Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome
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.).
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2020, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :In normal human colon epithelium MET is the most prominent RTK, with particularly high expression in ISCs, while its ligand HGF is produced by stromal niche cells at the crypt bottom [13–15,77]. In adenomas and invasive CRC, MET expression is usually strongly upregulated and is correlated with tumour progression, metastasis, and unfavorable prognosis [15,78,79]. Although genetic MET alterations, including gene amplification and exon 14 skipping, have been reported in CRC, these lesions appear to be rare and do not explain the enhanced expression of MET in most cases of CRC.
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2018, Annals of Diagnostic PathologyCitation Excerpt :Dysregulation of cMET has been reported in tumors from various organ systems. The increased cMET activity has been indicated as a negative prognostic factor associated with poor prognosis and worse clinical outcome [4-9]. cMET overexpression was reported to be observed in 12–52% in TNBC [10-15].