Interference with TGF-β1 and -β3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma

Abstract

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-β1 and -β3 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-β receptor type II-murine Fc:IgG2A chimeric protein that specifically inhibits TGF-β1 and -β3, 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-β1 and -β3 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 p27Kip1, were, however, increased in TGF-β1 and -β3 inhibitor-treated tumors. Prolonged treatment periods and administration of a second dose of the inhibitor decreased tumor growth rate. The TGF-β1 and -β3 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-β family are potential targets for novel anti-cancer treatment directed to the stroma. First by controlling TIFP and by that potentially the uptake of anti-cancer drugs into tumors and second by their suggested role in maintaining a supportive tumor stroma. © 2002 Wiley-Liss, Inc.