Epigenetics and cancer, CNRS FRE3239.
The antitumor effects of pharmacological inhibitors of angiogenesis are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here, we reevaluated the role of the endogenous antiangiogenic Thrombospondin 1 (TSP1) in prostate carcinomas where angiogenesis is an active process. In xenografted tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered tumor development. Our results show that TSP1 is a potent stimulator of prostate tumor cells migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived peptide. As suspected for pharmacological inhibitors of angiogenesis, the TSP1 capacities to increase hypoxia and to trigger cell migration are thus inherently linked. Importantly, while antiangiogenic TSP1 increases hypoxia in vivo, our data show that, in turn, hypoxia induced TSP1, thus generating a vicious circle in prostate tumors. In radical prostatectomy specimens, we found TSP1 expression significantly associated with invasive tumors and with tumors which eventually recurred. TSP1 may thus help select patients at risk of PSA relapse. Together, the data suggest that intra-tumor disruption of the hypoxic cycle through TSP1 silencing will limit tumor invasion.
Written by:
Firlej V, Mathieu JR, Gilbert C, Lemonnier L, Nakhlé J, Gallou-Kabani C, Guarmit B, Morin A, Prevarskaya N, Barry-Delongchamps N, Cabon F. Are you the author?
Reference: Cancer Res. 2011 Oct 28. Epub ahead of print.
PubMed Abstract
PMID: 22037878
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