Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect.
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, alpha-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.
Sheffer
Yuval
Y
Institute of Animal Sciences, Volcani Center, P.O. Box 6, Bet Dagan 50250, Israel.
Leon
Oded
O
Pinthus
Jehonathan H
JH
Nagler
Arnon
A
Mor
Yoram
Y
Genin
Olga
O
Iluz
Maya
M
Kawada
Norifumi
N
Yoshizato
Katsutoshi
K
Pines
Mark
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009132:Muscles / Q000166:cytology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D052999:Quinazolinones / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D009396:Wilms Tumor / Q000188:drug therapy* / Q000473:pathology
D010880:Piperidines; D052999:Quinazolinones; D043823:Taxoids; D000077143:Docetaxel; C010176:halofuginone