ZIA BC 011390 (ZIA) | |||
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Title | Vascular Biology in Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Lin, Pengnian Charles | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,299,113 | Project Dates | 10/01/2010 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Arthritis (5.0%) Autoimmune Diseases (5.0%) Cancer (100.0%) Digestive Diseases (25.0%) Metastasis (30.0%) |
Breast (25.0%) Colon/Rectum (25.0%) Lung (25.0%) Vascular Disease (25.0%) |
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Research Type | |||
Cancer Progression and Metastasis Development and Characterization of Model Systems |
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Abstract | |||
1. Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer. A fluorescence-based, high-resolution imaging approach was developed to visualize longitudinally the cellular events unfolding during T cell-mediated tumor destruction. The dynamic interplay of T cells, cancer cells, and stromal cells-all color-coded in vivo-was analyzed in established, solid tumors that had developed behind windows implanted on the backs of mice. Events could be followed repeatedly within precisely the same tumor region-before, during and after adoptive T cell therapy-thereby enabling for the first time a longitudinal in vivo evaluation of protracted events, an analysis not possible with terminal imaging of surgically exposed tumors. T cell infiltration, stromal interactions, and vessel destruction, as well as the functional consequences thereof, including the elimination of cancer cells and cancer cell variants were studied. Minimal perivascular T cell infiltrates initiated vascular destruction inside the tumor mass eventually leading to macroscopic central tumor necrosis. Prolonged engagement of T cells with tumor antigen-cross presenting stromal cells correlated with high IFNgamma cytokine release and bystander elimination of antigen-negative cancer cells. This high-resolution, longitudinal, in vivo imaging approach described here will help to further a better mechanistic understanding of tumor eradication by T cells and other anti-cancer therapies. This work was published in Oncoimmunology 2013. 2. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. In this study, we set out to identify cancer-secreted miRNAs that participate in cancer metastasis by adapting the niche cells. Our results demonstrate an important role of miR-105 in destroying the vascular endothelial barriers in the host during early premetastatic niche formation by targeting the cellular tight junctions. In breast cancer patients, increased levels of miR-105 in the circulation can be detected at the premetastatic stage and correlate with the occurrence of metastasis. Anti-miR-105 treatment suppresses metastasis and abolishes the systemic effect of tumor-derived miR-105 on niche adaptation. Therefore, these observations strongly suggest clinical applications of miR-105 as a predictive or early diagnostic blood-borne marker as well as a therapeutic target for breast cancer metastasis. This work was published as a featured article in Cancer Cell 2014, received commentary in Sci. Signal, Nature Medicine, Nature Review Genetics, Nature Review Cancer, Nature Review Drug Discovery, SciBX, and Cancer Research. 3. Critical roles of Vav1 in vascular homeostasis that protects the heart from ischemia-induced injury. Myocardial perfusion is a key component of cardiac homeostasis. Failure to induce sufficient perfusion represents a major cause of myocardial dysfunction and heart failure. This study reveals a novel function of Vav1 in maintaining cardiac homeostasis under ischemic stress. Vav1 is a GEF protein known to be expressed in hematopoietic cells. Since blood and endothelial cells share a common progenitor, we found expression of Vav1 in coronary endothelium in the heart, but not in myocardiocytes. Notably, genetic deletion of Vav1 in mice leads to the development of pathological cardiac hypertrophy with impaired left ventricular (LV) function with aging, which is associated with a significant reduction of coronary vascular density. This finding is consistent with its GEF function in regulating endothelial cell motility and angiogenesis. Although there is no difference in LV function or vascular density between the Vav1 null and WT mice at a young age, the Vav1 null mice show a fragile cardiac phenotype when cardiac hypertrophy is induced by isoproterenol administration. Moreover, Vav1 deficient mice exhibit a tendency to sudden death after coronary ligation, which is associated with leaky vasculature and in" |