Abstract 3846: Pleiotrophin in the tumor microenvironment induces expression of VEGFR2 on macrophages and promotes an anti-inflammatory phenotype

Abstract

Abstract Macrophages are an abundant immune cell in the tumor microenvironment that contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor-A (VEGF). We are interested in investigating the effects of VEGF inhibition on macrophages and other stromal cells within the tumor. We demonstrated recently that macrophages (systemic and tumor associated) in tumor-bearing animals express VEGFR2 in contrast to macrophages from non tumor-bearing animals. Furthermore, we found that selective inhibition of VEGFR2 inhibits macrophage infiltration into tumors in vivo. These results demonstrate that when VEGFR2 is expressed on macrophages it is the dominant receptor driving VEGF-induced migration in vitro and in vivo. Additionally, we found that the cytokine pleiotrophin (PTN) is sufficient to induce VEGFR2 expression on macrophages. PTN is expressed by many human breast cancer cells (e.g., MDA-MB-231) and the majority of human primary breast tumors. However, the connection between PTN and macrophage phenotype is still unexplored. Macrophages can be divided into two functional sub-types: M1 or classically activated macrophages and M2 or alternatively activated macrophages. M1 macrophages are powerful effector cells that produce pro-inflammatory cytokines and are capable of destroying tumor cells. In contrast, M2 macrophages inhibit the inflammatory response and promote tumor growth and angiogenesis. We employed the MMTV-PyMT transgenic, spontaneous breast cancer model to characterize PTN expression, immune cell infiltration, and immune cell function during the course of tumor progression. We found that PTN levels correlate with VEGFR2+ macrophage and M2 macrophage levels, which all peak during the transition from hyperplasia to early malignancy. Whereas, MDSC and Treg levels as well as levels of the anti-inflammatory cytokines IL-10 and IL-1β peak during the early carcinoma stage. We identified that PTN not only induces VEGFR2 expression by macrophages but also promotes an M2 phenotype in vitro. In addition, we have evidence that VEGF can modulate the level of PTN expression through VEGFR1. These results suggest a mechanism through which anti-VEGF therapy modulates PTN and M2 macrophage levels in vivo. Based on these observations, we hypothesize that PTN is a critical cytokine involved in breast tumor progression through promotion of a VEGFR2+, M2 macrophage phenotype in the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3846.