VEGF and c-Met drives tumor invasion and metastasis in pancreatic islet cancer.

You WK, Sennino B, Williamson CW, Falc√≥n B, Hashizume H, Yao LC, Aftab DT, McDonald DM. “Cancer Res. 2011 Jul”

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling sluggish the growth of numerous kinds of tumors, but ultimately the disease progresses. Many techniques are becoming explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK).

GSK1363089 (foretinib, XL880) and XL184 (cabozantinib) are small-molecule inhibitors that potently block numerous RTKs, such as VEGFR and also the receptor of hepatocyte development factor c-Met, which may push tumor invasion and metastasis. This study compared the mobile effects of GSK1363089 and XL184 with these of an RTK inhibitor (XL999) that blocks VEGFR although not c-Met.

Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but therapy with GSK1363089 or XL184 removed approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused prevalent intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature soon after drug withdrawal. Importantly, GSK1363089 and XL184 also decreased invasiveness of primary tumors and decreased metastasis.

Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the results of VEGFR blockade and leads to fast, sturdy, and progressive regression of tumor vasculature, elevated intratumoral hypoxia and apoptosis, and decreased tumor invasiveness and metastasis.

Concentrations:

receptor tyrosine kinases (RTK), GSK1363089

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