Abstract 419: Motility pathways identified in invasive tumor cells isolated from live human breast tumors.

Metastasis is a multicomponent process, with potentially different tumor cell properties and molecules of the motility pathways playing critical roles in the individual steps of metastasis (Nat Rev Cancer. 2007. 7:429-40, Nat Rev Cancer. 2003. 3:921-30). Therefore, the development of new molecular and imaging methods to identify new genes that contribute to specific cell behavioral steps in metastasis is crucial. We have used 2-photon intravital imaging to observe tumor cell invasion and intravasation directly in living mouse and rat mammary tumors and have shown that dissemination of tumor cells involves active motility and transendothelial migration into blood vessels (Cancer Res. 2007. 67:3505-11). Infiltrating macrophages promote these behaviors of carcinoma cells via a colony-stimulating factor-1/epidermal growth factor (CSF-1/EGF) paracrine loop (Cancer Res. 2005. 65:5278-83; Cancer Res. 2004. 64:8585-94). Finally we have exploited these observations to develop methods to collect invasive tumor cells for expression profiling to derive an invasion gene signature (ARCDB 2005 21:695). We are using the methods we developed in the rat and mouse models to investigate microenvironments in human breast tumor metastasis. Recently we have showed that invasion in the human breast cancer MDA-MB-231 xenograft is dependent on both the EGF/CSF-1 paracrine signaling with host macrophages, as well as an autocrine signaling in the tumor cells that express both CSF-1 and its receptor, CSF-1R (Cancer Res. 2009. Nov 24 Epub). Most interestingly, the autocrine-mediated invasion is a tumor microenvironment specific event, as it occurs only in the mammary tumor in vivo due to a transforming growth factor-β1 -mediated upregulation of the CSF-1R. In addition, we have used microarray analysis and quantitative PCR to directly compare the invasive human tumor cells as collected from the live mammary primary tumor, to the average tumor cells of the same primary tumor in the MDA-MB-231 xenograft. We found changes in gene expression in a pattern that is unique to the invasive subpopulation of human tumor cells. This pattern (Human Invasion Signature) is reminiscent of the Invasion Signature described for invasive tumor cells from mouse mammary tumors but the specific genes involved are often different. These results suggest that invasive tumor cells use slightly different patterns of gene expression to achieve the same migratory phenotype and that human tumor cells will be different from mouse tumor cells in terms of the individual genes involved in determining the invasive phenotype. These results emphasize the importance of studying human tumors and patterns of expression rather than individual genes. Ultimately, the discovery of gene expression patterns involved in invasion and the formation of autocrine and paracrine loops in human tumors will provide new therapeutic targets and diagnostic markers. 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 419.