Cancer Letters

Cancer Letters

Volume 248, Issue 2, 18 April 2007, Pages 219-228
Cancer Letters

Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome

https://doi.org/10.1016/j.canlet.2006.07.007Get rights and content

Abstract

Introduction/hypothesis

Over-expression of the c-Met receptor tyrosine kinase has been described in a variety of cancers and implicated in tumor progression. Unlike some solid tumors, current evidence indicates that c-Met activation in colon cancer is unrelated to gene mutation, is ligand dependent, and occurs via a paracrine fashion. We hypothesize that over-expression of the c-Met receptor and its ligand, hepatocyte growth factor (HGF) in the tumor microenvironment is associated with tumor progression and metastases.

Methods

Primary tumor c-Met and HGF mRNA expression was analyzed in 60 colon adenocarcinomas. Receptor and ligand expression was analyzed for correlation and association with clinicopathologic features and outcome.

Results

Compared to adjacent normal mucosa, 69% and 48% of tumors showed a greater than 2- and greater than 10-fold elevation in c-Met mRNA, respectively. Elevated HGF mRNA was noted in 47% of tumors with 19% having a greater than 10-fold increase. Tumor c-Met expression was correlated with HGF expression, and a cohort of 33 patients could be defined with both low c-Met and HGF expression. Compared with the 27 tumors with either high c-Met or HGF, the cohort with low c-Met and HGF expression had fewer nodal and distant metastases as well as improved overall survival (HR = 2.3, p < 0.05).

Conclusion

Evaluation of the c-Met receptor in context of ligand, HGF, allows identification of a metastatic phenotype that correlates with advanced stage and poor survival. c-Met and HGF co-expression in the tumor microenvironment could be useful in the molecular staging of colon cancer and viable therapeutic targets.

Introduction

Worldwide, colorectal cancer (CRC) afflicts over 1 million individuals annually [1], and in industrialized countries CRC is the most common gastrointestinal malignancy [2]. For localized disease, surgical resection is the foundation of treatment. However, distant micrometastatic disease is present in over 50% of patients that have undergone curative surgery. Since low volume metastatic disease may be responsive to chemotherapy, patients at risk for harboring clinically inapparent distant disease are offered postoperative chemotherapy. Randomized trials have shown that patients receiving the most contemporary chemotherapy regimen after curative resection have 40–50% reduction in recurrence and improved survival when compared to patients not receiving adjuvant therapy [3], [4]. The importance of identifying those patients with micrometastatic disease is further evidenced by the fact that when relapse becomes clinically apparent, cure is almost never achieved even with the most effective combinations of cytotoxic and biologic therapy [5].

This study investigates the role of the c-met oncogene and its ligand, hepatocyte growth factor (HGF) in CRC progression and metastases. The c-met encoded protein is a receptor tyrosine kinase (RTK) which, under normal circumstances, binds HGF produced by stromal cells. A fundamental gene required for embryogenesis, c-met is also a critical oncogene for tumor metastasis, enabling cellular proliferation, motility, and invasion [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Previous studies have generally examine c-Met overexpression in CRC with semiquantitative techniques such as immunoblotting [9], [10], [11], [12], [13] or immunohistochemistry [16]. Few studies have reported more accurate quantitative methodology such as gene expression analysis [17], [18]. There has been comparably minimal emphasis placed on quantitation of the c-Met ligand, HGF. Although ligand independence as a result of activating mutation has been noted in select hereditary renal cell cancers, childhood liver tumors, and head and neck cancers, the majority of solid gastrointestinal tumors appear to be ligand-responsive to HGF [19]. Therefore, we hypothesize that evaluating the co-expression of both c-Met and HGF is critical to better understand the role of this RTK and its natural ligand in the behavior of primary CRC.

In this series of human CRC specimens, we report that c-Met and HGF co-expression predicts tumor phenotype, specifically propensity for nodal and distant metastases. Co-expression is also associated with poor outcome. These findings lend credence to the theory that c-met is a critical oncogene for colorectal cancer progression and that co-expression of ligand and receptor can be used for molecular staging. Further, the data supports investigation of c-Met and HGF as therapeutic targets in CRC.

Section snippets

Patients and samples

Tissue specimens were analyzed from 63 randomly selected patients who underwent standard of care resection of primary colon adenocarcinoma at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1991 and 1993. Patients consented to enrollment in a prospective tissue procurement protocol that was approved by the Institutional Review Board of the MSKCC. Immediately after surgical resection, samples of tumor tissue and adjacent normal colonic mucosa were harvested and placed in liquid nitrogen

Patient demographics and tumor characteristics

Patient and tumor characteristics are summarized in Table 1. Clinical follow-up of this cohort has matured to a median follow-up of 6.1 years. At last follow-up, 22 patients had confirmed recurrence, 19 had died from disease, and another 5 died from other causes. Derived from the 63 patients were 60 high quality RNA samples of tumor and 39 samples of normal mucosa that were suitable for comparative quantitative gene analysis. In a subset of 36 patients, there were matched pairs of tumor tissue

Discussion

There is mounting evidence that c-Met is a critical oncogene involved in CRC progression and metastases, and this study emphasizes the importance of evaluating receptor in context of ligand. Although there are examples of c-Met mutation resulting in constitutive kinase domain activation, the majority of solid gastrointestinal tumors, including CRC, exhibit ligand-dependent c-Met activation [14]. These findings are central when considering c-Met receptor activation as a prognostic marker and

Acknowledgement

Work supported by an American Society of Clinical Oncology Foundation Clinical Research Career Development Award (M.R.W.).

References (42)

  • A. Jemal et al.

    Cancer statistics, 2005

    CA Cancer J. Clin.

    (2005)
  • T. Andre et al.

    Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer

    N. Engl. J. Med.

    (2004)
  • NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264 (1990)...
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N. Engl. J. Med.

    (2004)
  • A. Danilkovitch-Miagkova et al.

    Dysregulation of Met receptor tyrosine kinase activity in invasive tumors

    J. Clin. Invest.

    (2002)
  • M. Jeffers et al.

    Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis

    J. Mol. Med.

    (1996)
  • M. Jeffers et al.

    Activating mutations for the met tyrosine kinase receptor in human cancer

    Proc. Natl. Acad. Sci. USA

    (1997)
  • S. Fujita et al.

    Expression of c-met proto-oncogene in primary colorectal cancer and liver metastases

    Jpn. J. Clin. Oncol.

    (1997)
  • S.E. Hiscox et al.

    Expression of the HGF/SF receptor, c-met, and its ligand in human colorectal cancers

    Cancer Invest.

    (1997)
  • M.F. Di Renzo et al.

    Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer

    Clin. Cancer Res.

    (1995)
  • C. Birchmeier et al.

    Met, metastasis, motility and more

    Nat. Rev. Mol. Cell Biol.

    (2003)
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