Abstract 2331: One of the first steps of metastasis is remodeling of the extracellular matrix microenvironment

Abstract

Abstract During metastasis tumor cells initiate processes that lead to the loss of normal tissue architecture and formation of the tumor microenvironment. The main site of metastasis in ovarian cancer (OvCa) is the omentum. Little is known about the initial changes in extra-cellular matrix (ECM) during early OvCa metastasis. A 3-dimensional (D) organotypic model of the omentum was used to investigate the remodeling of the ECMs during the initial steps of OvCa metastasis. Vitronectin and fibronectin increased when OvCa cells (SKOV3ip1 and Hey A8) were added to the 3D omental model, while collagen type I decreased. Vitronectin was produced by the cancer cells and stroma, while fibronectin was produced solely by cancer cells. Collagen type I decreases in stroma and increases in OvCa when co-cultured. Vitronectin, fibronectin and collagen type I are produced by primary human mesothelial cells and fibroblasts and are present in ascites. Two immunohistochemical studies with human tumors confirmed the above findings. First during early OvCa metastasis in humans, fibronectin is present in the stroma, while vitronectin and collagen type I are present in both cancer cells and the stroma. Second, ECM localization in 20 sets of primary and omental metastasis tumors from the same patients was performed. Fibronectin was absent in the primary tumor and present in the metastatic tumor stroma, while vitronectin was produced in cancer cells and stroma in primary and metastatic tumors. Additionally, a Reverse-Phase Protein Array was performed on primary versus omental metastasis tissue from 20 postmenopausal patients with FIGO Stage III/IV, high grade papillary-serous OvCa. Fibronectin was significantly increased, while vitronectin was significantly decreased in the omental metastasis vs. primary tumor, respectively. Additional experiments revealed changes in the tumor cell cytoskeleton in conjunction with increased expression of integrins (α5β1-and αvβ3-integrin) and proteases (uPA, uPAR, MMP-2 and MMP-9). Integrins and proteases were transiently knocked down using sequence-specific siRNA. Both α5β1-integrin and MMP-2, but not αvβ3-integrin and MMP-9, were found to be necessary for the remodeling of fibronectin. Taken together, these findings reveal the initial transformation of ECM in the normal omental architecture during early OvCa metastasis. 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 2331.