The tumor microenvironment has a variety of important effects in cancer progression. These include tumor growth rate, metastatic potential, and therapeutic response. Using 4 transgenic mouse models carrying selected sets of mutations, we have documented that the initiating genetic signature of a tumor has a significant impact on the form and function of the tumor vasculature arising in otherwise genetically identical mammary glands. In addition, we find that the response to angiogenesis inhibitors varies depending on the initiating mutation. The findings imply that the tumor microenvironment imprints alterations on the tumor vasculature; One (1) consequence is an altered response to anti-angiogenic therapy. Since in our hands no single anti-angiogenic therapy worked equally well on all transgenic tumor models, we became interested in pursuing a different strategy for anti-angiogenesis. Specifically """"""""Is it possible to identify therapies that affect endothelial cells prior to the acquisition of microenvironmentally-induced changes?"""""""" Using a genetically trackable system for endothelial cell progenitors (from a transgenic line we have produced), we found that a significant percentage of the vascular endothelial cells in tumors originates from these precursor population present in bone marrow. A greater understanding of this population could lead to novel, and perhaps more effective, targets for anti-angiogenic therapies. The driving hypothesis of this application is that genetic modification of bone marrow-derived endothelial cell progenitors (BM-ECP) can effectively reduce neovascularization in tumors. We propose to directly test this hypothesis and gain insights into the role of BM-ECPs in tumor neovascularization.
The specific aims of this application include: (1) Evaluate the contribution of endothelial cell progenitors to the neovasculature of tumors with specific oncogenic signatures; (2) Determine whether manipulation of endothelial cell progenitors can effectively suppress neovascularization in tumors; and (3) Determine whether molecular alterations in endothelial cell progenitors can affect their vascular engraftment with consequent inhibition of tumor growth.
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| Miranda-Carboni, Gustavo A; Krum, Susan A; Yee, Kathleen et al. (2008) A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors. Genes Dev 22:3121-34 |
| Monvoisin, Arnaud; Alva, Jackelyn A; Hofmann, Jennifer J et al. (2006) VE-cadherin-CreERT2 transgenic mouse: a model for inducible recombination in the endothelium. Dev Dyn 235:3413-22 |
