Abstract 1358: Focal adhesion kinase (FAK) regulates myeloid lineage cell activities that control murine tumor progression

Abstract

Abstract The tumor microenvironment is a critical regulator of tumor progression. Results from a broad spectrum of experimental models and analyses of human tumor specimens provide strong evidence that cells of the myeloid lineage have functional attributes that can potentiate the growth, invasion, and metastasis of cancer. Our approach to investigate the role of the microenvironment in tumor progression is centered on the activity of focal adhesion kinase (FAK) in myeloid lineage cells. We have recently shown in macrophages that FAK, a non-receptor tyrosine kinase, regulates adhesion dynamics and migration toward soluble growth factors and chemokines located at sites of tumor growth. Additionally, mice that have FAK conditionally deleted in this lineage display reduced peritoneal infiltration of macrophages following thioglycollate-induced inflammation. These data suggest that FAK may be involved in regulating the migration of myeloid lineage cells to the tumor and the response of macrophages to factors within the tumor microenvironment. We hypothesize that FAK regulates critical aspects of myeloid/macrophage behavior that allow these cells to support tumor progression and metastasis. This hypothesis is being tested in several tumor models. First, using myeloid-specific conditional FAK knockout mice (FAK-/-), we have tested this hypothesis in the context of both a xenograft tumor model using MDA-MB-231 breast cancer cells and a spontaneous breast tumor model driven by mammary-specific expression of the polyoma virus middle T antigen (MMTV-PyVmT). Significantly fewer tumors developed from orthotopic injection of MDA-MB-231 cells in mice lacking FAK in myeloid lineage cells. F4/80 staining of tumor sections from these mice showed reduced infiltration of macrophages into the tumor mass compared to tumors from wild type (WT) mice. Initial data from the spontaneous MMTV-PyVmT tumor model show no significant differences in time to tumor onset and rate of tumor outgrowth between the FAK-/- and WT mice. Analysis of the lung metastatic tumor burden is ongoing. Second, we have conducted preliminary experiments testing the influence of FAK expression in myeloid lineage cells on the adaptive immune response to tumor growth. Following subcutaneous implantation of the syngeneic B16/F1 melanoma cell line, we observed a significant delay in the onset of tumor formation in FAK-/- mice compared to WT mice. However, when a similar study was performed in a severe combined immunodeficient (SCID) background, tumor outgrowth was identical in WT and conditional knockout mice. Based on these results, we are currently investigating mechanisms through which FAK expression in myeloid lineage cells may regulate the response of lymphocytes to the early stages of tumor outgrowth. 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 1358.