c-Met Overexpression Is a Prognostic Factor in Ovarian Cancer and an Effective Target for Inhibition of Peritoneal Dissemination and Invasion

Abstract

The hepatocyte growth factor receptor c-Met is a receptor tyrosine kinase that plays an important role in tumor growth by activating mitogenic signaling pathways.

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

“…To test this, we examined a set of inhibitors at effective concentrations that specifically inhibit various RTKs, including general RTKs (genistein), IGF-1R (AG1024), fibroblast growth factor receptor 1 (SU5402), epidermal growth factor receptor (EGFR) (AG1478) and hepatocyte growth factor receptor c-Met (K252a), which have been previously implicated in the progression and metastasis of ovarian cancer (Ellerbroek et al, 2001;Steele et al, 2001;Brokaw et al, 2007;Sawada et al, 2007). Among these inhibitors, we found that only genistein used to block RTK or AG1024 used to inhibit IGF-1R led to a marked decrease in p120 ctn activation ( Figure 3a) and translocation ( Figure 3b) following GnRHa stimulation.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…In recent years, mis-regulation of the HGF/cMET pathway has been investigated in ovarian cancer, and high expression of cMET has been identified in subsets of all four major histotypes of EOC (high grade serous, clear cell, mucinous, and endometrioid [22][23][24][25][26][27][28][29]). It must be noted, however, that the outcome from this over-expression remains unclear.…”

“…It must be noted, however, that the outcome from this over-expression remains unclear. While several studies have demonstrated a correlation between high cMET expression and poor prognosis [25,30], others have shown no statistically significant correlation between cMET expression and shorter survival [26,29], and still others suggest that cMET is expressed in early tumours, and is associated with good prognostic factors [23]. It should be noted that the majority of these studies were performed on relatively small numbers of samples, and usually contained mixed subtypes of EOC, thus further confusing the matter.…”

“…For example, recent IHC studies performed on gastric tumour samples have reported cMET over-expression in 4-63% of cases [72][73][74][75][76][77] and various studies performed in ovarian cancer estimate high expression of cMET to be present in 11-68 % of cases [30,22,23,26,25] (Table 1). The majority of the estimates above come from IHC studies, using a number of different antibodies, but no consensus on scoring criteria yet exists, nor whether cytoplasmic or membranous staining for cMET is important.…”

“…However, surprisingly, no biomarkers were used, nor were analyses performed post-hoc on patients responding to treatment. With current estimates of high cMET expression occurring in 11-68% of ovarian cancer cases (see Table 1) [30,22,23,26,25], it is possible that as few as 3 patients enrolled within the study were in a position to benefit from receiving the anti-HGF antibody, and that as many as 29 patients potentially to do worse upon receiving the therapy.…”