers. CONCLUSIONS The tight junction protein claudin-1 has gastric tumor suppressive activity and is a direct transcriptional target of RUNX3. Claudin-1 is down-regulated during the epithelial-mesenchymal transition; RUNX3 might therefore act as a tumor suppressor to antagonize the epithelial-mesenchymal transition.
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Affiliation(s)
- Ti Ling Chang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
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43
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Wu Y, Li ZW, Li JY. Phenotypic classification of well-differentiated gastric adenocarcinoma. Chin J Cancer Res 2009. [DOI: 10.1007/s11670-009-0278-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Korc M. Smad4: gatekeeper gene in head and neck squamous cell carcinoma. J Clin Invest 2009; 119:3208-11. [PMID: 19841540 DOI: 10.1172/jci41230] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Unchecked cell growth is a hallmark of cancer. During oncogenesis, cancerous cells become resistant to the TGF-beta signaling pathway that usually keeps cell growth in check. The role of a critical mediator of this pathway, Smad4, in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this issue of the JCI, Bornstein and colleagues report that Smad4 expression is decreased in malignant HNSCC and, surprisingly, also in normal-appearing buccal mucosa adjacent to HNSCC (see the related article beginning on page 3408). They also show that targeted conditional deletion of Smad4 in the head and neck epithelium of mice is alone sufficient to initiate spontaneous HNSCC, in conjunction with DNA repair gene dysregulation, genetic instability, and inflammation. These findings point to a novel function for Smad4 as a guardian gene that maintains genomic stability.
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Affiliation(s)
- Murray Korc
- Departments of Medicine, Pharmacology, and Toxicology, and Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center,Lebanon, New Hampshire 03755, USA.
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45
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Lee EH, Bae KJ, Kim TK, Park HS, Lee EJ, Kim J. Genetic mutation of transforming growth factor beta type II receptor in oral squamous cell carcinoma. ACTA ACUST UNITED AC 2009. [DOI: 10.1111/j.1755-9294.2009.01046.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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46
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Serum factors potentiate hypoxia-induced hepatotoxicity in vitro through increasing transforming growth factor-β1 activation and release. Cytokine 2009; 47:11-22. [DOI: 10.1016/j.cyto.2009.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Revised: 02/02/2009] [Accepted: 03/10/2009] [Indexed: 01/18/2023]
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47
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Dancea HC, Shareef MM, Ahmed MM. Role of Radiation-induced TGF-beta Signaling in Cancer Therapy. ACTA ACUST UNITED AC 2009; 1:44-56. [PMID: 20336170 DOI: 10.4255/mcpharmacol.09.06] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [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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48
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Chowdhury S, Ammanamanchi S, Howell GM. Epigenetic Targeting of Transforming Growth Factor β Receptor II and Implications for Cancer Therapy. ACTA ACUST UNITED AC 2009; 1:57-70. [PMID: 20414468 DOI: 10.4255/mcpharmacol.09.07] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.
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Affiliation(s)
- Sanjib Chowdhury
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 987696 Nebraska Medical Center, Omaha, Nebraska
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49
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Brown KA, Ham AJL, Clark CN, Meller N, Law BK, Chytil A, Cheng N, Pietenpol JA, Moses HL. Identification of novel Smad2 and Smad3 associated proteins in response to TGF-beta1. J Cell Biochem 2008; 105:596-611. [PMID: 18729074 PMCID: PMC2700048 DOI: 10.1002/jcb.21860] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Transforming growth factor-beta 1 (TGF-beta1) is an important growth inhibitor of epithelial cells and insensitivity to this cytokine results in uncontrolled cell proliferation and can contribute to tumorigenesis. TGF-beta1 signals through the TGF-beta type I and type II receptors, and activates the Smad pathway via phosphorylation of Smad2 and Smad3. Since little is known about the selective activation of Smad2 versus Smad3, we set out to identify novel Smad2 and Smad3 interacting proteins in epithelial cells. A non-transformed human cell line was transduced with Myc-His(6)-Smad2 or Myc-His(6)-Smad3-expressing retrovirus and was treated with TGF-beta1. Myc-His(6)-Smad2 or Myc-His(6)-Smad3 was purified by tandem affinity purification, eluates were subject to SDS-PAGE and Colloidal Blue staining, and select protein bands were digested with trypsin. The resulting tryptic peptides were analyzed by liquid chromatography (LC) and tandem mass spectrometry (MS/MS) and the SEQUEST algorithm was employed to identify proteins in the bands. A number of proteins that are known to interact with Smad2 or Smad3 were detected in the eluates. In addition, a number of putative novel Smad2 and Smad3 associated proteins were identified that have functions in cell proliferation, apoptosis, actin cytoskeleton regulation, cell motility, transcription, and Ras or insulin signaling. Specifically, the interaction between Smad2/3 and the Cdc42 guanine nucleotide exchange factor, Zizimin1, was validated by co-immunoprecipitation. The discovery of these novel Smad2 and/or Smad3 associated proteins may reveal how Smad2 and Smad3 are regulated and/or uncover new functions of Smad2 and Smad3 in TGF-beta1 signaling.
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Affiliation(s)
- Kimberly A. Brown
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
| | - Amy-Joan L. Ham
- Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232
- Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232
| | - Cara N. Clark
- Department of Pathology, Vanderbilt University, Nashville, TN 37232
| | - Nahum Meller
- Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908
| | - Brian K. Law
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610
| | - Anna Chytil
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232
| | - Nikki Cheng
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232
| | - Jennifer A. Pietenpol
- Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232
| | - Harold L. Moses
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232
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Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer 2008; 99:1307-15. [PMID: 18827816 PMCID: PMC2570518 DOI: 10.1038/sj.bjc.6604682] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gene expression profiling is a valuable tool for identifying differentially expressed genes in studies of disease subtype and patient outcome for various cancers. However, it remains difficult to assign biological significance to the vast number of genes. There is an increasing awareness of gene expression profile as an important part of the contextual molecular network at play in complex biological processes such as cancer initiation and progression. This study analysed the transcriptional profiles commonly activated at different stages of gastric cancers using an integrated approach combining gene expression profiling of 222 human tissues and gene regulatory dynamic mapping. We focused on an inferred core network with CDKN1A (p21WAF1/CIP1) as the hub, and extracted seven candidates for gastric carcinogenesis (MMP7, SPARC, SOD2, INHBA, IGFBP7, NEK6, LUM). They were classified into two groups based on the correlation between expression level and stage. The seven genes were commonly activated and their expression levels tended to increase as disease progressed. NEK6 and INHBA are particularly promising candidate genes overexpressed at the protein level, as confirmed by immunohistochemistry and western blotting. This integrated approach could help to identify candidate players in gastric carcinogenesis and progression. These genes are potential markers of gastric cancer regardless of stage.
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