Inhibition of TGF-β modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF- β receptor type II-murine Fc:IgG 2A chimeric protein (Fc:T β RII) 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:T β RII. Treatment with Fc:T β RII reduced albumin extravasation, increased coverage of α -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:T β RII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:T β RII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:T β RII 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.