Abstract 129: AIP1 suppresses tumor metastasis by regulating tumor microenvironment and metastatic niche

Abstract

Abstract AIP1 (also called DAB2IP, a new member of RAS-GAP family protein) is downregulated in a variety of human cancer tissues. We and others have recently reported that AIP1 functions as a tumor suppressor in prostate cancer models. However, the role of AIP1 in regulating tumor microenvironment and metastatic niche is not known. In the present study, we implanted tumor cells with the same genetic background into C57BL/6 wild type (WT) and AIP1-deficient (AIP1-KO) mice to address this question. In subcutaneous (SQ) allograft models using B16 melanoma and LLC Lewis lung carcinoma, tumor growth and metastasis to multiple organs including lymph node, lung, liver, spleen and bone marrow were significantly enhanced in AIP1-KO host, suggesting AIP1 in tumor microenvironment limits tumor metastases. However, a direct intravenously injection of tumor cells resulted in no differences in tumor metastasis between WT and AIP1-KO mice, indicating AIP1 in host regulates tumor metastasis at steps prior to extravasation to target tissues. We examined effects of AIP1 deletion on the induction of local inflammation, tumor cell epithelial-mesenchymal transition (EMT), generation of metastatic routes (formation of new blood and lymphatic vessels) and establishment of pre-metastatic niche in distance tissues. SQ tumors in AIP1-KO host showed more profound increases in macrophage infiltration, tumor cell EMT, intratumoral angiogenesis and peri-tumoral lymphangiogenesis as well as lymphangiogenesis in lymph nodes prior to the detection of metastatic tumor cells. Finally, SQ tumor induced an establishment of pre-metastatic niche in lung as indicated by increased immunostaining for fibronectin and accumulation of VEGFR1, c-Kit and CXCR-positive cells which were augmented in AIP1-KO mice. Importantly, WT recipient with AIP1-KO bone marrow-derived cells showed similar phenotype to AIP1-KO mice in tumor growth and metastasis. Taken together, our data suggest that AIP1 functions as tumor metastasis suppressor by regulating tumor microenvironment, metastatic routes and pre-metastatic niche. Citation Format: Wang Min. AIP1 suppresses tumor metastasis by regulating tumor microenvironment and metastatic niche. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 129. doi:10.1158/1538-7445.AM2014-129