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Research Articles: Therapeutics, Targets, and Development

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

¹ Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel; ² Department of Surgery, McMaster University, Hamilton, Ontario, Canada; ³ Division of Hematology and ⁴ Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; ⁵ Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan; and ⁶ Developmental Biology Laboratory, CLUSTER Project, and 21st Century COE Program, Department of Biological Science, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Japan

Requests for reprints: Mark Pines, Institute of Animal Sciences, Volcani Center, P.O. Box 6, Bet Dagan, 50250, Israel. Phone: 972-8-9484408; Fax: 972-8-9475075. E-mail: pines{at}agri.huji.ac.il

Abstract

Stromal myofibroblasts play an important role in tumor progression. The transition of fibroblasts to myofibroblasts is characterized by expression of smooth muscle genes and profuse synthesis of extracellular matrix proteins. We evaluated the efficacy of targeting fibroblast-to-myofibroblast transition with halofuginone on tumor progression in prostate cancer and Wilms' tumor xenografts. In both xenografts, low doses of halofuginone treatment, independent of the route of administration, resulted in a trend toward inhibition in tumor development. Moreover, halofuginone synergizes with low dose of docetaxel in prostate cancer and vincristine and dactinomycin in Wilms' tumor xenografts, resulting in significant reduction in tumor volume and weight comparable to the effect observed by high doses of the respective chemotherapies. In prostate cancer and Wilms' tumor xenografts, halofuginone, but not the respective chemotherapies, inhibited the synthesis of collagen type I, -smooth muscle actin, transgelin, and cytoglobin, all of which are characteristics of activated myofibroblasts. Halofuginone, as the respective chemotherapies, increased the synthesis of Wilms' tumor suppressor gene product (WT-1) and prostate apoptosis response gene-4 (Par-4), resulting in apoptosis/necrosis. These results suggest that targeting the fibroblast-to-myofibroblast transition with halofuginone may synergize with low doses of chemotherapy in achieving a significant antitumoral effect, avoiding the need of high-dose chemotherapy and its toxicity without impairing treatment efficacy. [Mol Cancer Ther 2007;6(2)570–7

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Note: Y. Sheffer and O. Leon contributed equally to this work.

This article is a contribution from the Agricultural Research Organization, Volcani Center, Bet Dagan, Israel.

Received 8/ 7/06; revised 11/26/06; accepted 12/12/06.

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