Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism.
Halofuginone inhibits fibrosis by decreasing type I collagen synthesis and tumor growth through an anti-angiogenic mechanism. In vitro data suggested that halofuginone inhibits angiogenesis through upregulating thrombospondin-1 (TSP-1) expression and by inhibiting cell proliferation. To determine whether thrombospondin-1 (TSP-1) is necessary for inhibition of tumor growth and angiogenesis by halofuginone, we tested the effect of halofuginone on mammary tumor growth in polyoma middle T antigen, TSP-1 null (TSP-1-/-PyT) transgenic mice. After 30 days of treatment, we found a significant decrease in tumor weight in these mice and the extent of tumor growth inhibition was comparable to that found in TSP-1 expressing PyT mice (TSP-1+/+PyT). However, no significant difference in tumor weight was observed after 60 days of halofuginone treatment between control and treated mice in both genotypes. Interestingly, type I collagen level was lower in the halofuginone treated TSP-1+/+PyT tumors at 30 days, but this was not observed in the TSP-1-/-PyT mice. Levels of type I collagen did not correlate with blood vessel number as a decrease in the number of vessels was observed in the halofuginone treated tumors from both the TSP-1+/+PyT and TSP-1-/-PyT mice as compared to control tumors. Because halofuginone has been shown to inhibit type I collagen synthesis by inhibiting the TGF-beta signaling pathway, we measured Smad 2/3 phosphorylation levels and found that halofuginone inhibited Smad 2/3 phosphorylation in cells derived from TSP-1+/+PyT tumors. We also found that it inhibited Smad 2/3 phosphorylation in cells treated with the TGF-beta activating sequence of TSP-1, TSR2+RFK. Our data demonstrate that halofuginone inhibits mammary tumor growth in a transgenic mouse model via a TSP-1 independent pathway, by decreasing tumor angiogenesis and by inhibiting TGF-beta signaling.
Yee
Karen O
KO
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massuchusetts 02215, USA.
Connolly
Caitlin M
CM
Pines
Mark
M
Lawler
Jack
J
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D024042:Collagen Type I / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D010880:Piperidines; D011120:Polyomavirus / Q000235:genetics / Q000276:immunology; D011799:Quinazolines / Q000627:therapeutic use*; D052999:Quinazolinones; D051899:Smad2 Protein / Q000037:antagonists & inhibitors; D051900:Smad3 Protein / Q000037:antagonists & inhibitors; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents; D024042:Collagen Type I; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; C010176:halofuginone