Abstract 378: The significance of vascular endothelial growth factor C in the lymphangiogenesis and lymph node metastasis of ovarian cancer.

Abstract

Abstract Purpose: Vascular endothelial growth factor-C (VEGF-C) is commonly expressed in malignant cells, creating a favorable environment for generation of new lymphatic vessels. It has been recently reported that mammalian target of rapamycin (mTOR) stimulates tumor-lymphangiogenesis by inducing the production of VEGF-C. In the current study, we investigated the significance of VEGF-C in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer. Moreover, we investigated whether mTOR complex 1 (mTORC1) is involved in the VEGF-C-induced lymphangiogensis and lymph node metastasis in ovarian cancer. Experimental design: Using human ovarian cancers, we first performed immunostaining for VEGF-C, and examined the correlation between VEGF-C expressions and the extent of lymphvascular space invasion (LVSI) or the number of lymph node metastasis. Using two pairs of ovarian cancer cell lines producing different level of VEGF-C (VEGF-C-low and VEGF-C-high cells), we next investigated the role of VEGF-C in tumor-lymphangiogenesis in a mouse xenograft model. We then examined whether mTORC1 is involved in the production of VEGF-C in ovarian cancer cells as well as in tumor-lymphangiogenesis in a mouse xenograft model. Finally, by using a mouse model of paraaortic-node metastasis, we investigated whether inhibition of mTORC1 suppress lymph node metastasis. Results: VEGF-C expression was significantly associated with the extent of LVSI or the number of lymph node metastasis in ovarian cancer specimens. In a mouse xenograft model, tumors derived from VEGF-C-high cells showed greater lymphatic vessel density than that observed in tumors from VEGF-C-low cells. Inhibition of mTORC1 by everolimus decreased the expression of VEGF-C in ovarian cancer cells in vitro, lymphangiogenesis in tumors, and paraaortic-node metastasis in mouse models. Conclusion: Inhibition of mTORC1 may represent a novel molecular-targeted approach for lymph node metastasis prevention in patients with ovarian cancer. Citation Format: Takeshi Hisamatsu, Seiji Mabuchi, Tomoyuki Sasano, Ryoko Takahashi, Mahiru Kawano, Yuri Matsumoto, Kae Hashimoto, Aki Isobe, Kenjiro Sawada, Kenichiro Morishige, Tadashi Kimura. The significance of vascular endothelial growth factor C in the lymphangiogenesis and lymph node metastasis of ovarian cancer. [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 378. doi:10.1158/1538-7445.AM2013-378