Abstract LB-343: Host response to paclitaxel chemotherapy promotes metastasis via the secretion of VEGF-C by macrophages.

Abstract

Abstract Recent studies indicate that while chemotherapy can strongly restrict or reverse tumor growth, the response of the normal host tissue to the therapy can counteract tumor growth control by promoting the re-growth of residual tumor cells and the outgrowth of metastases. We sought for host factors promoting metastasis following paclitaxel (PTX) chemotherapy. The prolymphangiogenic growth factor, VEGF-C, was highly expressed in plasma of PTX-treated mice, and could induce migration, invasion, and tube formation of lymphatic vessels when compared to plasma from control mice. In both 4T1 breast and Lewis lung carcinomas we found an increased number of lymphatic vessels positioned at the center of the tumors from PTX-treated mice, in contrast to tumors from control mice, in which lymphatic vessels were positioned at the tumor periphery. Since VEGFR3 is the major receptor for VEGF-C-induced lymphangiogenesis, we evaluated the therapeutic effect of anti-VEGFR3 blocking antibody in combination with PTX. 4T1 bearing mice treated with PTX+anti-VEGFR3 exhibited a significant reduction in tumor re-growth and inhibition of metastasis which enhanced their overall survival, when compared to mice treated with PTX alone. However, no significant difference in survival of mice bearing 4T1 experimental metastasis in the lungs, was observed in any of the treatment groups, suggesting that VEGFR3 and VEGF-C promote tumor cell dissemination from treated tumors, but may not affect their seeding at metastatic sites. In addition, an abundant number of macrophages highly secreting VEGF-C were found to colonize 4T1 tumors from PTX-treated mice when compared to tumors from untreated mice. Similarly, breast carcinomas from cancer patients after neoadjuvant chemotherapy exhibited high expression of VEGF-C when compared to their pre-treated biopsies. Overall, our results suggest an additional role for macrophages in the tumor microenvironment, which in response to chemotherapy promote tumor re-growth and metastasis spread, a process which can be blocked by the disruption of VEGF-C/VEGF-R3 pathway. Citation Format: Svetlana Gingis-Velitski, Orit Kaidar-Person, Dror Alishekevitz, Rotem Bril, Ella Fremder, Yuval Shaked. Host response to paclitaxel chemotherapy promotes metastasis via the secretion of VEGF-C by macrophages. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-343. doi:10.1158/1538-7445.AM2013-LB-343