The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressed and stimulated by its ligand somatostatin in pancreatic cancer. We reveal a mechanism underlying oncosuppressive action of sst2, whereby this inhibitory receptor upregulates the expression of the secreted angioinhibitory factor thrombospondin-1 (TSP-1), as demonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation of TSP-1 occurs through the inhibition of the PI3K pathway. It depends on transcriptional and translational events, involving a previously undescribed IRES in the 5'-UTR of TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivo model to demonstrate that TSP-1 is a critical effector of the inhibitory role of sst2 on the neoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced in vitro tubulogenesis of endothelial cells when grown in conditioned medium from pancreatic cancer cells expressing sst2, as compared to those expressing the control vector. TSP-1 inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenic factor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation in endothelial cells. Using human pancreatic tissue-microarrays, the expression of both sst2 and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Both proteins are nearly undetectable in normal exocrine pancreas and in most invasive cancer lesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacent lesions. The upregulation of both sst2 and TSP-1 tumor suppressors may function as an early negative feedback to restrain pancreatic carcinogenesis.