A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental
carcinoma. The soluble
TGF-beta receptor type II-murine Fc:
IgG2A chimeric
protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for
anaplastic thyroid carcinoma. Analyses of
messenger RNA (
mRNA) expressions by Affymetrix microarrays and
RNase protection assays, as well as of
protein expressions identified
tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced
albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4
carcinoma blood vessels. Specific inhibition of
interleukin-1 (IL-1), a major
cytokine produced by activated macrophages, lowered
carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of
IL-1 changed blood vessel density. Finally, pretreatment of KAT-4
carcinomas with Fc:TbetaRII increased the antitumor efficacy of
doxorubicin. Our data emphasize a potential role of
tumor macrophages in
carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of
chemotherapy.