Abstract SY30-01: Metastasis mediated by lysyl oxidases

Abstract

Abstract Metastasis is responsible for over 90% of cancer patient deaths. Understanding the molecular processes that enable tumor cells to metastasize is key to understanding how best to prevent and treat metastases in cancer patients. Metastasis is a complex, multistep process driven by the tumor microenvironment. Two potent driving forces are hypoxia (low oxygen) and increased matrix stiffness. These are common features of aggressive solid tumors, and are clinically associated with metastasis and decreased survival of cancer patients. Both hypoxia and stiffness have been shown to greatly enhance the invasive and metastatic potential of cancer cells. We have identified two key mediator molecules, lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2). These are hypoxia-induced secreted enzymes that increase matrix stiffness through mediating the crosslinking of collagens and elastin in the extracellular matrix. We have investigated their role in metastasis using a variety of in vitro and in vivo models. We showed that LOX expression is clinically correlated with hypoxia, metastasis and poor patient survival. Furthermore, inhibition of LOX through genetic, chemical or antibody means significantly reduces invasion and metastasis in several in vivo models of solid tumor metastasis. LOX enhances invasion through increasing matrix stiffness, thereby activating integrins, Src and FAK. LOX additionally enhances formation of distant metastases by playing a role in formation of premetastatic niches through recruitment of CD11b+ cells, which greatly enable metastatic colonization. We have also investigated the role of LOXL2 in breast cancer metastasis and normal mammary tissue function. Like LOX, LOXL2 is clinically correlated with metastasis and poor patient survival. LOXL2 enhances invasion through regulation of matrix remodeling. Inhibition of LOXL2 through genetic, chemical or antibody means prevents invasion and metastatic dissemination in vivo. We further show that LOXL2 activity is highest during normal mammary gland involution, consistent with its role in matrix remodeling. These findings provide insight into metastasis mediated by the tumor microenvironment and demonstrate preclinical effectiveness of anti-LOX/LOXL2 therapy, which may have important clinical implications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY30-01. doi:10.1158/1538-7445.AM2011-SY30-01