Mechanisms of cancer cell invasion
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An important step in the process of metastasis from the primary tumor is invasive spread into the surrounding stroma. In this thesis, I have studied the process of tumor cell invasion in the primary tumor. It has been previously shown that imposed gradients of epidermal growth factor (EGF) or colony-stimulating factor-1 (CSF-1) can induce invasion through an EGF/CSF-1 paracrine loop between breast cancer cells and macrophages. We found that invasion induced by other ligands also relies on this EGF/CSF-1 paracrine invasive loop. Using an in vivo invasion assay, we showed that MTLn3 breast cancer cells overexpressing ErbB3 and transgenic MMTV-Neu tumors invade in response to HRG-betal, and that CXCL12 also triggers in vivo invasion of transgenic MMTV-PyMT tumors in an EGF/CSF-1-dependent manner.;We studied signaling from ErbB3 in more detail. ErbB3 contains motifs for the binding of the p85 subunit of PI3-kinase. We tested the hypothesis that the PI3-kinase signaling pathway coupled to ErbB3 is critical for motility, and therefore crucial for invasion, intravasation and metastasis to occur. This overexpression of the mutant ErbB3 does not enhance chemotaxis towards HRG-betal in vitro or in vivo. It reduced total tumor cell motility in the primary tumor, as well as a dramatically reduced ability of these cells to intravasate, and metastasize.;While our studies in breast cancer models indicate that macrophages are critical to in vivo invasion, we tested whether this would apply in another type of cancer. Utilizing orthotopic models of head and neck squamous cell carcinoma (HNSCC), we tested the in vivo invasion response to EGF and CXCL12. Surprisingly, macrophage contributions were not required. CXCL12-induced in vivo invasion of HNSCC cells was observed and found to occur via a unidirectional transactivation of EGFR by CXCR4. Further experiments suggested that CXCL12 activates EGFR by stimulating the release of EGFR ligands.;In summary, these studies reveal the complexity of cancer cell invasion. To understand how to target and inhibit this process, we must study not only how tumor cells respond to external stimuli, but also identify synergistic interactions in the tumor microenvironment and how these interactions can vary with tumor type.