Transcriptional Upregulation of C-MET is Associated with Invasion and Tumor Budding in Colorectal Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Oct 30

PMID 27793046

Citations 22

Authors

Conor A Bradley

Philip D Dunne

Victoria Bingham

Stephen McQuaid

Hajrah Khawaja

Stephanie Craig

Jackie James

Wendy L Moore

Darragh G McArt

Mark Lawler

Sonali Dasgupta

Patrick G Johnston

Sandra Van Schaeybroeck

Affiliations

Soon will be listed here.

Abstract

c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity. Importantly, HGF-induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered. Using RNA in situ hybridization (RNA ISH), we further showed that MET mRNA, but not protein levels, were significantly upregulated in tumor budding foci at the invasive front of a cohort of stage III CRC tumors (p < 0.001). Taken together, we show for the first time that transcriptional upregulation of MET is a key molecular event associated with CRC invasion and tumor budding. This data also indicates that RNA ISH, but not immunohistochemistry, provides a robust methodology to assess MET levels as a potential driving force of CRC tumor invasion and metastasis.

Citing Articles

Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.

Shakhpazyan N, Mikhaleva L, Bedzhanyan A, Gioeva Z, Sadykhov N, Mikhalev A Biomedicines. 2023; 11(9).

PMID: 37760801 PMC: 10525158. DOI: 10.3390/biomedicines11092361.

Relationship between Tumor Budding and Partial Epithelial-Mesenchymal Transition in Head and Neck Cancer.

Okuyama K, Suzuki K, Yanamoto S Cancers (Basel). 2023; 15(4).

PMID: 36831453 PMC: 9953904. DOI: 10.3390/cancers15041111.

Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer.

Khawaja H, Briggs R, Latimer C, Rassel M, Griffin D, Hanson L Mol Cancer Ther. 2022; 22(1):135-149.

PMID: 36279564 PMC: 9808374. DOI: 10.1158/1535-7163.MCT-22-0301.

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide.

Novoa Diaz M, Carriere P, Gigola G, Zwenger A, Calvo N, Gentili C World J Gastroenterol. 2022; 28(26):3177-3200.

PMID: 36051345 PMC: 9331538. DOI: 10.3748/wjg.v28.i26.3177.

Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours.

Nestler T, Dalvi P, Haidl F, Wittersheim M, von Brandenstein M, Paffenholz P Br J Cancer. 2022; 126(6):937-947.

PMID: 35022523 PMC: 8927344. DOI: 10.1038/s41416-021-01621-5.

References

Ichimura E, Maeshima A, Nakajima T, Nakamura T . Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res. 1996; 87(10):1063-9. PMC: 5920996. DOI: 10.1111/j.1349-7006.1996.tb03111.x. View

Joyce J, Pollard J . Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009; 9(4):239-52. PMC: 3251309. DOI: 10.1038/nrc2618. View

Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T . Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005; 5(9):744-9. DOI: 10.1038/nrc1694. View

Fodde R, Brabletz T . Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007; 19(2):150-8. DOI: 10.1016/j.ceb.2007.02.007. View

Wang L, Kevans D, Mulcahy H, OSullivan J, Fennelly D, Hyland J . Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol. 2008; 33(1):134-41. DOI: 10.1097/PAS.0b013e318184cd55. View

Sadanandam A, Lyssiotis C, Homicsko K, Collisson E, Gibb W, Wullschleger S . A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013; 19(5):619-25. PMC: 3774607. DOI: 10.1038/nm.3175. View

Wikberg M, Edin S, Lundberg I, van Guelpen B, Dahlin A, Rutegard J . High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol. 2013; 34(2):1013-20. PMC: 3597266. DOI: 10.1007/s13277-012-0638-2. View

Seiden-Long I, Brown K, Shih W, Wigle D, Radulovich N, Jurisica I . Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. Oncogene. 2005; 25(1):91-102. DOI: 10.1038/sj.onc.1209005. View

Haggar F, Boushey R . Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2010; 22(4):191-7. PMC: 2796096. DOI: 10.1055/s-0029-1242458. View

10.

Brabletz T . To differentiate or not--routes towards metastasis. Nat Rev Cancer. 2012; 12(6):425-36. DOI: 10.1038/nrc3265. View

11.

Di Renzo M, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L . Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1995; 1(2):147-54. View

12.

de Oliveira A, Matos D, Logullo A, Morini da Silva S, Artigiani Neto R, Longatto Filho A . MET Is highly expressed in advanced stages of colorectal cancer and indicates worse prognosis and mortality. Anticancer Res. 2009; 29(11):4807-11. View

13.

Furlan A, Kherrouche Z, Montagne R, Copin M, Tulasne D . Thirty years of research on met receptor to move a biomarker from bench to bedside. Cancer Res. 2014; 74(23):6737-44. DOI: 10.1158/0008-5472.CAN-14-1932. View

14.

Garcia S, Dales J, Charafe-Jauffret E, Carpentier-Meunier S, Andrac-Meyer L, Jacquemier J . Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. Hum Pathol. 2007; 38(6):830-41. DOI: 10.1016/j.humpath.2006.11.015. View

15.

Brabletz S, Schmalhofer O, Brabletz T . Gastrointestinal stem cells in development and cancer. J Pathol. 2008; 217(2):307-17. DOI: 10.1002/path.2475. View

16.

Del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F, Chakravarty P . Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization. Cell Rep. 2015; 13(11):2456-2469. PMC: 4695340. DOI: 10.1016/j.celrep.2015.11.025. View

17.

Sierra J, Tsao M . c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011; 3(1 Suppl):S21-35. PMC: 3225018. DOI: 10.1177/1758834011422557. View

18.

Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M . c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res. 2003; 9(4):1480-8. View

19.

Wilson T, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E . Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012; 487(7408):505-9. PMC: 3724525. DOI: 10.1038/nature11249. View

20.

. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-7. PMC: 3401966. DOI: 10.1038/nature11252. View