Hgf Cmet And Metastasis

The presence of metastatic disease in cancer patients is the most significant factor affecting their survival (53). Many studies have demonstrated that tumour cell stimulation with HGF results in an enhancement of cellular functions that are central to the process of metastasis. HGF, upon complexing with its specific receptor, c-Met, evokes an array of biological actions within cancer cells, such as enhanced cell migration, matrix degradation, invasion, and induction of angiogenesis. The significance of HGF activity in cancer development and progression has also been confirmed through clinical studies; where the level of HGF and its receptor correlated with disease progression and prognosis of cancer patients. The significance of the HGF-Met complex in cancer has been reviewed recently (54, 55).

Our studies, and others, have shown that in contrast to what occurs in normal epithelium, HGF and Met are frequently overexpressed in a wide variety of cancers, including invasive human breast carcinomas (26, 50, 56-59). The forced expression of HGF within mouse mammary epithet-lium led to the formation of metastatic carcinomas (60), however, the mechanism behind HGF expression in breast carcinoma cells is currently unclear. A recent study suggests it may be in response to an activating function of c-Src and Stat3 on HGF transcription (61). Reports demonstrate that patients with breast cancer have elevated serum HGF levels; however, following removal of the malignant breast tumours serum HGF levels decrease (62-65). Elevated HGF expression levels correlate with disease progression, with levels rising in cases of recurrence (66-68). One study even reports that the immunoreactive level of HGF was a stronger independent predictor of recurrence and survival than that of lymph node involvement (69). We also report that HGF levels are elevated in breast cancer patients with an overall poor prognosis, in comparison with patients who remained disease-free (26). These observations suggest that establishment of an autocrine HGF loop and sustained activation of the Met-signalling pathway in carcinoma cells may promote progression to more aggressive cancers.

The status of the c-Met receptor has also been evaluated in a wide variety of cancers. These reports demonstrate that c-Met is overexpressed by many tumours, including tumours of the breast, thyroid, ovary, pancreas, prostate, and gastrointestinal tract (70-75). An elevated level of c-Met will result in the tumour being more sensitive to the influence of HGF. Reports reveal that c-Met overexpression is associated with breast cancer progression and poor outcome in breast cancer patients (48, 76-79). Interestingly, c-Met has also demonstrated the ability to act as an independent prognostic factor for breast cancer patients, when compared against traditional breast markers in a multivariate analysis comparison (80). Collectively, these studies have strongly indicated that

HGF and its receptor are potential therapeutic targets in cancer treatment. This aspect has been documented in recent articles (54, 55, 81). In the current chapter, we focus on the biological and clinical aspects of the hepatocyte growth factor regulators in breast cancer.

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