Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma.
Proliferation of fibrotic tissue (desmoplasia) is one of the hallmarks of several epithelial tumors including pancreatic adenocarcinoma. This tissue reaction may be deleterious or advantageous to the host or tumor. In a systematic analysis, we identified two growth factors expressed by human pancreatic carcinoma cells that are positively correlated with the ability to induce fibroblast proliferation both in vitro and in vivo, i.e., transforming growth factor (TGF)-beta1 and fibroblast growth factor-2. Here we demonstrate that the overexpression of TGF-beta1 induced up-regulation of matrix proteins and growth factors in the TGFbeta1-transfected pancreatic tumor cells. Furthermore, transfection of PANC-1 cells induces the same change in fibroblasts in either cocultivation experiments or when they are grown in conditioned medium from TGF-beta1-transfected PANC-1 cells. TGF-beta1-transfected pancreatic tumor cells induced a rich stroma after orthotopical transplantation in the nude mouse pancreas. The transfer of a single growth factor, TGF-beta1, conveys the ability to induce a fibroblast response similar to that seen in desmoplasia in human pancreatic adenocarcinoma. This effect cannot only be attributed to direct effects of TGF-beta1 but also results from the up-regulation of several other factors including collagen type I, connective tissue growth factor, and platelet-derived growth factor.
Löhr
M
M
Department of Medicine, University of Rostock, Germany. matthias.loehr@med4.ma.uni-heidelberg.de
Schmidt
C
C
Ringel
J
J
Kluth
M
M
Müller
P
P
Nizze
H
H
Jesnowski
R
R
D000818:Animals; D002455:Cell Division; D018920:Coculture Techniques; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
D016326:Extracellular Matrix Proteins; D006133:Growth Substances; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2