Metastasis disease is the leading cause of cancer-related mortality with very few effective treatment options available for patients. Metastases are characterized by the presence of vascular proliferation, a subpopulation of stem-like cells and infiltration by various bone marrow derive cells (BMDCs). BMDCs have been shown to provide the premetastatic niches that promote the angiogenic process and create an environment permissive for tumor cell homing and colonization. The cancer stem cell (CSC) theory defines a subset of cancer cells with the exclusive ability to drive the growth and spread of a tumor. This research proposal is founded on the hypothesis that the CSC theory also applies to the metastasic process. The aims are to determine the relative contribution of CSCs to tumor cell homing, their ability to recruit BMDCs and induce angiogenesis. The final goals are to elucidate the mechanisms that participate in these phenomena and to develop novel therapeutic strategies to overcome metastasis initiation and progression.Briefly, using well-defined models of lung and liver metastasis, we will 1- determine if CSCs are more metastatic and angiogenic than non-CSCs; 2- identify the genes responsible for the metastatic and angiogenic capacity; 3- characterize the role of CSCs in the recruitment of BMDC; 4- examine whether cancer cells secrete factors that directly activate myeloid cells to produce tumor-promoting cytokines; 5- quantify the number of CSCs in samples from patients with lung and liver metastasis and validate their metastatic potential.