The outcome of treating primary and metastatic brain tumors with anti-angiogenic therapy in which these agents were delivered in conjunction with chemotherapy and irradiation has been limited to minimal increase in the survival of patients. Paradoxically, in certain mouse tumor models, anti-angiogenic agents injected as single agents, presumably through the inducfion of hypoxia, have enhanced tumor invasiveness. These data have suggested that endothelial cells (ECs) regulate tumor growth not merely by passively delivering oxygen and nutrients. ECs also establish an instructive vascular niche that by production of paracrine growth factors, which we define as "angiocrine factors", support progression of brain tumors (Butler JM et al, Nature Cancer Reviews 2010). We have shown that Akt-activated ECs by producing angiocrine factors support regenerafion of certain organs, including bone marrow (BM) (Butler JM et al Cell Stem Cell, 2010), liver (Ding B et al Nature, 2010), and tesfis (Seandel et al Nature, 2007) and progression of leukemias (Vincent et al JCI, 2007), Based on these data, we propose that brain ECs establish an instructive "Vascular Niche" that by producing angiocrine factors directly promote progression and invasiveness of primary and metastatic brain tumors. In project 3, we have proposed experiments to identify and target key angiocrine factors that are upregulated by the human and mouse brain tumor ECs, in the hope of abrogating brain tumor growrth and metastasis as well as reversing resistance to standard therapy. We will take advantage of the human and mouse brain tumor models and bioluminescence imaging established in Holland's lab (PDGF-B/proneural gliomas) and metastatic lung and breast xenograft models developed by Massague lab to identify the key angiocrine factors induced in the ECs that initiate and sustain brain tumors.
These aims will be achieved by executing the following specific aims. Determine the potential of conditional selective activation of mryAktl and MAPkinase in ECs in sustaining the growth of human and mouse primary and metastatic brain tumors, in vitro (Aim1) and in vivo (Aim2), Aim 3) Assess whether conditional deletion or overexpression.of glioma-active angiocrine factors in ECs or non-EC stromal cells abrogates metastasis to brain and impairs the growth of gliomas (Aim 3).
Aim 4) Identify as yet unrecognized angiocrine factors in ECs of human and mouse tumors (Aim 4). Finally, in Aim 5 we plan to determine the effectiveness of targeting angiocrine factors via systemic delivery of highly efficient sIRNA against brain tumor specific angiocrine factors in blocking the growth and reversing chemotherapy resistance of brain tumors.
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