This PPG focuses on the spatial and temporal regulation of tumor angiogenesis, associated vascular hyperpermeability, and stroma generation. The overriding hypothesis is that tumor vessels and stroma are essential for tumor growth and survival and that they offer attractive targets for tumor therapy. The goal is to achieve a much better understanding of the pro- and anti-angiogenic forces that regulate these processes in order to find novel points of attack that can prevent tumor angiogenesis and stroma formation and deprive tumors of existing vessels and stroma. Four interactive Projects are proposed: Project 1 will focus on the role of TR3/Nur77, an orphan transcription factor critical for the induction of VEGF-A-induced angiogenesis and vascular permeability. It will also elucidate the signaling pathways by which VEGF-A regulates TR3/Nur77's expression and transcriptional activation. Project 2 will investigate the effects of rapamycin on the Akt-mTOR signaling pathway and its effects on tumor stroma that lead to tumor growth inhibition. The Hypothesis is that rapamycin inhibits tumor angiogenesis more potently than it inhibits tumor cells and that these anti-stromal effects mediate much of rapamycin's anti-tumor efficacy.
Aims will seek to identify the vascular targets of rapamycin, the molecular changes in the Akt-mTOR signaling pathway that mediate its anti-angiogenic effects, and explore the role of Akt signaling on tumor cell trafficking across vascular endothelium. Project 3 will investigate the role of estrogen and its receptor (ER?) on angiogenesis and other aspects of stroma generation that favor systemic angiogenesis and tumor growth. Further, it will investigate the mechanisms by which estrogen-ER? interactions lead to bone marrow mobilization, accumulation in tumor sites, and differentiation into tumor-supporting myofibroblasts and histiocytes. Project 4 will investigate the effectiveness of the three type 1 repeats (3TSR) component of thrombospondin-1 (TSP-1), in combination with TRAIL receptor agonist antibodies, in inhibiting tumor growth. It will also identify the receptors and signaling molecules that mediate the anti-angiogenic activity of TSP-1 and 3TSR. Together these preclinical studies will contribute much to an understanding of the signaling pathways by which tumors induce angiogenesis and stroma formation and are expected to identify pathways and molecules that can be used as therapeutic targets in cancer treatment.
|Skibinski, Adam; Breindel, Jerrica L; Prat, Aleix et al. (2014) The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment. Cell Rep 6:1059-72|
|Lin, Chi-Iou; Merley, Anne; Sciuto, Tracey E et al. (2014) TM4SF1: a new vascular therapeutic target in cancer. Angiogenesis 17:897-907|
|Chin, Y Rebecca; Yoshida, Taku; Marusyk, Andriy et al. (2014) Targeting Akt3 signaling in triple-negative breast cancer. Cancer Res 74:964-73|
|Chin, Y Rebecca; Yuan, Xin; Balk, Steven P et al. (2014) PTEN-deficient tumors depend on AKT2 for maintenance and survival. Cancer Discov 4:942-55|
|Phillips, Sarah; Prat, Aleix; Sedic, Maja et al. (2014) Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation. Stem Cell Reports 2:633-47|
|Lin, Chi-Iou; Lau, Chun-Yee; Li, Dan et al. (2014) Nanopodia--thin, fragile membrane projections with roles in cell movement and intercellular interactions. J Vis Exp :|
|Rowe, Glenn C; Raghuram, Srilatha; Jang, Cholsoon et al. (2014) PGC-1? induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115:504-17|
|Elloul, Sivan; Kedrin, Dmitriy; Knoblauch, Nicholas W et al. (2014) The adherens junction protein afadin is an AKT substrate that regulates breast cancer cell migration. Mol Cancer Res 12:464-76|
|Kazerounian, Shiva; Gerald, Damien; Huang, Minzhou et al. (2013) RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Cancer Res 73:50-61|
|Arendt, Lisa M; McCready, Jessica; Keller, Patricia J et al. (2013) Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 73:6080-93|
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