Inhibition of extracellular matrix mediated TGF-β signalling suppresses endometrial cancer metastasis
| Autor: | Murray J. Cairns, Joshua R. Atkins, Min Yuan Quah, Sarah Nielsen, Gough G. Au, Pradeep S. Tanwar, Subhransu S. Sahoo, Pravin Nahar, Janine M. Lombard |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
SMAD Metastasis Extracellular matrix 03 medical and health sciences 0302 clinical medicine Medicine metastasis ECM biology business.industry Endometrial cancer TGF-β signalling medicine.disease microenvironment Fibronectin 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Immunology endometrial cancer Cancer research biology.protein business Biomedical sciences Transforming growth factor Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Subhransu S. Sahoo 1 , Min Yuan Quah 2 , Sarah Nielsen 3 , Joshua Atkins 4 , Gough G. Au 2 , Murray J. Cairns 4 , Pravin Nahar 5 , Janine M. Lombard 6 and Pradeep S. Tanwar 1 1 Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 2 The Picornaviral Research Unit, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 3 Hunter Cancer Biobank, University of Newcastle, Callaghan, New South Wales, Australia 4 Discipline of Pharmacy and Experimental Pharmacology, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 5 Department of Maternity and Gynaecology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia 6 Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia Correspondence to: Pradeep S. Tanwar, email: // Keywords : microenvironment, ECM, endometrial cancer, TGF-β signalling, metastasis Received : May 05, 2017 Accepted : May 07, 2017 Published : May 22, 2017 Abstract Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-β signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-β pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-β signalling in non-glandular colonies. Importantly, alteration of TGF-β pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-β pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-β signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells. |
| Databáze: | OpenAIRE |
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