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

PurposeAlthough 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.MethodsBy 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.ResultsWe 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).ConclusionsThe 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.

[1]  M. Mattei,et al.  A novel putative receptor protein tyrosine kinase of the met family. , 1993, Oncogene.

[2]  C. Heldin,et al.  Dimerization of cell surface receptors in signal transduction , 1995, Cell.

[3]  Parfrey,et al.  bcl‐2 protein expression is associated with better prognosis in colorectal cancer , 1999, Histopathology.

[4]  T. Tzai,et al.  Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder , 2005, British Journal of Cancer.

[5]  M. Stella,et al.  Cross-talk between the proto-oncogenes Met and Ron , 2000, Oncogene.

[6]  E. Sabo,et al.  Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. , 2004, Clinical cancer research : an official journal of the American Association for Cancer Research.

[7]  V J Wielenga,et al.  Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. , 2000, The American journal of pathology.

[8]  H. Wiley,et al.  ErbB-2 Amplification Inhibits Down-regulation and Induces Constitutive Activation of Both ErbB-2 and Epidermal Growth Factor Receptors* , 1999, The Journal of Biological Chemistry.

[9]  C. Mcsherry,et al.  Carcinoma of the Distal Large Bowel: 32‐Year Review of 1,026 Cases , 1966, Annals of surgery.

[10]  Dong Wang,et al.  Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential , 2003, Oncogene.

[11]  Roderick Turner,et al.  c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  P. Comoglio,et al.  A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype , 1996, Molecular and cellular biology.

[13]  M. Greene,et al.  Intermolecular association of the p185 neu protein and EGF receptor modulates EGF receptor function , 1990, Cell.

[14]  Yuan Cheng,et al.  Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. , 2006, Cancer research.

[15]  D. Seol,et al.  Co‐expression and regulation of Met and Ron proto‐oncogenes in human hepatocellular carcinoma tissues and cell lines , 1997, Hepatology.

[16]  E. Raso,et al.  Experimental and clinicopathologic studies on the function of the HGF receptor in human colon cancer metastasis , 2004, Clinical & Experimental Metastasis.

[17]  M. H. Wang,et al.  Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. , 2000, Experimental cell research.

[18]  L. Trusolino,et al.  Scatter-factor and semaphorin receptors: cell signalling for invasive growth , 2002, Nature Reviews Cancer.

[19]  C. Balch,et al.  AJCC Cancer Staging Manual. 6th ed , 2002 .

[20]  P. Sismondi,et al.  Overexpression of the RON gene in human breast carcinoma , 1998, Oncogene.

[21]  Helen H. W. Chen,et al.  Prognostic Significance of Co-expression of RON and MET Receptors in Node-Negative Breast Cancer Patients , 2005, Clinical Cancer Research.

[22]  D. Katsaros,et al.  The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. , 2003, Experimental cell research.

[23]  E. Leonard,et al.  Identification of the ron gene product as the receptor for the human macrophage stimulating protein. , 1994, Science.

[24]  M. Sliwkowski,et al.  Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. , 1994, The Journal of biological chemistry.

[25]  K. Shimoda,et al.  Clinical significance of ras p21 overexpression for patients with an advanced colorectal cancer , 1991, Diseases of the colon and rectum.

[26]  B. Peace,et al.  Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis , 2001, Oncogene.

[27]  M. Weiser,et al.  Immunoblot analysis of c-Met expression in human colorectal cancer: Overexpression is associated with advanced stage cancer , 2005, Clinical & Experimental Metastasis.

[28]  Z. Han,et al.  HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. , 2003, Blood.

[29]  A. Tarnawski,et al.  Prostaglandins promote colon cancer cell invasion; signaling by cross‐talk between two distinct growth factor receptors , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  T. Tzai,et al.  Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  E. Sabo,et al.  Epidermal Growth Factor Receptor, c-MET, β-Catenin, and p53 Expression as Prognostic Indicators in Stage II Colon Cancer , 2004, Clinical Cancer Research.

[32]  M. H. Wang,et al.  Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. , 2000, Carcinogenesis.

[33]  M. Tsao,et al.  Overexpression of c-met proto-oncogene but not epidermal growth factor receptor or c-erbB-2 in primary human colorectal carcinomas. , 1992, Oncogene.

[34]  S. Hakomori,et al.  Sialosyl‐Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients , 1990, Cancer.

[35]  J. C. Lee,et al.  Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. , 2002, European journal of cancer.