Top

Published in:

01-08-2008 | Original Contribution

The Prognostic Significance of RON and MET Receptor Coexpression in Patients with Colorectal Cancer

Authors: Chung-Ta Lee, M.D., Nan-Haw Chow, M.D., Pei-Fang Su, M.S., Shao-Chieh Lin, M.D., Peng-Chan Lin, M.D., Jenq-Chang Lee, M.D.

Published in: Diseases of the Colon & Rectum | Issue 8/2008

Abstract

Purpose

Although Recepteur d’Origine Nantais (RON), a member of the MET receptor tyrosine kinase family, is overexpressed and constitutively active in some primary tumors and tumor cell lines, its expression pattern and clinical significance in colorectal cancer are not well documented.

Methods

By using immunohistochemical staining, we examined RON and MET expression in 135 colorectal cancer specimens and investigated the association of the immunoreactivity of both receptors with colorectal cancer clinical parameters and prognosis.

Results

We found moderate to strong expression in 99 cases (73 percent) for RON and 97 cases (72 percent) for MET. Univariate analysis showed that increased immunoreactivity of RON or MET was associated with shorter patient survival and that moderate to strong coexpression of both receptors was associated with a significantly worse prognosis. Multivariate Cox analysis showed that the risk of tumor recurrence for patients with high-RON/high-MET expression was approximately 11 times greater than for patients with low-RON/low-MET expression (P = 0.001). In addition, RON and MET expression levels were positively correlated (P ≤ 0.001; τ = 0.306).

Conclusions

The crosstalk between RON and MET in colorectal cancer seems important. Evaluating the expression patterns of RON and MET was predictive of clinical outcome for patients with colorectal cancer.

Glenn F, McSherry CK. Carcinoma of the distal large bowel: 32-year review of 1026 cases. Ann Surg 1966;163:838–49.PubMedCrossRef

Itzkowitz SH, Bloom EJ, Kokal WA, et al. Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients. Cancer 1990;66:1960–6.PubMedCrossRef

Miyahara M, Saito T, Kaketani K, et al. Clinical significance of ras p21 overexpression for patients with an advanced colorectal cancer. Dis Colon Rectum 1991;34:1097–102.PubMedCrossRef

Leahy DT, Mulcahy HE, O’Donoghue DP, et al. bcl-2 protein expression is associated with better prognosis in colorectal cancer. Histopathology 1999;35:360–7.PubMedCrossRef

Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2002;2:289–300.PubMedCrossRef

Liu C, Park M, Tsao MS. Overexpression of c-met proto-oncogene but not epidermal growth factor receptor or c-erbB-2 in primary human colorectal carcinomas. Oncogene 1992;7:181–5.PubMed

Fazekas K, Csuka O, Koves I, Raso E, Timar J. Experimental and clinicopathologic studies on the function of the HGF receptor in human colon cancer metastasis. Clin Exp Metastasis 2001;18:639–49.CrossRef

Wielenga VJ, van der Voort R, Taher TE, et al. Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. Am J Pathol 2000;157:1563–73.PubMed

Takeuchi H, Bilchik A, Saha S, et al. c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 2003;9:1480–8.PubMed

10.

Resnick MB, Routhier J, Konkin T, Sabo E, Pricolo VE. Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res 2004;10:3069–75.PubMedCrossRef

11.

Zeng Z, Weiser MR, D’Alessio M, Grace A, Shia J, Paty PB. Immunoblot analysis of c-Met expression in human colorectal cancer: Overexpression is associated with advanced stage cancer. Clin Exp Metastasis 2004;21:409–17.PubMedCrossRef

12.

Ronsin C, Muscatelli F, Mattei MG, Breathnach R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene 1993;8:1195–202.PubMed

13.

Wang MH, Ronsin C, Gesnel MC, et al. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 1994;266:117–9.PubMedCrossRef

14.

Collesi C, Santoro MM, Gaudino G, Comoglio PM. A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype. Mol Cell Biol 1996;16:5518–26.PubMed

15.

Maggiora P, Marchio S, Stella MC, et al. Overexpression of the RON gene in human breast carcinoma. Oncogene 1998;16:2927–33.PubMedCrossRef

16.

Chen YQ, Zhou YQ, Angeloni D, Kurtz AL, Qiang XZ, Wang MH. Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res 2000;261:229–38.PubMedCrossRef

17.

Wang MH, Kurtz AL, Chen Y. Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis 2000;21:1507–12.PubMedCrossRef

18.

Peace BE, Hughes MJ, Degen SJ, Waltz SE. Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis. Oncogene 2001;20:6142–51.PubMedCrossRef

19.

Zhou YQ, He C, Chen YQ, Wang D, Wang MH. Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 2003;22:186–97.PubMedCrossRef

20.

O’Toole JM, Rabenau KE, Burns K, et al. Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. Cancer Res 2006;66:9162–70.PubMedCrossRef

21.

Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell 1995;80:213–23.PubMedCrossRef

22.

Wada T, Qian XL, Greene MI. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 1990;61:1339–47.PubMedCrossRef

23.

Sliwkowski MX, Schaefer G, Akita RW, et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994;269:14661–5.PubMed

24.

Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS. Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001;7:1957–62.PubMed

25.

Lee JC, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 2002;38:1065–71.PubMedCrossRef

26.

Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM. Cross-talk between the proto-oncogenes Met and Ron. Oncogene 2000;19:3041–9.PubMedCrossRef

27.

Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 1997;26:59–66.PubMed

28.

Maggiora P, Lorenzato A, Fracchioli S, et al. The RON and MET oncogenes are coexpressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res 2003;288:382–9.PubMedCrossRef

29.

Cheng HL, Liu HS, Lin YJ, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer 2005;92:1906–14.PubMedCrossRef

30.

Lee WY, Chen HH, Chow NH, et al. Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res 2005;11:2222–8.PubMedCrossRef

31.

Greene FL, Balch CM, Fleming ID, et al. AJCC cancer staging handbook: TNM classification of malignant tumors. 6th ed. New York: Springer, 2002.

32.

Pai R, Nakamura T, Moon WS, Tarnawski AS. Prostaglandins promote colon cancer cell invasion; signaling by cross-talk between two distinct growth factor receptors. FASEB J 2003;17:1640–7.PubMedCrossRef

33.

Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem 1999;27:8865–74.CrossRef

34.

Ding S, Merkulova-Rainon T, Han ZC, Tobelem G. HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 2003;101:4816–22.PubMedCrossRef

Title: The Prognostic Significance of RON and MET Receptor Coexpression in Patients with Colorectal Cancer
Authors: Chung-Ta Lee, M.D.
Nan-Haw Chow, M.D.
Pei-Fang Su, M.S.
Shao-Chieh Lin, M.D.
Peng-Chan Lin, M.D.
Jenq-Chang Lee, M.D.
Publication date: 01-08-2008
Publisher: Springer-Verlag
Published in: Diseases of the Colon & Rectum / Issue 8/2008
Print ISSN: 0012-3706
Electronic ISSN: 1530-0358
DOI: https://doi.org/10.1007/s10350-008-9297-1

At a glance: The STEP trials

Springer Medicine

The Prognostic Significance of RON and MET Receptor Coexpression in Patients with Colorectal Cancer

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2008

Autonomic Nerve-Preserving Total Mesorectal Excision in the Laparoscopic Era

Staple Line Failure Using the Proximate® 100 mm Linear Cutter

Most Patients with Colorectal Tumors at Young Age Do Not Visit a Cancer Genetics Clinic

Acute Intestinal Obstruction after Endoscopic Submucosal Dissection: Report of a Case

Tracking Outcomes of Anorectal Surgery: The Need for a Disease-Specific Quality Assessment Tool

Associations Between Exercise, Quality of Life, and Fatigue in Colorectal Cancer Survivors