Abstract
Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control.
Highlights
Liver cancers, and in particular the most prevalent form of these tumors, hepatocellular carcinoma (HCC), are aggressive, chemotherapy-resistant human malignancies, which exhibit an increasing annual incidence and are associated with poor prognosis [1, 2]
Taking into consideration the important emerging role of MET-dependent signaling in liver cancer pathogenesis with particular emphasis on MET-associated tumor vascularization, we investigated in the current study the potential of the MET tyrosine kinase inhibitors (TKIs) to control growth and angiogenesis in models of MET-driven liver tumors, which consist of isogenic cell lines that ectopically express MET mutated variants that differ exclusively by their responsiveness to MET targeting
Another evidence for the benefit for interference with tumor-associated angiogenesis in liver cancers is provided by data from clinical and pre-clinical studies with mTOR inhibitors such as everolimus and sirolimus. mTOR inhibitors are believed to exert their antiangiogenic effects largely through regulation of vascular endothelial growth factor (VEGF) expression and translation of other proteins involved in angiogenesis [32, 33]
Summary
In particular the most prevalent form of these tumors, hepatocellular carcinoma (HCC), are aggressive, chemotherapy-resistant human malignancies, which exhibit an increasing annual incidence and are associated with poor prognosis [1, 2]. The multi-kinase inhibitor sorafenib [4], which is believed to exert its major antitumor activity primarily by blocking the pro-angiogenic activity of vascular endothelial growth factor (VEGF) receptors 2 and 3 (VEGFR2 and VEGFR3), is the only approved treatment for advanced HCC and provides a median overall survival of 10.7 months in previously untreated patients [5,6,7]. Aberrant activation of the hepatocyte growth factor (HGF) receptor tyrosine kinase MET, mostly due to overexpression of the MET gene, is a common event in numerous types of human cancers and is frequently associated with poor prognosis [9]. Patients with MET overexpression usually have a significantly shorter 5-year survival than patients with low MET expression after a curative surgical resection [11, 17, 18]
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