Thrombospondin-1 (TSP-1) is a homotrimeric secreted glycoprotein that functions in a wide variety of biologic activities including embryonic development, tissue differentiation, neurite outgrowth, and responses to injury and inflammation. TSP-1 is also a potent inhibitor of angiogenesis, the growth of new blood vessels from the existing vasculature. Decreased TSP-1 expression contributes to the angiogenic environment that supports the growth of glioblastoma, fibrosarcomas and bladder cancer. Data is presented that show TSP-1 expression is down-regulated or lost in benign prostatic hyperplasia (BPH) and prostate cancer and identify TSP-1 as a key functional inhibitor of angiogenesis in the prostate. The normal and diseased prostate is exquisitely sensitive to changes in TSP-1 levels as TSP-1 null mice develop prostatic hyperplasia and TSP-1 expression increased after androgen ablation therapy in human prostate cancer specimens. Thus, we hypothesize that TSP- 1 plays a key role in the regulation of normal prostatic growth and that dysregulated TSP-1 expression contributes to disease. To study the functions of TSP-1 in normal prostate growth and discern how dysregulated expression contributes to disease states, we plan to 1) characterize the prostate phenotype in the TSP-1 null mice, establishing a time course of disease development, and determine the underlying mechanism of the hyperplasia (i.e. increased proliferation or angiogenesis, decreased apoptosis or a combination of these), and 2) determine if androgen regulation of TSP-1 expression is critical to modulation of prostatic growth, using in vitro methods and the TSP-1 null mouse model. Results from these experiments should establish the function of TSP-1 in prostatic growth regulation and determine how TSP-1 may be useful as a prognostic indicator or as a treatment for prostatic diseases.
| Fitchev, Philip P; Wcislak, Susan M; Lee, Chung et al. (2010) Thrombospondin-1 regulates the normal prostate in vivo through angiogenesis and TGF-beta activation. Lab Invest 90:1078-90 |
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