Abstract A34: VEGFR‐2 expression in carcinoid cancer cells and its role in tumor growth and metastasis

Cancer Research(2009)

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Carcinoid tumors are slow growing and highly vascular neuroendocrine neoplasms that have been increasing in incidence since the 1970s. Carcinoid tumors express vascular endothelial growth factor receptor 2 (VEGFR‐2); however, its role is not completely understood. The aims of this study were 1) to assess the expression and regulation of VEGFR‐2 in carcinoid tumors and cells and 2) to evaluate the effect of VEGFR‐2 on carcinoid growth and metastasis. Methods: 1) The expression of VEGFR‐2 in carcinoid tumor sections and in the novel carcinoid cell line BON, which was established and characterized in our laboratory, was assessed by immunohistochemistry andWestern blot, respectively. As VEGFR‐2 signals through the PI3K/Akt pathway, signaling through Akt was adjusted chemically and through RNAi to delineate its effect on VEGFR‐2 expression. 2) BON cell proliferation was measured following treatment with the VEGFR‐2 inhibitor sunitinib malate to assess the effect of VEGF signaling on cell growth. A BON cell line with stably decreased VEGFR‐2 expression, designated as BON shVEGFR‐2, was generated by transfecting cells with shRNA to VEGFR‐2. Boyden chamber and scratch assays were performed on BON shVEGFR‐2 cells to assess the effect of VEGFR‐2 on invasion and migration. Results: 1) Immunhistochemical analysis confirmed positive expression of VEGFR‐2 in the endothelial and epithelial components of carcinoid tumor sections. Consistent with this finding, BON cells also expressed VEGFR‐2. Interestingly, we noted that the regulation of VEGFR‐2 expression is inversely related to PI3K/Akt signaling. Inhibition of PI3K/Akt signaling with wortmannin upregulated VEGFR‐2 expression, as noted with western blot and mRNA analysis. shRNA against PTEN increased phospho‐Akt, resulting in decreased expression of VEGFR‐2 in BON cells. BON shPTEN cells injected into the pancreas of nude mice formed increased liver metastases, compared to BON shControl cells, and the liver metastatic cells retained decreased VEGFR‐2 expression. 2) Treatment with sunitinib malate had only a modest effect on BON cell inhibition. Consistent with our in vivo studies, BON shVEGFR‐2 cells have decreased expression of E‐cadherin compared to BON shControl cells. Additionally, the migratory and invasive potential of BON shVEGFR‐2 cells is approximately four and 1.75 times that of control BON cells, respectively, at 48 h. Conclusions: We demonstrate the expression and activity of VEGFR‐2 in BON cells. The expression of VEGFR‐2 on the epithelial component of carcinoid tumors and in the BON cell line, suggests an alternate role for VEGFR‐2, in addition to its well‐defined role in angiogenesis. The modest inhibition of BON cell growth with sunitinib malate suggests that VEGFR‐2 on carcinoid tumor cells has a limited role in cell proliferation. Interestingly, we show that the level of VEGFR‐2 expression in BON cells is inversely proportional to the degree of total Akt signaling, suggesting a negative feedback loop in the regulation of VEGFR‐2. The finding that decreased VEGFR‐2 expression results in increased invasion and migration suggests that VEGFR‐2 may inhibit carcinoid metastasis. Thus, while VEGFR‐2 inhibition prevents angiogenesis, it may also increase the metastatic potential of surviving carcinoid cells. Citation Information: Cancer Res 2009;69(23 Suppl):A34.
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