title: Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells.
abstract: BACKGROUND
  Diabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment.
  
  
  RESULTS
  The effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: αSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARγ after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-β1 treatment (3.09-fold with a 2.73-fold without TGF-β1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC's conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour.
  
  
  CONCLUSIONS
  Hyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration.
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Kiss
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: Children's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Sándor
authors.initials: S
authors.lastname: Spisák
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany; School of Ph.D. Studies, Semmelweis University, Budapest, Hungary.
authors.forename: Szilárd
authors.initials: S
authors.lastname: Szanyi
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Tulassay
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Zalatnai
authors.affiliation: Karolinska Institutet, Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J-Matthias
authors.initials: JM
authors.lastname: Löhr
authors.affiliation: University of Heidelberg, Medical Campus Mannheim, Dept. of Medicine II, Mannheim, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jesenofsky
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.affiliation: 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Firneisz
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D020935:MAP Kinase Signaling System; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D019718:Receptors, CXCR4