Interference with TGF-beta1 and -beta3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma.
A high tumor interstitial fluid pressure (TIFP) is a pathologic characteristic distinguishing the stroma of carcinomas from normal interstitial loose connective tissues. The role of TGF-beta1 and -beta3 in generating a high TIFP was investigated in xenografted experimental anaplastic thyroid carcinoma (ATC) derived from the human ATC cell line KAT-4. A single intravenous injection of a soluble recombinant TGF-beta receptor type II-murine Fc:IgG(2A) chimeric protein that specifically inhibits TGF-beta1 and -beta3, significantly lowered TIFP in a time and concentration dependent manner but did not change total tissue water content in the tumors. Tumor growth rate was higher in tumors treated with the TGF-beta1 and -beta3 inhibitor compared to control tumors during the first 10 days after administration of the inhibitor. The apoptotic index of carcinoma cells, and expression of the cell cycle inhibitor p27(Kip1), were, however, increased in TGF-beta1 and -beta3 inhibitor-treated tumors. Prolonged treatment periods and administration of a second dose of the inhibitor decreased tumor growth rate. The TGF-beta1 and -beta3 inhibitor did not affect proliferation or expression of phosphorylated Smad2 protein in KAT-4 cells cultured in vitro. Our results indicate that members of the TGF-beta family are potential targets for novel anti-cancer treatment directed to the stroma. First by controlling TIFP and by that potentially the uptake of anticancer drugs into tumors and second by their suggested role in maintaining a supportive tumor stroma.
Lammerts
Ellen
E
Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Uppsala, Sweden.
Roswall
Pernilla
P
Sundberg
Christian
C
Gotwals
Philip J
PJ
Koteliansky
Victor E
VE
Reed
Rolf K
RK
Heldin
Nils-Erik
NE
Rubin
Kristofer
K
D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005110:Extracellular Space / Q000502:physiology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D011312:Pressure; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D017154:Stromal Cells / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II