Authors: Mark Hartel Fabio F di Mola Andrea Gardini Arthur Zimmermann Pierluigi Di Sebastiano Ahmed Guweidhi Paolo Innocenti Thomas Giese Nathalia Giese Markus W Büchler Helmut Friess
Publish Date: 2004/08/03
Volume: 28, Issue: 8, Pages: 818-825
Abstract
Connective tissue growth factor CTGF which is regulated by transforming growth factorß TGFß has recently been implicated in the pathogenesis of fibrotic diseases and tumor stroma Inasmuch as generation of desmoplastic tissue is characteristic for pancreatic cancer it is not known whether it gives pancreatic cancer cells a growth advantage or is a reaction of the body to inhibit cancer cell progression In the present study we analyzed the expression and localization of CTGF and evaluated whether it influences the prognosis of pancreas cancer Tissue samples were obtained from 25 individuals 6 women 19 men undergoing pancreatic resection for pancreatic cancer Tissue samples from 13 previously healthy organ donors 5 women 8 men served as controls Expression of CTGF was studied by Northern blot analysis In situ hybridization and immunohistochemistry localized the respective mRNA moieties and proteins in the tissue samples Northern blot analysis revealed that pancreatic cancer tissue samples exhibited a 46fold increase in CTGF mRNA expression p 0001 over that of normal controls In vitro studies confirmed that pancreatic stellate cells are the major source of CTGF mRNA expression and revealed a large variance in basal and TGFßinduced CTGF expression in cultured pancreatic cancer cells This could also be confirmed by in situ hybridization indicating that CTGF mRNA signals were located principally in fibroblasts with only weak signals in the cancer cells High CTGF mRNA levels in the tissue samples correlated with better tumor differentiation p 003 In addition patients whose tumors exhibited high CTGF mRNA levels onefold increase above normal controls lived significantly longer than those whose tumors expressed low CTGF mRNA levels none to onefold p 004 multivariate analysis Our present data indicate that CTGF as a downstream mediator of TGFß is overexpressed in connective tissue cells and to a lesser extent in pancreatic cancer cells Because patients with high CTGF mRNA expression levels have a better prognosis our findings indicate that the desmoplastic reaction provides a growth disadvantage for pancreatic cancer cellsThis study was in part supported by the “Compagnia di San Paolo” Fund grant Italy Oncology Program awarded to P Innocenti grant 11583/23720 and by the DFG Deutsche Forschungsgemeinschaft grant SE 1095/11 awarded to P Di Sebastiano and H Friess Dr FF di Mola is a surgical resident whose research stay was supported by the University of Chieti Italy Dr A Gardini is a resident of the Department of General and Transplantation Surgery University of Bologna Italy and his research stay was supported by the Italian Ministry of University
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