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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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Zhang D, Hua M, Zhang N. LINC01232 promotes lung squamous cell carcinoma progression through modulating miR-181a-5p/SMAD2 axis. Am J Med Sci 2023; 365:386-395. [PMID: 36543302 DOI: 10.1016/j.amjms.2022.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/21/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND LINC01232 has been implicated in the progression of multiple malignancies. Yet, the function of LINC01232 in the carcinogenesis of lung squamous cell carcinoma (LUSC) remains unclear. This study aims to examine the role LINC01232 plays in LUSC progression. METHODS mRNA and protein levels were assessed using qRT-PCR and western blot, respectively. Cell proliferation was assessed by CCK-8 and colony formation assays. Cell migration and invasion were evaluated by transwell assay. The interactions between LINC01232, miR-181a-5p, and SMAD2 were assessed using luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. The subcellular distribution of LINC01232 was examined by cytosolic/nuclear fractionation assay RESULTS: LINC01232 was upregulated in both LUSC tissues and cell lines. Knockdown of LINC01232 impaired cell proliferation, migration and invasion capability in H1229 and A549 cells, a phenotype that could be reversed by miR-181a-5p silencing. In addition, LINC01232 silencing reduced levels of N-cadherin, Vimentin, and Snail in H1229 and A549 cells, but increased the level of E-cadherin, which can be abrogated by miR-181a-5p inhibitors. CONCLUSIONS In summary, our study demonstrates that LINC01232 expression increases in LUSC tissues and cell lines and promotes LUSC progression by modulating the miR-181a-5p/SMAD2 signaling, providing new potential drug targets for LUSC treatment.
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Affiliation(s)
- Dongliang Zhang
- Department of Thoracic Surgery, China Coast Guard Hospital of the People's Armed Police Force, Jiaxing, Zhejiang Province, China
| | - Minglei Hua
- Department of Respiratory Medicine, Xincheng Branch of Zaozhuang Municipal Hospital, Zaozhuang, Shandong Province, China
| | - Nan Zhang
- Department of Medical Oncology, China Coast Guard Hospital of the People's Armed Police Force, Jiaxing, Zhejiang Province, China.
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Ionica E, Gaina G, Tica M, Chifiriuc MC, Gradisteanu-Pircalabioru G. Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients' Stratification. Front Oncol 2022; 11:811486. [PMID: 35198435 PMCID: PMC8859258 DOI: 10.3389/fonc.2021.811486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
In order to ensure that primary endpoints of clinical studies are attained, the patients' stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients' stratification-mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts' diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients' stratification towards a personalized approach of early diagnosis and treatment.
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Affiliation(s)
- Elena Ionica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Gisela Gaina
- Laboratory of Cell Biology, Neuroscience and Experimental Miology, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Mihaela Tica
- Bucharest Emergency University Hospital, Bucharest, Romania
| | - Mariana-Carmen Chifiriuc
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
- Biological Science Division, Romanian Academy of Sciences, Bucharest, Romania
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Brown MA, Ried T. Shifting the Focus of Signaling Abnormalities in Colon Cancer. Cancers (Basel) 2022; 14:784. [PMID: 35159051 PMCID: PMC8834070 DOI: 10.3390/cancers14030784] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/26/2022] [Accepted: 01/30/2022] [Indexed: 12/12/2022] Open
Abstract
Colon cancer tumorigenesis occurs incrementally. The process involves the acquisition of mutations which typically follow an established pattern: activation of WNT signaling, activation of RAS signaling, and inhibition of TGF-β signaling. This arrangement recapitulates, to some degree, the stem cell niche of the intestinal epithelium, which maintains WNT and EGF activity while suppressing TGF-β. The resemblance between the intestinal stem cell environment and colon cancer suggests that the concerted activity of these pathways generates and maintains a potent growth-inducing stimulus. However, each pathway has a myriad of downstream targets, making it difficult to identify which aspects of these pathways are drivers. To address this, we utilize the cell cycle, the ultimate regulator of cell proliferation, as a foundation for cross-pathway integration. We attempt to generate an overview of colon cancer signaling patterns by integrating the major colon cancer signaling pathways in the context of cell replication, specifically, the entrance from G1 into S-phase.
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Affiliation(s)
| | - Thomas Ried
- Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA;
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Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol 2021; 237:59-85. [PMID: 34286853 DOI: 10.1002/jcp.30529] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Transforming growth factor-β (TGF-β) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-β-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-β serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-β signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-β-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-β-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-β as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.
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Affiliation(s)
- Sabreena Aashaq
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
| | - Asiya Batool
- Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Srinagar, JK, India
| | | | | | | | - Zaffar Amin Shah
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
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SMAD-oncoprotein interplay: Potential determining factors in targeted therapies. Biochem Pharmacol 2020; 180:114155. [DOI: 10.1016/j.bcp.2020.114155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/11/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022]
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Calpena E, Cuellar A, Bala K, Swagemakers SMA, Koelling N, McGowan SJ, Phipps JM, Balasubramanian M, Cunningham ML, Douzgou S, Lattanzi W, Morton JEV, Shears D, Weber A, Wilson LC, Lord H, Lester T, Johnson D, Wall SA, Twigg SRF, Mathijssen IMJ, Boardman-Pretty F, Boyadjiev SA, Wilkie AOM. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genet Med 2020; 22:1498-1506. [PMID: 32499606 PMCID: PMC7462747 DOI: 10.1038/s41436-020-0817-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. METHODS We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. RESULTS We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. CONCLUSION Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.
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Affiliation(s)
- Eduardo Calpena
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Araceli Cuellar
- Department of Pediatrics, University of California-Davis, Sacramento, CA, USA
| | - Krithi Bala
- Department of Pediatrics, University of California-Davis, Sacramento, CA, USA
| | - Sigrid M A Swagemakers
- Departments of Pathology and Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Nils Koelling
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Simon J McGowan
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Julie M Phipps
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Michael L Cunningham
- Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Sofia Douzgou
- Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester, UK
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK
| | - Wanda Lattanzi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Jenny E V Morton
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK
| | - Deborah Shears
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
| | - Astrid Weber
- Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK
| | - Louise C Wilson
- Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Helen Lord
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK
| | - Tracy Lester
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK
| | - David Johnson
- Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
| | - Steven A Wall
- Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
| | - Stephen R F Twigg
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Irene M J Mathijssen
- Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Freya Boardman-Pretty
- Genomics England, London, UK
- William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Simeon A Boyadjiev
- Department of Pediatrics, University of California-Davis, Sacramento, CA, USA
| | - Andrew O M Wilkie
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
- Craniofacial Unit, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
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8
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Emmerich AC, Wellstein J, Ossipova E, Baumann I, Lengqvist J, Kultima K, Jakobsson PJ, Steinhilber D, Saul MJ. Proteomics-Based Characterization of miR-574-5p Decoy to CUGBP1 Suggests Specificity for mPGES-1 Regulation in Human Lung Cancer Cells. Front Pharmacol 2020; 11:196. [PMID: 32231562 PMCID: PMC7082395 DOI: 10.3389/fphar.2020.00196] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/13/2020] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs) are one of the most important post-transcriptional repressors of gene expression. However, miR-574-5p has recently been shown to positively regulate the expression of microsomal prostaglandin E-synthase-1 (mPGES-1), a key enzyme in the prostaglandin E2 (PGE2) biosynthesis, by acting as decoy to the RNA-binding protein CUG-RNA binding protein 1 (CUGBP1) in human lung cancer. miR-574-5p exhibits oncogenic properties and promotes lung tumor growth in vivo via induction of mPGES-1-derived PGE2 synthesis. In a mass spectrometry-based proteomics study, we now attempted to characterize this decoy mechanism in A549 lung cancer cells at a cellular level. Besides the identification of novel CUGBP1 targets, we identified that the interaction between miR-574-5p and CUGBP1 specifically regulates mPGES-1 expression. This is supported by the fact that CUGBP1 and miR-574-5p are located in the nucleus, where CUGBP1 regulates alternative splicing. Further, in a bioinformatical approach we showed that the decoy-dependent mPGES-1 splicing pattern is unique. The specificity of miR-574-5p/CUGBP1 regulation on mPGES-1 expression supports the therapeutic strategy of pharmacological inhibition of PGE2 formation, which may provide significant therapeutic value for NSCLC patients with high miR-574-5p levels.
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Affiliation(s)
- Anne C Emmerich
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.,Institute of Pharmaceutical Chemistry, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Julia Wellstein
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.,Institute of Pharmaceutical Chemistry, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Elena Ossipova
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Isabell Baumann
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.,Institute of Pharmaceutical Chemistry, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Johan Lengqvist
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Kim Kultima
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Per-Johan Jakobsson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Meike J Saul
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.,Institute of Pharmaceutical Chemistry, Goethe-Universität Frankfurt, Frankfurt, Germany
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Shi Y, Wang L, Yu P, Liu Y, Chen W. MicroRNA‑486‑5p inhibits the growth of human hypertrophic scar fibroblasts by regulating Smad2 expression. Mol Med Rep 2019; 19:5203-5210. [PMID: 31059039 PMCID: PMC6522886 DOI: 10.3892/mmr.2019.10186] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 11/05/2018] [Indexed: 12/13/2022] Open
Abstract
The aim of the current study was to investigate the expression and role of microRNA-486-5p (miR-486-5p) in hypertrophic scar (HS) formation, and to examine the associated mechanisms. First, miR-486-5p expression was detected in HS tissues and human hypertrophic scar fibroblasts (hHSFs) by reverse transcription-quantitative polymerase chain reaction. Target genes of miR-486-5p were predicted using TargetScan and verified by dual-luciferase reporter assays. To investigate the role of miR-486-5p in HS formation, miR-486-5p was overexpressed in hHSFs through transfection with miR-486-5p mimics. MTT, cell apoptosis and cell cycle assays were preformed to investigate the proliferation, cell apoptosis and cell cycle distribution of hHSFs, respectively. Additionally, protein expression was measured by western blot analysis. The results demonstrated that miR-486-5p expression was significantly decreased in HS tissues and cells. Mothers against decapentaplegic homolog (Smad)2 was a target gene of miR-486-5p, and it was negatively regulated by miR-486-5p. It was also found that Smad2 expression was significantly increased in HS tissues and cells. Further analysis indicated that miR-486-5p mimic transfection inhibited the proliferation, induced cell apoptosis and increased G1/S phase arrest in hHSFs. Furthermore, the expression of cyclin-dependent kinase (CDK)2, CDK4 and apoptosis regulator Bcl-2 was repressed, while apoptosis regulator BAX expression was enhanced by miR-486-5p mimic transfection. Notably, the effects of miR-486-5p mimic on hHSFs were significantly eliminated by Smad2 plasmid transfection. Taken together, these results demonstrated that miR-486-5p inhibited the proliferation, induced apoptosis and increased G1/S phase arrest of hHSFs by targeting Smad2. miR-486-5p may be a promising therapeutic target for HS management.
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Affiliation(s)
- Yingying Shi
- Department of Decorative Plastic Surgery, The Eighth People's Hospital of Shanghai, Jiangsu University, Shanghai 200233, P.R. China
| | - Luping Wang
- Department of Decorative Plastic Surgery, The Eighth People's Hospital of Shanghai, Jiangsu University, Shanghai 200233, P.R. China
| | - Pijun Yu
- Department of Decorative Plastic Surgery, The Eighth People's Hospital of Shanghai, Jiangsu University, Shanghai 200233, P.R. China
| | - Yi Liu
- Department of Decorative Plastic Surgery, The Eighth People's Hospital of Shanghai, Jiangsu University, Shanghai 200233, P.R. China
| | - Wei Chen
- Department of Decorative Plastic Surgery, The Eighth People's Hospital of Shanghai, Jiangsu University, Shanghai 200233, P.R. China
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Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6:869-881. [PMID: 30568941 PMCID: PMC6288499 DOI: 10.12998/wjcc.v6.i15.869] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Maria Borzì
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
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11
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Shi J, Guo K, Su S, Li J, Li C. miR‑486‑5p is upregulated in osteoarthritis and inhibits chondrocyte proliferation and migration by suppressing SMAD2. Mol Med Rep 2018; 18:502-508. [PMID: 29749497 DOI: 10.3892/mmr.2018.8931] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/28/2017] [Indexed: 11/06/2022] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis and is caused by the breakdown of joint cartilage. The present study aimed to investigate an effective method for the treatment of OA. It was demonstrated that, compared with other patients, patients with OA exhibited lower mRNA expression levels of SMAD family member 2 (SMAD2). MicroRNA (miR)‑486‑5p was predicted to bind with SMAD2, which was verified by dual‑luciferase reporter assay. Compared withcontrol patients who had no known history of OA or rheumatoid arthritis, patients with OA exhibited higher miR‑486‑5p expression level. Treatment with miR‑486‑5p mimics inhibited proliferation and migration of CHON‑001 human chondrocytes, and also inhibited the expression levels of type II collagen and aggrecan. However, treatment with a miR‑486‑5p inhibitor promoted proliferation and migration, and the expression of type II collagen and aggrecan. Short interfering RNA‑directed silencing of SMAD2 reversed the upregulated proliferation and migration and the expression level of type II collagen and aggrecan induced by the miR‑486‑5p inhibitor. In conclusion, the results of the present study indicated that miR‑486‑5p was upregulated in OA and may inhibit chondrocyte proliferation and migration by suppressing SMAD2.
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Affiliation(s)
- Junkai Shi
- Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Kansuo Guo
- Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Shile Su
- Department of Orthopedics, Chinese People's Liberation Army No. 149 Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Jun Li
- Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Chunhui Li
- Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
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12
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Jia X, Shanmugam C, Paluri RK, Jhala NC, Behring MP, Katkoori VR, Sugandha SP, Bae S, Samuel T, Manne U. Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer. Oncotarget 2017; 8:20198-20212. [PMID: 28423626 PMCID: PMC5386755 DOI: 10.18632/oncotarget.15560] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/24/2017] [Indexed: 12/24/2022] Open
Abstract
Background Although loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage. Methods Genomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models. Results LOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs. Conclusions LOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.
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Affiliation(s)
- Xu Jia
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chandrakumar Shanmugam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Department of Pathology, ESIC Medical College and Hospital, Sanathnagar, Hyderabad, Telangana, India
| | - Ravi K Paluri
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nirag C Jhala
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Pathology & Laboratory Medicine, Temple University, Philadelphia, PA, USA
| | - Michael P Behring
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Venkat R Katkoori
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA
| | - Shajan P Sugandha
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sejong Bae
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Temesgen Samuel
- College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, USA
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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13
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Jung B, Staudacher JJ, Beauchamp D. Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer. Gastroenterology 2017; 152:36-52. [PMID: 27773809 PMCID: PMC5550896 DOI: 10.1053/j.gastro.2016.10.015] [Citation(s) in RCA: 191] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 09/29/2016] [Accepted: 10/11/2016] [Indexed: 02/07/2023]
Abstract
Transforming growth factor (TGF)-β cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-β family member signaling. We review how TGF-β family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.
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Affiliation(s)
- Barbara Jung
- University of Illinois at Chicago, Chicago, Illinois.
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14
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Kim DH, Chang MS, Yoon CJ, Middeldorp JM, Martinez OM, Byeon SJ, Rha SY, Kim SH, Kim YS, Woo JH. Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells. Oncotarget 2016; 7:82213-82227. [PMID: 27438138 PMCID: PMC5347686 DOI: 10.18632/oncotarget.10511] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 05/12/2016] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV)-encoded BamHI-A rightward frame 1 (BARF1) is a putative viral oncogene in EBV-infected stomach cancer. The aim of the present study was to investigate BARF1-induced cellular protein and microRNA alterations. In this study, BARF1-expressing stomach cancer cells showed a high rate of proliferation, high levels of NFκB, and miR-146a upregulation, which was reversed by NFκB knockdown. During BARF1-induced NFκB upregulation, hCSF1 receptor level was unchanged. Knockdown of BARF1 in the naturally EBV-infected YCCEL1 stomach cancer cells suppressed cell proliferation, and downregulated NFκB and miR-146a. SMAD4 was identified as a miR-146a target and was downregulated in BARF1-expressing cells, whereas SMAD4 expression was restored by anti-miR-146a. Knockdown of BARF1 in YCCEL1 cells upregulated SMAD4, and this effect was reversed by miR-146a overexpression. Transfection of BARF1-expressing cells with pCEP4-SMAD4 abolished the cell proliferating effect of BARF1. In stomach cancer tissues, miR-146a was expressed at higher levels, and more frequent NFκB nuclear positivity immunohistochemically, but not of SMAD4 nuclear loss was found in the EBV-positive group compared with the EBV-negative group. In conclusion, EBV-encoded BARF1 promotes cell proliferation in stomach cancer by upregulating NFκB and miR-146a and downregulating SMAD4, thereby contributing to EBV-induced stomach cancer progression.
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Affiliation(s)
- Dong Ha Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chan Jin Yoon
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaap M. Middeldorp
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Olivia M. Martinez
- Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Sun-ju Byeon
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Han Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yang Soo Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun Hee Woo
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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15
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Prime SS, Davies M, Pring M, Paterson IC. The Role of TGF-β in Epithelial Malignancy and its Relevance to the Pathogenesis of Oral Cancer (Part II). ACTA ACUST UNITED AC 2016; 15:337-47. [PMID: 15574678 DOI: 10.1177/154411130401500603] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The role of transforming growth factor-β (TGF-β) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-β can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-β are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-β signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-β to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.
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Affiliation(s)
- S S Prime
- Department of Oral and Dental Science, Division of Oral Medicine, Pathology and Microbiology, Bristol Dental Hospital and School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, United Kingdom.
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16
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Liu P, Wang C, Ma C, Wu Q, Zhang W, Lao G. MicroRNA-23a regulates epithelial-to-mesenchymal transition in endometrial endometrioid adenocarcinoma by targeting SMAD3. Cancer Cell Int 2016; 16:67. [PMID: 27601936 PMCID: PMC5011925 DOI: 10.1186/s12935-016-0342-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 08/23/2016] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND To investigate the role of total cellular microRNA (miRNA) in regulating epithelial-to-mesenchymal transition (EMT) during human endometrial endometrioid adenocarcinoma (EEC). METHODS A miRCURY LNA microRNA array was used to evaluate the miRNA profiles of human EEC tissues and corresponding nontumorous endometriums. An in vitro model of TGF-β induced EMT in HEC-1-A cells was used to investigate the role of miRNAs in the EEC during EMT. The expression of SMAD3, SMAD5, and a panel of EMT markers was detected by Western blot and quantitative PCR. RESULTS The results of miRNA profiling in human EEC tissues and corresponding nontumorous endometriums demonstrated that miR-23a expression was down-regulated. Using bioinformatics, we identified SMAD3 or SMAD5 maybe as a predicted target of miR-23a. The results of luciferase reporter assay showed miR-23a directly targets and down-regulates human SMAD3 protein levels, not SMAD5 protein levels. Furthermore, overexpression of miR-23a in HEC-1-A cells increased E-cadherin expression and decreased the expression of vimentin and alpha smooth muscle actin, markers of mesenchymal cellular phenotype. CONCLUSIONS Our data provide firm evidence of a role for miR-23a in the direct regulation of EMT through its targeting of SMAD3. Due to its ability to repress the EMT, miR-23a may be a novel target for EER therapeutic intervention.
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Affiliation(s)
- Ping Liu
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
| | - Chao Wang
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
| | - Chengbin Ma
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
| | - Qiongwei Wu
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
| | - Wenying Zhang
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
| | - Guoying Lao
- Gynecology Department, Changning Maternity and Infant Health Hospital, No. 773, Wuyi Road, Changning District, Shanghai, 200051 China
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17
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Ali IHA, Brazil DP. Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. Br J Pharmacol 2016; 171:3620-32. [PMID: 24758361 DOI: 10.1111/bph.12724] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 04/02/2014] [Accepted: 04/08/2014] [Indexed: 12/13/2022] Open
Abstract
Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily of secreted cysteine knot proteins that includes TGFβ1, nodal, activins and inhibins. BMPs were first discovered by Urist in the 1960s when he showed that implantation of demineralized bone into intramuscular tissue of rabbits induced bone and cartilage formation. Since this seminal discovery, BMPs have also been shown to play key roles in several other biological processes, including limb, kidney, skin, hair and neuronal development, as well as maintaining vascular homeostasis. The multifunctional effects of BMPs make them attractive targets for the treatment of several pathologies, including bone disorders, kidney and lung fibrosis, and cancer. This review will summarize current knowledge on the BMP signalling pathway and critically evaluate the potential of recombinant BMPs as pharmacological agents for the treatment of bone repair and tissue fibrosis in patients.
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Affiliation(s)
- Imran H A Ali
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
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18
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Scarfì S. Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair. World J Stem Cells 2016; 8:1-12. [PMID: 26839636 PMCID: PMC4723717 DOI: 10.4252/wjsc.v8.i1.1] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/04/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted cell-type lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.
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Affiliation(s)
- Sonia Scarfì
- Sonia Scarfì, Department of Earth, Environment and Life Sciences, University of Genova, 16132 Genova, Italy
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19
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Hover LD, Abel TW, Owens P. Genomic Analysis of the BMP Family in Glioblastomas. TRANSLATIONAL ONCOGENOMICS 2015; 7:1-9. [PMID: 25987829 PMCID: PMC4406393 DOI: 10.4137/tog.s22256] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/22/2015] [Accepted: 01/29/2015] [Indexed: 12/29/2022]
Abstract
Glioblastoma multiforme (GBM) is a grade IV glioma with a median survival of 15 months. Recently,
bone morphogenetic protein (BMP) signaling has been shown to promote survival in xenograft murine
models. To gain a better understanding of the role of BMP signaling in human GBMs, we examined the
genomic alterations of 90 genes associated with BMP signaling in GBM patient samples. We completed
this analysis using publically available datasets compiled through The Cancer Genome Atlas and the
Glioma Molecular Diagnostic Initiative. Here we show how mRNA expression is altered in GBM samples
and how that is associated with patient survival, highlighting both known and novel associations
between BMP signaling and GBM biology.
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Affiliation(s)
- Laura D Hover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ty W Abel
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Philip Owens
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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20
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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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Abstract
Background Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR. Methods Baseline plasma TGF-β levels of 22 healthy controls and 99 MFS patients, and TGF-β levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up. Results Patients with MFS had higher TGF-β levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p = 0.006). After 1 month of therapy, losartan normalised the TGF-β level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-β. After 3 years of losartan therapy, patients with a decrease in TGF-β had significantly higher AoDR compared with patients with increased TGF-β (1.5 mm/3 years versus 0.5 mm/3 years, p = 0.04). Patients showing a decrease in TGF-β after losartan therapy had significantly elevated baseline TGF-β levels compared with patients with increased TGF-β (189 pg/ml versus 94 pg/ml, p = 0.05). Conclusion Patients responding to losartan therapy with a reduction of the plasma TGF-β level had higher baseline TGF-β levels and a higher AoDR. Most likely, TGF-β levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-β levels in MFS. The concept of TGF-β as initiator of aortic dilatation in MFS patients should be nuanced.
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22
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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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23
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Bell GP, Thompson BJ. Colorectal cancer progression: lessons from Drosophila? Semin Cell Dev Biol 2014; 28:70-7. [PMID: 24583474 DOI: 10.1016/j.semcdb.2014.02.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 02/13/2014] [Indexed: 12/31/2022]
Abstract
Human colorectal cancers arise as benign adenomas, tumours that retain their epithelial character, and then progress to malignant adenocarcinomas and carcinomas in which the epithelium becomes disrupted. Carcinomas often exhibit transcriptional downregulation of E-cadherin and other epithelial genes in an epithelial-to-mesenchymal transition (EMT), a mechanism first discovered in Drosophila to be mediated by the transcription factors Twist and Snail. In contrast, adenocarcinomas retain expression of E-cadherin and disruption of the epithelium occurs through formation of progressively smaller epithelial cysts with apical Crumbs/CRB3, Stardust/PALS1, and Bazooka/PAR3 localised to the inner lumen. Results from Drosophila show that morphologically similar cysts form upon induction of clonal heterogeneity in Wnt, Smad, or Ras signalling levels, which causes extrusion of epithelial cells at clonal boundaries. Thus, intratumour heterogeneity might also promote formation of adenocarcinomas in humans. Finally, epithelial cysts can collectively migrate, as in the case of Drosophila border cells, a potential model system for the invasive migration of adenocarcinoma cells.
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Affiliation(s)
- Graham P Bell
- Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom
| | - Barry J Thompson
- Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom.
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24
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Küry S, Garrec C, Airaud F, Breheret F, Guibert V, Frenard C, Jiao S, Bonneau D, Berthet P, Bossard C, Ingster O, Cauchin E, Bezieau S. Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles. World J Gastroenterol 2014; 20:204-213. [PMID: 24415873 PMCID: PMC3886009 DOI: 10.3748/wjg.v20.i1.204] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 08/07/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the risk associated with variants of the UNC5C gene recently suspected to predispose to familial colorectal cancer (CRC).
METHODS: We screened patients with familial CRC forms as well as patients with sporadic CRCs. In a first time, we analyzed exon 11 of the UNC5C gene in 120 unrelated patients with suspected hereditary CRC, 58 patients with suspected Lynch-associated cancer or polyposis, and 132 index cases of Lynch syndrome families with a characterized mutation in a DNA mismatch repair (MMR). Next, 1023 patients with sporadic CRC and 1121 healthy individuals were screened for the variants identified in patients with familial cancer.
RESULTS: Of 120 patients with familial CRC of unknown etiology, one carried the previously reported mis-sense mutation p.Arg603Cys (R603C) and another exhibited the unreported variant of unknown significance p.Thr617Ile (T617I). The p.Ala628Lys (A628K) mutation previously described as the main UNC5C risk variant for familial CRC was not detected in any cases of familial CRC of unknown etiology, but was present in a patient with familial gastric cancer and in two Lynch syndrome patients in co-occurrence with MMR mutations. A statistically non-significant increase in cancer risk was identified in familial CRC and/or other Lynch-associated cancers (1/178 patients vs 2/1121 healthy controls, OR = 3.2, 95%CI: 0.29-35.05, P = 0.348) and in sporadic CRCs (4/1023 patients vs 2/1121 healthy controls, OR = 2.2, 95%CI: 0.40-12.02, P = 0.364).
CONCLUSION: We confirm that UNC5C mutations are very rare in familial and sporadic CRCs, but further investigations are needed to justify routine UNC5C testing for diagnostic purposes.
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Norris AM, Gore A, Balboni A, Young A, Longnecker DS, Korc M. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 2012; 32:3867-76. [PMID: 22945649 PMCID: PMC3515713 DOI: 10.1038/onc.2012.394] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 07/11/2012] [Accepted: 07/16/2012] [Indexed: 12/14/2022]
Abstract
The mechanisms controlling expression of the putative oncogene AGR2 in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a TGF-β-responsive gene in human pancreatic cancer cells, whose down-regulation is SMAD4-dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is co-expressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-KrasG12D/Smad4lox/lox mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the up-regulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.
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Affiliation(s)
- A M Norris
- Department of Medicine, Dartmouth Medical School, Hanover, NH, USA
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Ge X, Vajjala A, McFarlane C, Wahli W, Sharma M, Kambadur R. Lack of Smad3 signaling leads to impaired skeletal muscle regeneration. Am J Physiol Endocrinol Metab 2012; 303:E90-102. [PMID: 22535746 DOI: 10.1152/ajpendo.00113.2012] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Smad3 is a key intracellular signaling mediator for both transforming growth factor-β and myostatin, two major regulators of skeletal muscle growth. Previous published work has revealed pronounced muscle atrophy together with impaired satellite cell functionality in Smad3-null muscles. In the present study, we have further validated a role for Smad3 signaling in skeletal muscle regeneration. Here, we show that Smad3-null mice had incomplete recovery of muscle weight and myofiber size after muscle injury. Histological/immunohistochemical analysis suggested impaired inflammatory response and reduced number of activated myoblasts during the early stages of muscle regeneration in the tibialis anterior muscle of Smad3-null mice. Nascent myofibers formed after muscle injury were also reduced in number. Moreover, Smad3-null regenerated muscle had decreased oxidative enzyme activity and impaired mitochondrial biogenesis, evident by the downregulation of the gene encoding mitochondrial transcription factor A, a master regulator of mitochondrial biogenesis. Consistent with known Smad3 function, reduced fibrotic tissue formation was also seen in regenerated Smad3-null muscle. In conclusion, Smad3 deficiency leads to impaired muscle regeneration, which underscores an essential role of Smad3 in postnatal myogenesis. Given the negative role of myostatin during muscle regeneration, the increased expression of myostatin observed in Smad3-null muscle may contribute to the regeneration defects.
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MESH Headings
- Animals
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Fibrosis
- Gene Expression Regulation
- Macrophages/immunology
- Male
- Mice
- Mice, Knockout
- Mitochondria, Muscle/metabolism
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism
- Muscle, Skeletal/immunology
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Muscular Atrophy/immunology
- Muscular Atrophy/metabolism
- Muscular Atrophy/pathology
- Myoblasts, Skeletal/enzymology
- Myoblasts, Skeletal/metabolism
- Myoblasts, Skeletal/pathology
- Myogenic Regulatory Factors/genetics
- Myogenic Regulatory Factors/metabolism
- Myostatin/genetics
- Myostatin/metabolism
- Necrosis
- Neutrophil Infiltration
- RNA, Messenger/metabolism
- Satellite Cells, Skeletal Muscle/enzymology
- Satellite Cells, Skeletal Muscle/metabolism
- Satellite Cells, Skeletal Muscle/pathology
- Signal Transduction
- Smad3 Protein/genetics
- Smad3 Protein/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism
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Affiliation(s)
- Xiaojia Ge
- School of Biological Sciences, Nanyang Technological University, Singapore
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27
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Malkoski SP, Wang XJ. Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 2012; 586:1984-92. [PMID: 22321641 DOI: 10.1016/j.febslet.2012.01.054] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 01/26/2012] [Accepted: 01/27/2012] [Indexed: 12/31/2022]
Abstract
TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.
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Affiliation(s)
- Stephen P Malkoski
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
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28
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Liu X, Liu ZP, Zhao XM, Chen L. Identifying disease genes and module biomarkers by differential interactions. J Am Med Inform Assoc 2011; 19:241-8. [PMID: 22190040 DOI: 10.1136/amiajnl-2011-000658] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE A complex disease is generally caused by the mutation of multiple genes or by the dysfunction of multiple biological processes. Systematic identification of causal disease genes and module biomarkers can provide insights into the mechanisms underlying complex diseases, and help develop efficient therapies or effective drugs. MATERIALS AND METHODS In this paper, we present a novel approach to predict disease genes and identify dysfunctional networks or modules, based on the analysis of differential interactions between disease and control samples, in contrast to the analysis of differential gene or protein expressions widely adopted in existing methods. RESULTS AND DISCUSSION As an example, we applied our method to the study of three-stage microarray data for gastric cancer. We identified network modules or module biomarkers that include a set of genes related to gastric cancer, implying the predictive power of our method. The results on holdout validation data sets show that our identified module can serve as an effective module biomarker for accurately detecting or diagnosing gastric cancer, thereby validating the efficiency of our method. CONCLUSION We proposed a new approach to detect module biomarkers for diseases, and the results on gastric cancer demonstrated that the differential interactions are useful to detect dysfunctional modules in the molecular interaction network, which in turn can be used as robust module biomarkers.
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Affiliation(s)
- Xiaoping Liu
- Institute of Systems Biology, Shanghai University, Shanghai, China
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29
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Sclabas GM, Barton JG, Smyrk TC, Barrett DA, Khan S, Kendrick ML, Reid-Lombardo KM, Donohue JH, Nagorney DM, Que FG. Frequency of subtypes of biliary intraductal papillary mucinous neoplasm and their MUC1, MUC2, and DPC4 expression patterns differ from pancreatic intraductal papillary mucinous neoplasm. J Am Coll Surg 2011; 214:27-32. [PMID: 22112419 DOI: 10.1016/j.jamcollsurg.2011.09.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 09/27/2011] [Accepted: 09/30/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Biliary intraductal papillary mucinous neoplasm (B-IPMN) has been proposed as a unique clinicopathologic disease with distinct histopathologic features, although wide acceptance remains controversial. A recent consensus conference classified pancreatic IPMN (P-IPMN) into 4 subtypes (ie, gastric, intestinal, pancreatobiliary, oncocytic) based on morphologic appearance and mucin (MUC) staining properties. The aim of this study was to determine whether B-IPMN has similar histopathologic and immunologic subtypes to P-IPMN. STUDY DESIGN Specific immunostaining for MUC1, MUC2, and deleted for pancreas cancer, locus 4 were performed on specimens from 19 patients with a histopathologic diagnosis of B-IPMN. Immunostaining patterns of B-IPMN were correlated with histopathology. RESULTS Based on histopathology, the following subtypes of B-IPMN were identified: pancreatobiliary n = 9 (47%), intestinal n = 8 (42%), oncocytic n = 2 (11%), and gastric n = 0 (0%). Pancreatobiliary and oncocytic subtypes of B-IPMN were positive for MUC1 and negative for MUC2, and intestinal subtypes were positive for MUC2 and negative for MUC1. Thirteen of the 19 B-IPMN were associated with invasive carcinoma; loss of deleted for pancreas cancer, locus 4 was found in 6 of 13 invasive components and in 3 of 19 noninvasive components of B-IPMN. Five-year survival for patients with resected B-IPMN and invasive carcinoma was 38%, which is similar to that for resected P-IPMN with invasive carcinoma. CONCLUSIONS Histopathologic subtypes and type-specific MUC expression patterns of B-IPMN resemble those of P-IPMN. MUC1 expression and/or absence of MUC2 expression, which correlate with aggressive features of P-IPMN, were found in B-IPMN and correlate with invasive B-IPMN. Loss of deleted for pancreas cancer, locus 4 parallels the findings observed in P-IPMN. These findings provide additional support that B-IPMN is a unique entity with similarities to main duct P-IPMN.
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Affiliation(s)
- Guido M Sclabas
- Division of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN 55905, USA
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30
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Beggs AD, Hodgson SV. The genomics of colorectal cancer: state of the art. Curr Genomics 2011; 9:1-10. [PMID: 19424478 PMCID: PMC2674304 DOI: 10.2174/138920208783884865] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Revised: 02/07/2008] [Accepted: 02/09/2008] [Indexed: 01/12/2023] Open
Abstract
The concept of the adenoma-carcinoma sequence, as first espoused by Morson et al. whereby the development of colorectal cancer is dependent on a stepwise progression from adenomatous polyp to carcinoma is well documented. Initial studies of the genetics of inherited colorectal cancer susceptibility concentrated on the inherited colorectal cancer syndromes, such as Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (also known as HNPCC). These syndromes, whilst easily characterisable, have a well understood sequence of genetic mutations that predispose the sufferer to developing colorectal cancer, initiated for example in FAP by the loss of the second, normal allelle of the tumour supressor APC gene. Later research has identified other inherited variants such as MUTYH (MYH) polyposis and Hyperplastic Polyposis Syndrome. Recent research has concentrated on the pathways by which colorectal adenomatous polyps not due to one of these known inherited susceptibilities undergo malignant transformation, and determination of the types of polyps most likely to do so. Also, why do individuals in certain families have a predisposition to colorectal cancer. In this article, we will discuss briefly the current state of knowledge of the genomics of the classical inherited colorectal cancer syndromes. We will also discuss in detail the genetic changes in polyps that undergo malignant transformation as well as current knowledge with regards to the epigenomic changes found in colorectal polyps.
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Affiliation(s)
- Andrew D Beggs
- Section of Medical Genetics, St. Georges University of London, London, UK
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31
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Cao Y, Gao X, Zhang W, Zhang G, Nguyen AK, Liu X, Jimenez F, Cox CS, Townsend CM, Ko TC. Dietary fiber enhances TGF-β signaling and growth inhibition in the gut. Am J Physiol Gastrointest Liver Physiol 2011; 301:G156-64. [PMID: 21454444 PMCID: PMC3129933 DOI: 10.1152/ajpgi.00362.2010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Accepted: 03/23/2011] [Indexed: 02/06/2023]
Abstract
Dietary fiber intake links to decreased risk of colorectal cancers. The underlying mechanisms remain unclear. Recently, we found that butyrate, a short-chain fatty acid produced in gut by bacterial fermentation of dietary fiber, enhances TGF-β signaling in rat intestinal epithelial cells (RIE-1). Furthermore, TGF-β represses inhibitors of differentiation (Ids), leading to apoptosis. We hypothesized that dietary fiber enhances TGF-β's growth inhibitory effects on gut epithelium via inhibition of Id2. In this study, Balb/c and DBA/2N mice were fed with a regular rodent chow or supplemented with a dietary fiber (20% pectin) and Smad3 level in gut epithelium was measured. In vitro, RIE-1 cells were treated with butyrate and TGF-β(1), and cell functions were evaluated. Furthermore, the role of Ids in butyrate- and TGF-β-induced growth inhibition was investigated. We found that pectin feeding increased Smad3 protein levels in the jejunum (1.47 ± 0.26-fold, P = 0.045, in Balb/c mice; 1.49 ± 0.19-fold, P = 0.016, in DBA/2N mice), and phospho-Smad3 levels (1.92 ± 0.27-fold, P = 0.009, in Balb/c mice; 1.83 ± 0.28-fold, P = 0.022, in DBA/2N mice). Butyrate or TGF-β alone inhibited cell growth and induced cell cycle arrest. The combined treatment of butyrate and TGF-β synergistically induced cell cycle arrest and apoptosis in RIE-1 cells and repressed Id2 and Id3 levels. Furthermore, knockdown of Id2 gene expression by use of small interfering RNA caused cell cycle arrest and apoptosis. We conclude that dietary fiber pectin enhanced Smad3 expression and activation in the gut. Butyrate and TGF-β induced cell cycle arrest and apoptosis, which may be mediated by repression of Id2. Our results implicate a novel mechanism of dietary fiber in reducing the risk of colorectal cancer development.
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Affiliation(s)
- Yanna Cao
- Department of Surgery, University of Texas Health Science Center at Houston, 77026, USA
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32
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Bordonaro M, Tewari S, Atamna W, Lazarova DL. The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways. Exp Cell Res 2011; 317:1368-81. [PMID: 21473864 PMCID: PMC3097118 DOI: 10.1016/j.yexcr.2011.03.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 02/25/2011] [Accepted: 03/30/2011] [Indexed: 12/31/2022]
Abstract
Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.
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Affiliation(s)
- Michael Bordonaro
- Department of Basic Sciences, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA
| | - Shruti Tewari
- Department of Basic Sciences, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA
| | - Wafa Atamna
- Department of Basic Sciences, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA
| | - Darina L. Lazarova
- Department of Basic Sciences, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA
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33
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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 PMCID: PMC3075468 DOI: 10.1158/0008-5472.can-09-3269] [Citation(s) in RCA: 175] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [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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MESH Headings
- Cell Hypoxia/genetics
- Cell Movement/genetics
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colonic Neoplasms/blood supply
- Colonic Neoplasms/drug therapy
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Drug Resistance, Neoplasm
- Fluorouracil/pharmacology
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- HCT116 Cells
- Humans
- Matrix Metalloproteinase 9/metabolism
- Neoplasm Metastasis
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Protein Serine-Threonine Kinases/metabolism
- Receptor, Transforming Growth Factor-beta Type II
- Receptors, Transforming Growth Factor beta/metabolism
- Smad4 Protein/biosynthesis
- Smad4 Protein/genetics
- Smad4 Protein/metabolism
- Transforming Growth Factor beta/metabolism
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/biosynthesis
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Affiliation(s)
- Panagiotis Papageorgis
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
- Genetics & Genomics Graduate Program, Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
| | - Kuanghung Cheng
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
- Department of Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
| | - Sait Ozturk
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
| | - Yi Gong
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, DA-805 Boston, MA 02215
| | - Arthur W. Lambert
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
| | - Hamid M. Abdolmaleky
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
- Genetics & Genomics Graduate Program, Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
| | - Jin-Rong Zhou
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, DA-805 Boston, MA 02215
| | - Sam Thiagalingam
- Department of Medicine (Genetics & Molecular Medicine Programs and Cancer Center), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
- Genetics & Genomics Graduate Program, Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
- Department of Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118
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Patel VB, Misra S, Patel BB, Majumdar APN. Colorectal cancer: chemopreventive role of curcumin and resveratrol. Nutr Cancer 2011; 62:958-67. [PMID: 20924971 DOI: 10.1080/01635581.2010.510259] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or without chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma-carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents-curcumin and resveratrol-for chemoprevention of CRC.
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Affiliation(s)
- Vaishali B Patel
- Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201, USA
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35
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Sameer AS, Chowdri NA, Syeed N, Banday MZ, Shah ZA, Siddiqi MA. SMAD4--molecular gladiator of the TGF-beta signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene. BMC Cancer 2010; 10:300. [PMID: 20565773 PMCID: PMC2927996 DOI: 10.1186/1471-2407-10-300] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2009] [Accepted: 06/17/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of SMAD4 gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and KRAS mutant genotype. METHODS We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of SMAD4 and exon 1 of KRAS by PCR-SSCP and/or PCR-Direct sequencing. RESULTS The overall mutation rate of mutation cluster region (MCR) region of SMAD4 gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the SMAD4 gene mutants were found to have mutations in KRAS gene as well. The association between the KRAS mutant genotype with SMAD4 mutants was found to be significant (P = or < 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the SMAD4 gene (P = or < 0.05). CONCLUSION Our study suggests that SMAD4 gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the KRAS mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.
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Affiliation(s)
- A Syed Sameer
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nissar A Chowdri
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Nidda Syeed
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mujeeb Z Banday
- Department of Biotechnology, Kashmir University, Hazratbal, Srinagar, Kashmir, India. 190006
| | - Zaffar A Shah
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
| | - Mushtaq A Siddiqi
- Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. 190011
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36
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Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2010. [PMID: 20018966 DOI: 10.1056/ne] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Sanford D Markowitz
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, USA.
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37
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Affiliation(s)
- Sanford D Markowitz
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, USA.
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38
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Chaudhury A, Howe PH. The tale of transforming growth factor-beta (TGFbeta) signaling: a soigné enigma. IUBMB Life 2009; 61:929-39. [PMID: 19787707 DOI: 10.1002/iub.239] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor-beta (TGFbeta) is a secreted cytokine, which intricately controls a plethora of physiological and pathological processes during development and carcinogenesis. TGFbeta exerts antiproliferative effects and functions as a tumor suppressor during early stages of tumorigenesis, whereas at later stages it functions as a tumor promoter aiding in metastatic progression through an autocrine TGFbeta loop. Intricate knowledge of TGFbeta signaling and its regulation are still evolving. In this review, we make an attempt to showcase the associated enigma of TGFbeta signaling in its dual functional role as tumor suppressor and metastatic promoter during early and late stages of carcinogenesis, respectively.
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Affiliation(s)
- Arindam Chaudhury
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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39
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Matsuzaki K, Kitano C, Murata M, Sekimoto G, Yoshida K, Uemura Y, Seki T, Taketani S, Fujisawa JI, Okazaki K. Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer. Cancer Res 2009; 69:5321-30. [PMID: 19531654 DOI: 10.1158/0008-5472.can-08-4203] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Transforming growth factor (TGF)-beta initially inhibits growth of mature epithelial cells. Later, however, autocrine TGF-beta signaling acts in concert with the Ras pathway to induce a proliferative and invasive phenotype. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also Ras-associated kinases, which differentially phosphorylate the mediators Smad2 and Smad3 to create distinct phosphorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C) and both linker and COOH-terminally phosphorylated Smad2/3 (pSmad2L/C and pSmad3L/C). In this study, we investigated actions of pSmad2L/C and pSmad3L/C in cancer progression. TGF-beta inhibited cell growth by down-regulating c-Myc oncoprotein through the pSmad2C and pSmad3C pathway; TGF-beta signaling, in turn, enhanced cell growth by up-regulating c-Myc through the cyclin-dependent kinase (CDK) 4-dependent pSmad2L/C and pSmad3L/C pathways in cell nuclei. Alternatively, TbetaRI and c-Jun NH2-terminal kinase (JNK) together created cytoplasmic pSmad2L/C, which entered the nucleus and stimulated cell invasion, partly by up-regulating matrix metalloproteinase-9. In 20 clinical samples, pSmad2L/C and pSmad3L/C showed nuclear localization at invasion fronts of all TGF-beta-producing human metastatic colorectal cancers. In vitro kinase assay confirmed that nuclear CDK4 and cytoplasmic JNK obtained from the tumor tissue could phosphorylate Smad2 or Smad3 at their linker regions. We suggest that CDK4, together with JNK, alters tumor-suppressive TGF-beta signaling to malignant characteristics in later stages of human colorectal cancer. The linker phosphorylation of Smad2 and Smad3 may represent a target for intervention in human metastatic cancer.
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Affiliation(s)
- Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan.
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40
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Lin X, Chen Y, Meng A, Feng X. Termination of TGF-beta superfamily signaling through SMAD dephosphorylation--a functional genomic view. J Genet Genomics 2009; 34:1-9. [PMID: 17469772 DOI: 10.1016/s1673-8527(07)60001-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2006] [Accepted: 10/31/2006] [Indexed: 12/11/2022]
Abstract
The transforming growth factor-beta (TGF-beta) and related growth factors activate a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. They play key roles in the pathogenesis of many diseases especially cancer, fibrotic diseases, autoimmune diseases and cardiovascular diseases. TGF-beta receptor-mediated phosphorylation of R-SMADs represents the most critical step in the TGF-beta signaling pathways that triggers a cascade of intracellular events from SMAD complex assembly in the cytoplasm to transcriptional control in the nucleus. Conversely, dephosphorylation of R-SMADs is a key mechanism for terminating TGF-beta signaling. Our labs have recently taken an integrated approach combining functional genomics, biochemistry and development biology to describe the isolation and functional characterization of protein phosphatase PPM1A in controlling TGF-beta signaling. This article briefly reviews how dynamic phosphorylation and dephosphorylation of SMADs control or fine-tune the signaling strength and duration and ultimately the physiological consequences in TGF-beta signaling.
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Affiliation(s)
- Xia Lin
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston TX 77030, USA
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41
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Sampieri K, Amenduni M, Papa FT, Katzaki E, Mencarelli MA, Marozza A, Epistolato MC, Toti P, Lazzi S, Bruttini M, De Filippis R, De Francesco S, Longo I, Meloni I, Mari F, Acquaviva A, Hadjistilianou T, Renieri A, Ariani F. Array comparative genomic hybridization in retinoma and retinoblastoma tissues. Cancer Sci 2009; 100:465-71. [PMID: 19183342 PMCID: PMC11159683 DOI: 10.1111/j.1349-7006.2008.01070.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In retinoblastoma, two RB1 mutations are necessary for tumor development. Recurrent genomic rearrangements may represent subsequent events required for retinoblastoma progression. Array-comparative genomic hybridization was carried out in 18 eye samples, 10 from bilateral and eight from unilateral retinoblastoma patients. Two unilateral cases also showed areas of retinoma. The most frequent imbalance in retinoblastomas was 6p gain (40%), followed by gains at 1q12-q25.3, 2p24.3-p24.2, 9q22.2, and 9q33.1 and losses at 11q24.3, 13q13.2-q22.3, and 16q12.1-q21. Bilateral cases showed a lower number of imbalances than unilateral cases (P = 0.002). Unilateral cases were divided into low-level (< or = 4) and high-level (> or = 7) chromosomal instability groups. The first group presented with younger age at diagnosis (mean 511 days) compared with the second group (mean 1606 days). In one retinoma case ophthalmoscopically diagnosed as a benign lesion no rearrangements were detected, whereas the adjacent retinoblastoma displayed seven aberrations. The other retinoma case identified by retrospective histopathological examination shared three rearrangements with the adjacent retinoblastoma. Two other gene-free rearrangements were retinoma specific. One rearrangement, dup5p, was retinoblastoma specific and included the SKP2 gene. Genomic profiling indicated that the first retinoma was a pretumoral lesion, whereas the other represents a subclone of cells bearing 'benign' rearrangements overwhelmed by another subclone presenting aberrations with higher 'oncogenic' potential. In summary, the present study shows that bilateral and unilateral retinoblastoma have different chromosomal instability that correlates with the age of tumor onset in unilateral cases. This is the first report of genomic profiling in retinoma tissue, shedding light on the different nature of lesions named 'retinoma'.
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Affiliation(s)
- Katia Sampieri
- Medical Genetics, Department of Molecular Biology, University of Siena, Policlinico Le Scotte, Siena, Italy
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42
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Yang SM, Guo WW, Hu YY, Sun YX, Hou ZH, Sun JH, Wang X, He DZ, Zhai SQ, Young WY, Han DY, Yang X. Smad5 haploinsufficiency leads to hair cell and hearing loss. Dev Neurobiol 2009; 69:153-61. [DOI: 10.1002/dneu.20692] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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43
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Sakai Y, Honda M, Fujinaga H, Tatsumi I, Mizukoshi E, Nakamoto Y, Kaneko S. Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Res 2009; 68:10267-79. [PMID: 19074895 DOI: 10.1158/0008-5472.can-08-0911] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is frequently associated with infiltrating mononuclear inflammatory cells. We performed laser capture microdissection of HCC-infiltrating and noncancerous liver-infiltrating mononuclear inflammatory cells in patients with chronic hepatitis C (CH-C) and examined gene expression profiles. HCC-infiltrating mononuclear inflammatory cells had an expression profile distinct from noncancerous liver-infiltrating mononuclear inflammatory cells; they differed with regard to genes involved in biological processes, such as antigen presentation, ubiquitin-proteasomal proteolysis, and responses to hypoxia and oxidative stress. Immunohistochemical analysis and gene expression databases suggested that the up-regulated genes involved macrophages and Th1 and Th2 CD4 cells. We next examined the gene expression profile of peripheral blood mononuclear cells (PBMC) obtained from CH-C patients with or without HCC. The expression profiles of PBMCs from patients with HCC differed significantly from those of patients without HCC (P < 0.0005). Many of the up-regulated genes in HCC-infiltrating mononuclear inflammatory cells were also differentially expressed by PBMCs of HCC patients. Analysis of the commonly up-regulated or down-regulated genes in HCC-infiltrating mononuclear inflammatory cells and PBMCs of HCC patients showed networks of nucleophosmin, SMAD3, and proliferating cell nuclear antigen that are involved with redox status, the cell cycle, and the proteasome system, along with immunologic genes, suggesting regulation of anticancer immunity. Thus, exploring the gene expression profile of PBMCs may be a surrogate approach for the assessment of local HCC-infiltrating mononuclear inflammatory cells.
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Affiliation(s)
- Yoshio Sakai
- Department of Gastroenterology, Kanazawa University, School of Medicine, Kanazawa, Japan
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Abstract
The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.
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Affiliation(s)
- Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
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Smith JJ, Deane NG, Dhawan P, Beauchamp RD. Regulation of metastasis in colorectal adenocarcinoma: a collision between development and tumor biology. Surgery 2008; 144:353-66. [PMID: 18707034 PMCID: PMC2594010 DOI: 10.1016/j.surg.2008.05.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2008] [Accepted: 05/08/2008] [Indexed: 01/29/2023]
Affiliation(s)
- J. Joshua Smith
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Natasha G. Deane
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN
- Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
- Department of Radiology and the Vanderbilt Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN
| | - Punita Dhawan
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN
- Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - R. Daniel Beauchamp
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN
- Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN
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Lurje G, Zhang W, Lenz HJ. Molecular prognostic markers in locally advanced colon cancer. Clin Colorectal Cancer 2008; 6:683-90. [PMID: 18039421 DOI: 10.3816/ccc.2007.n.037] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
For patients who undergo successful surgery for colon cancer, additional chemotherapy is recommended in high-risk stage II and stage III disease. Colorectal cancer prognosis is stage and grade dependent, and many tumors with similar histopathologic features show significantly different clinical outcomes. Therefore, tumor recurrence after curative resection continues to be a significant problem in the management of colon cancer, and approximately 50% of patients will develop recurrent disease. There are a few clinical and potential molecular markers that can predict clinical outcome in locally advanced colon cancer. Accordingly, the development of molecular markers of prognosis is critical in making a tailored adjuvant treatment with molecular stratification possible. Many new biomarkers have been investigated; however, none of them have yet been validated in large prospective clinical trials. To date, the two most promising and most studied mechanisms of genomic instability are chromosomal instability with deletion of chromosome 18q and 17p and microsatellite instability (MSI). Eastern Cooperative Oncology Group 5202 is a prospective clinical trial which is randomizing patients with stage II disease based on their MSI and 18q status to observation versus adjuvant chemotherapy with the intention of prospectively determining their prognostic value as molecular markers. This review will discuss the most promising molecular prognostic markers and provide an update on the most recent developments.
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Affiliation(s)
- Georg Lurje
- Division of Medical Oncology, Sharon A. Carpenter Laboratory, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA
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Kodach LL, Bleuming SA, Musler AR, Peppelenbosch MP, Hommes DW, van den Brink GR, van Noesel CJM, Offerhaus GJA, Hardwick JCH. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer 2008; 112:300-6. [PMID: 18008360 DOI: 10.1002/cncr.23160] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Transforming growth factor beta (TGFbeta) is important in colorectal cancer (CRC) progression. Bone morphogenetic proteins (BMPs), a subgroup within the TGFbeta superfamily, recently also have been implicated in CRC, but their precise role in CRC has yet to be investigated. METHODS The authors used a tissue microarray and immunohistochemistry of BMP receptors and signal transduction elements in adenomas and CRC specimens to elucidate the role of BMP signaling in CRC carcinogenesis. RESULTS The adenoma specimens expressed all 3 BMP receptors (BMPRs) (BMPR type 1a [BMPR1a], BMPR1b, and BMPR2) and expressed SMAD family member 4 (SMAD4); and 20 of 22 adenomas (90.9%) exhibited active BMP signaling, as determined by nuclear phosphorylated SMAD1,5,8 (pSMAD1,5,8) expression. In contrast, pSMAD1,5,8 nuclear staining was present in 5 CRC specimens (22.7%) but was lost in 17 CRC specimens (77.3%; cancer vs adenoma; P< .0001). The earliest loss of pSMAD1,5,8 nuclear staining was detected in regions of high-grade dysplasia/carcinoma in situ within adenomas. CRCs showed frequent loss of BMPR2 (P< .0001) and SMAD4 (P< .01) compared with adenomas. Negative expression of BMPR2 was observed more frequently in earlier stage cancers (Dukes stage B) than in advanced cancers (Dukes stage C; P< .05). CONCLUSIONS Taken together, the current results indicated that loss of BMP signaling correlates tightly with progression of adenomas to cancer and occurs relatively early during cancer progression.
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Affiliation(s)
- Liudmila L Kodach
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
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Baugé C, Legendre F, Leclercq S, Elissalde JM, Pujol JP, Galéra P, Boumédiene K. Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. ACTA ACUST UNITED AC 2007; 56:3020-32. [PMID: 17763417 DOI: 10.1002/art.22840] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1beta (IL-1beta) and transforming growth factor beta1 (TGFbeta1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1beta on TGFbeta receptor type II (TGFbetaRII) regulation and TGFbeta1 responsiveness in human articular chondrocytes. METHODS TGFbeta1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (R-Smad) phosphorylation, TGFbeta receptors, and Smad expression were determined by Western blotting and real-time reverse transcription-polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors. RESULTS IL-1beta down-regulated TGFbetaRII expression at both the protein and mRNA levels and led to inhibition of the TGFbeta1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1beta strongly stimulated the expression of inhibitory Smad7. TGFbetaRII overexpression abolished the loss of TGFbeta1 responsiveness induced by IL-1beta. The decrease in TGFbetaRII required de novo protein synthesis and involved both the NF-kappaB and JNK pathways. CONCLUSION We demonstrate that IL-1beta impairs TGFbeta1 signaling through down-regulation of TGFbetaRII, which is mediated by the p65/NF-kappaB and activator protein 1/JNK pathways, and secondarily through the up-regulation of Smad7. These findings show that there is cross-talk in the signaling of 2 regulatory cytokines involved in inflammation.
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Affiliation(s)
- C Baugé
- University of Caen Lower Normandy, Caen, France
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Loverde PT, Osman A, Hinck A. Schistosoma mansoni: TGF-beta signaling pathways. Exp Parasitol 2007; 117:304-17. [PMID: 17643432 PMCID: PMC2149906 DOI: 10.1016/j.exppara.2007.06.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Revised: 05/25/2007] [Accepted: 06/05/2007] [Indexed: 10/23/2022]
Abstract
Schistosome parasites have co-evolved an intricate relationship with their human and snail hosts as well as a novel interplay between the adult male and female parasites. We review the role of the TGF-beta signaling pathway in parasite development, host-parasite interactions and male-female interactions. The data to date support multiple roles for the TGF-beta signaling pathway throughout schistosome development, in particular, in the tegument which is at the interface with the host and between the male and female schistosome, development of vitelline cells in female worms whose genes and development are regulated by a stimulus from the male schistosome and embryogenesis of the egg. The human ligand TGF-beta1 has been demonstrated to regulate the expression of a schistosome target gene that encodes a gynecophoric canal protein in the schistosome worm itself. Studies on signaling in schistosomes opens a new era for investigation of host-parasite and male-female interactions.
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Affiliation(s)
- Philip T Loverde
- Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
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50
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Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A. TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer 2007; 7:156. [PMID: 17692120 PMCID: PMC1988827 DOI: 10.1186/1471-2407-7-156] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2006] [Accepted: 08/10/2007] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited. METHODS Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed. RESULTS High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival. CONCLUSION Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.
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Affiliation(s)
- David Bacman
- Institute of Pathology, University of Erlangen-Nuremberg, Germany
| | - Susanne Merkel
- Department of Surgery, University of Erlangen-Nuremberg, Germany
| | - Roland Croner
- Department of Surgery, University of Erlangen-Nuremberg, Germany
| | | | - Wolfgang Brueckl
- Department of Internal Medicine I, University of Erlangen-Nuremberg, Germany
| | - Arno Dimmler
- Institute of Pathology, St. Vincentius hospital, Karlsruhe, Germany
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