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Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2005 (English)In: Laboratory Investigation, ISSN 0023-6837, Vol. 85, no 4, 512-521 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2005. Vol. 85, no 4, 512-521 p.
Keyword [en]
anaplastic thyroid carcinoma, growth factors, interleukins, vasculature, xenograft tumors, soluble receptors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-73595DOI: 10.1038/labinvest.3700252PubMedID: 15711566 OAI: oai:DiVA.org:uu-73595DiVA: diva2:101505
Available from: 2005-06-10 Created: 2005-06-10 Last updated: 2017-11-10Bibliographically approved

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Salnikov, Alexei V.Roswall, PernillaSundberg, ChristianHeldin, Nils-ErikRubin, Kristofer

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