The VEGFC/VEGFR3 pathway in the malignancy of ovarian carcinoma

Decio, Alessandra Agnese (2013). The VEGFC/VEGFR3 pathway in the malignancy of ovarian carcinoma. PhD thesis The Open University.



Vascular endothelial growth factor C (VEGFC) promotes tumor progression in several tumor types, mainly through the stimulation of lymphangiogenesis and lymphatic metastasis. The expression and biological significance of the VEGFCNEGFR3 pathway in ovarian cancer growth and dissemination has been investigated in this thesis using ovarian carcinoma cell lines and tumor animal models.

In patient-derived ovarian carcinoma xenografts (HOC), high levels of soluble VEGFC in ascites and serum were detected, in association with disease progression and tumor burden. Peak VEGFC expression preceded para-aortic lymph node infiltration by HOCS neoplastic cells. Histological detection of tumor cells in blood and lymphatic vessels indicated both hematogenous and lymphatic dissemination.

VEGFC was over-expressed in the VEGFR3-positive and luciferase-expressing 1A9 and IGROV1 ovarian cancer cells. In vitro, VEGFC released by the expressing turnor cells stimulated turnor cell migration in an autocrine manner. In vivo, over-expression of VEGFC promoted . IGROVl dissemination after orthotopic intraovarian transplantation in nude mice. VEGFC released in serum of mice correlated with tumor burden and metastasis.

Cediranib, a small molecule receptor tyrosine kinase inhibitor of VEGFR1-3 and c-Kit, inhibited in vivo metastasis of VEGFC-overexpressing [GROVI and in vitro autocrine effects on turnor cell migration; cediranib improved the survival of mice bearing the four HOC xenografts analyzed. The therapeutic benefit was proportional to soluble VEGFC levels in serum and ascites and to VEGFR3 expression by tumor cells.

Different schedules of cediranib were tested on HOC8 xenograft, The survival benefit of cediranib in maintenance regimen (14 weeks) was superior to 3-weeks treatment. A significant prolongation of mice survival was observed in mice treated with advanced tumor. Treatment benefits were improved combining cediranib with chemotherapy (paclitaxel plus cisplatin).

These findings suggest that the VEGFC/VEGFR3 pathway acts as an enhancer of ovarian cancer progression through autocrine and paracrine mechanisms, hence offering a potential target for therapy.

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