Abstract A16: Stromal LOX promotes TGFβR2 null breast cancer 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 tumors. Tumor cell invasion is a dynamic process which is regulated by many microenvironmental influences such as ECM composition, MMP activity, and exposure of proper integrin binding sites. 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 highly invasive cells express higher levels of lysyl oxidase and treatment with a lysyl oxidase inhibitor significantly decreases cellular invasion. Recent reports suggest that hypoxia induced metastasis is facilitated by lysyl oxidase crosslinking of the extracellular matrix. TGF-β is another molecule that is known to promote lysyl oxidase expression and will be the focus of our studies. In this study we utilize transgenic mice which express PyMT under a mammary epithelial specific promoter 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 the presence of a higher degree of collagen crosslinking. In PyMT tumors originating from the RII KO mammary glands, increased deposition and maturation of collagen is present in the tumor microenvironment. However, this is not correlated with an increased expression of collagen genes. Subsequent analysis has shown an increased expression and activity of lysyl oxidase present in these TGFβR2KO PyMT tumors. Increased levels of lysyl oxidase are correlated with increased levels of available TGF-β in the RII KO tumors. Upon in vivo inhibition of lysyl oxidase, with beta-aminoproprionitrile, we see a significant decrease in tumor metastasis to the lungs through the inability to escape into the vasculature. Interestingly, these phenotypes are not driven by hypoxia, as shown in previous publications, and instead appear to be driven by TGFβ signaling in the stroma of these tumors. With the source of the TGFβ driving the increase expression of stromal LOX appears to be infiltrating immune cells, MDSCs. This work points to a new paradigm of LOX induction in tumors and presents a new therapeutic target group for LOX inhibition outside of patients presenting with hypoxic tumors. Citation Format: Michael W. Pickup, Philip Owens, Agnes Gorska, Anna Chytil, Valerie Weaver, Harold Moses. Stromal LOX promotes TGFβR2 null breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A16.