title: Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay.
abstract: The effect of the characteristic desmoplastic reaction of pancreatic cancer on tumor progression is largely unknown. We investigated whether pancreatic stellate cells, which are responsible for the desmoplastic reaction, support tumor progression. Immunohistology revealed that matrix metalloproteinase-2 (MMP-2), which is suggested to promote pancreatic cancer progression, is present in stellate cells adjacent to cancer cells. In vitro, stellate cells exhibited a much higher basal expression of MMP-2 compared with cancer cells. Panc1-, MiaPaCa2- and SW850-conditioned media stimulated MMP-2 release of stellate cells as detected by zymography. Cancer cells expressed and released basigin [BSG, extracellular matrix metalloproteinase inducer (EMMPRIN), CD147], a glycoprotein that is known to stimulate MMP-2 in mesenchymal cells, as detected by immunostaining, western blot and reverse transcription-polymerase chain reaction. Tumor cell-conditioned medium and BSG purified by affinity chromatography from supernatants of cancer cells, but not supernatants depleted from BSG, stimulated expression of MMP-1 and MMP-2 of stellate cells as demonstrated by western blot and zymography. Moreover, the interaction of stellate cells and cancer cells promoted the invasiveness of Panc-1 cells in the chorioallantoic membrane assay and increased the weight of tumors induced by all carcinoma cell lines in nude mice by 2.1-3.7-fold. Our findings support the assumption that the interaction of stellate cells and cancer cells promotes progression of pancreatic cancer.
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schneiderhan
authors.forename: Fredy
authors.initials: F
authors.lastname: Diaz
authors.forename: Martin
authors.initials: M
authors.lastname: Fundel
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Zhou
authors.forename: Marco
authors.initials: M
authors.lastname: Siech
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hasel
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Gschwend
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.forename: Thomas
authors.initials: T
authors.lastname: Gress
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Max G
authors.initials: MG
authors.lastname: Bachem
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D051926:Basigin; D001681:Biological Assay; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000166:cytology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010179:Pancreas / Q000166:cytology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D017077:Culture Media, Conditioned; D051926:Basigin; D020778:Matrix Metalloproteinase 2