Abstract 2456: TGF-Beta regulates tumor ECM remodeling and progression to metastasis

Abstract

Abstract To understand how loss of TGF-β signaling in cancer cells promotes tumor progression, we are evaluating modifications to the extracellular matrix in TGF-β type II receptor KO mammary tumors. Previous work from our lab supports a stromal expansion and increased TGF-β availability in PyMT tumors lacking TGF-β signaling in the epithelium. This expansion is characterized by increased activated fibroblasts, collagen deposition, and MDSC infiltration. We hypothesize that the increased TGF-β availability and fibroblast activation in TGF-β receptor II knock out tumors will also lead to increased ECM remodeling. Crosslinking of collagen fibers increases the overall stiffness of affected tissue providing the mechanical force necessary for tumor cell migration and invasion. Lysyl oxidase is a potent extracellular enzyme that crosslinks collagen and elastin fibers. The study of human breast cancer cell lines shows that HIF-1a upregulates lysyl oxidase in highly invasive cells and treatment with a lysyl oxidase inhibitor significantly decreases cellular invasion. Past work also supports TGF-B driving lysyl oxidase expression in the stroma of many tissue types. The interaction between the TGF-β secreted by infiltrating myeloid cells and stromal fibroblasts has yet to be elucidated and the combination of these effects on ECM remodeling and tumor metastasis will be the focus of this study. In this study we utilize transgenic mice which express PyMT under a mammary epithelial specific promoter, MMTV, and have the type II TGF-β receptor conditionally deleted from mammary epithelial cells. Prior to tumor palpation, we see an increase in collagen deposition as well as tissue tensile strength indicating a higher degree of collagen crosslinking. In PyMT tumors originating from the RII KO mammary glands, we see an increased deposition of collagen as well as an increased expression of lysyl oxidase. In our model, both in vitro and in vivo evidence supports stromal expression of lysyl oxidase by fibroblasts. Increased levels of stromal lysyl oxidase are correlated with increased levels of available TGF-β in the RII KO tumors which is primarily derived from infiltrating myeloid cells. Upon inhibition of lysyl oxidase activity during development of PyMT tumors in vivo, we observe a dramatic decrease in the ability of the cells to metastasize primarily through a loss of the ability to intravasate into the circulation. These results suggest that loss of the TGF-β type II receptor in mammary carcinoma cells promotes invasion through increases in lysyl oxidase activity and tissue stiffness. Future studies will focus on cellular response to variability in tissue stiffness and how the changes relate to in vivo tumors and their ability to enter the blood stream. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2456. doi:1538-7445.AM2012-2456