Our results failed to show any modification of IL-6 after rosiglitazone or pioglitazone treatment

ecurrence of PaC, we first report that CHG is capable to increase the CXCL12 concentration in human PSC culture medium. Majority of PaC cell lines express CXCR4 and CXCR7, the receptors of CXCL12. Beta-arrestin-2 and K-Ras dependent pathways coordinate the transduction of CXCL12 signals, and the source of CXCL12 in PaC tissue is the PSC that acts in a paracrine way on cancer cells. T3M4 cells express CXCR4 as the majority of other pancreatic cancer cell lines and we also report that direct hyperglycemia and both types of PSC culture media exposures slightly increased the CXCR4 protein expression on T3M4 cells. In addition the partial inhibition of the CHG exposed PSC/CCM induced cancer cell proliferation by AMD3100, a specific CXCR4 blocker strongly refers to the functional role 12 / 18 Effect of Hyperglycemia on Pancreatic Stellate and Cancer Cells Fig 6. Summary of signaling pathways induced by chronic hyperglycemia in human pancreatic stellate cells and PaC cells. These results suggest a role of metabolic factors in PSC activation that may provide profibrogenic stimuli to a lesser extent proliferation signals in these stromal cells. Hyperglycemia also induced a cancer-associated secretion pattern of PSCs that may alter the pancreatic tumor microenvironment. Increased p38 phosphorylation may play an important role and CDC25/SP1 may convey the signals in the PSC nucleus that results in increased secretion of CXCL12 and IGFBP2 that may have an effect on pancreatic cancer cells. doi:10.1371/journal.pone.0128059.g006 of the CXCL12-CXCR4 binding. The T3M4 cells 946128-88-7 web PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19698015 also posessed CXCR7, a scavanger receptor for CXCL12. Despite that in our system some of the previously reported key beta-arrestin dependent signaling molecules were not induced by the treatments, a role for the CXCR7 receptor induction of the MAPK pathways in the T3M4 cells may still not be excluded. We concluded that CHG influences the communication between PSCs and PaC cells and the increased CXCL12 levels may contribute to the progression of PaC. IGFBP2 overexpression was found in the pancreatic juice collected during ERCP in patients with PaC compared to those with benign pancreatic lesions. We report that CHG exposure with subsequent TGF-1 treatment significantly increases IGFBP2 protein production by PSCs. The increased IGFBP2 levels may not only be biomarkers of PaC, but also may contribute to the development 13 / 18 Effect of Hyperglycemia on Pancreatic Stellate and Cancer Cells and progression of PaC via their RGD domain binding to integrins . The PSC-CCM medium significantly induced the proliferation of cancer cells in the SRB test after 72 hours, provided that PSCs were prior exposed to CHG. In addition to CXCR4-dependent mechanisms other signals are likely to contribute to the cancer cell PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19697363 proliferation induced by the PSCCCM due to that AMD3100 could only partially antagonize this proliferation promoting effect. Hyperglycemia profoundly increased the migration of T3M4 cells both directly and also indirectly via the alteration of PSC cell culture medium. The GLUT-1 and GLUT-3 transporters that are expressed on T3M4 cells may indicate a potentially increased glucose uptake occuring concomittantly to the Warburg effect in cancer cells. It was reported that GLUT-1 is essential in the maintenance of self-renewal of the pancreatic cancer stem cell population and the inhibition of GLUT-1 resulted in the inhibition of the tumor initiating capacity of CSC, suggesting that increas