John S. Condeelis, PhD [ View bio ](Albert Einstein College of Medicine, Yeshiva University)
Multi-photon microscopy (MPM) allows the direct observation of the behavior of individual cells in vivo. In mammary tumors MPM demonstrates that invasive/migratory carcinoma cells form migratory streams and intravasate when associated with macrophages. Taking advantage of this macrophage tropism allows collection of the migratory competent macrophages and tumor cells as live cells directly from the primary tumor. Expression profiling of these co-migratory tumor cells and macrophages has led to the surprising conclusion that both cell types exhibit embryonic expression patterns. Further analysis indicates that the tumor cells express genes associated with breast cancer stem cells, apoptosis and cell cycle arrest, and DNA repair. Consistent with this unusual expression pattern are the phenotypes of the isolated tumor cells: radiation and chemotherapy resistance, arrest in G0-1 and a greatly amplified ability of tumor cells to find and co-migrate with macrophages, interact with endothelial cells and intravasate. Consistent with the embryonic expression pattern is the observation that tumor cell migration with macrophages in vivo in mammary tumors is reminiscent of cell migration during angiogenesis and morphogenesis in the embryonic breast.
The expression pattern unique to the migratory tumor cells is called the Invasion Signature. Invasion, adhesion and motility pathways identified in the Invasion Signature converge on the RhoC/Cofilin/Mena pathway identifying it as a master regulator of chemotaxis, invasion and dissemination of breast tumor cells in vivo. Using markers derived from the RhoC/Cofilin/Mena pathway, anatomical landmarks have been developed to identify sites of intravasation in breast cancer patients. One of these, composed of a carcinoma cell in direct contact with the endothelium, marked by Mena over-expression, and a peri-vascular macrophage, is called TMEM (Tumor MicroEnvironment for Metastasis) in human breast tumors. TMEM is the site of intravasation-directed transendothelial migration and its assembly is related to the efficiency of tumor cell dissemination. The functioning of TMEM in live tumors in vivo has been imaged using high resolution MPM. The number of TMEM per unit area of breast tumor tissue is predictive of metastatic risk in human invasive ductal carcinomas. The molecular mechanisms behind TMEM assembly and its function in transendothelial migration will be discussed.
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