review of literature on clinical pancreatology - The Pancreapedia

immunostain (-60 %). Rosiglitazone reduced fasting glucose and insulin but induced weightgain. Fibrates impeded weight gain, but only bezafibrate prevented islet hypertrophy. TheGLUT2 stain was improved in all treatments, and there were no alterations in PPAR-alpha.There were morphological signs <strong>of</strong> pancreatitis with fen<strong>of</strong>ibrate, although there were noalterations in amylase and lipase. Rosiglitazone exacerbated pancreatic fat infiltration (+75 %vs HFHS group), and bezafibrate increased PPAR-beta expression in pancreatic islets. Theauthors concluded that rosiglitazone is shown for the first time to exacerbate pancreatic fatinfiltration; therefore, precaution has to be taken when rosiglitazone is prescribed to obesepatients [397].Somatostatin receptor subtype 2The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressedand stimulated by its ligand somatostatin in pancreatic cancer. It was reveal a mechanismunderlying oncosuppressive action <strong>of</strong> sst2, whereby this inhibitory receptor upregulates theexpression <strong>of</strong> the secreted angioinhibitory factor thrombospondin-1 (TSP-1), asdemonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation <strong>of</strong> TSP-1 occurs through the inhibition <strong>of</strong> the PI3K pathway. Itdepends on transcriptional and translational events, involving a previously undescribed IRESin the 5'-UTR <strong>of</strong> TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivomodel to demonstrate that TSP-1 is a critical effector <strong>of</strong> the inhibitory role <strong>of</strong> sst2 on theneoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced invitro tubulogenesis <strong>of</strong> endothelial cells when grown in conditioned medium from pancreaticcancer cells expressing sst2, as compared to those expressing the control vector. TSP-1inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenicfactor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation inendothelial cells. Using human pancreatic tissue-microarrays, the expression <strong>of</strong> both sst2and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Bothproteins are nearly undetectable in normal exocrine pancreas and in most invasive cancerlesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacentlesions. The upregulation <strong>of</strong> both sst2 and TSP-1 tumor suppressors may function as anearly negative feedback to restrain pancreatic carcinogenesis [398].SphingolipidsDefeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains achallenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improvingtumor chemosensitivity has recently emerged as a promising strategy. The fine balancebetween intracellular levels <strong>of</strong> the prosurvival sphingosine-1-phosphate (S1P) and theproapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control thismetabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed inmany cancers, favors survival through S1P production, and inhibitors <strong>of</strong> SphK1 are used inongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to variouschemotherapeutic drugs. It was reported that the cellular ceramide/S1P ratio is a criticalbiosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level <strong>of</strong> theceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsicpancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing theceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or smallinterfering RNA-based approaches to up-regulate intracellular ceramide levels or reduceSphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasingthe ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance inthese cells [399].