The process of metastasis involves many distinct steps starting from migration of tumor cells out of the I 9rimary tumor into the blood stream and ending with the final formation of a colony at a distant site. During previous work on this grant, we had shown that expression of MMP-9 enhanced lung colomzanon ori netastasis and conversely that down-regulation of MMP-9 in tumor cells depressed pulmonary metastasis. It is now our goal to determine more precisely how MMP-9 facilitates metastasis. To further this goal, we first needed to develop methods to study the steps of metastasis individually. Many of the more commonly used assays for metastasis involve formation of primary tumors followed by necropsy or intravenous injection similarly followed by necropsy. These assays simulate metastasis and certainly allow quantitative assessments of metastasic potential, but they do not allow the dissection of steps during metastasis formation. Accordingly we have developed methods of visualizing the lung and its blood vessels during early lung colonization. These methods have allowed us to formulate a series of steps during metastasis that include first, attachment of the tumor cell to the pulmonary vessels, then survival at that site, followed by intravascular proliferation. Finally extravasation is achieved after intravascular colonies result in loss of vascular integrity. We now intend to determine where in this sequence of events, MMP-9 affects metastasis. Our preliminary results indicate that MMP-9 augments attachment to the pulmonary vessels. Pulmonary arrest is a little studied, but critical facet of metastasis. Pursuit of the aims proposed will enhance our understanding of pulmonary attachment. These experiments will allow us to better understand how MMP-9 affects metastasis. They will also provide new information about the processes tumor cells use to attach to pulmonary vessels. They will provide a paradigm for delineating the steps of metastasis that can be applied to many proteins known to affect metastasis.
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