Inhibition of angiogenesis and tumorigenesis, and induction of dormancy by p53 in a p53-null thyroid carcinoma cell line in vivo.
Our recent in vitro findings for suppression of thrombospondin-1 (TSP1; an antiangiogenic factor) expression by wild-type (wt) p53 in a p53-null thyroid carcinoma cell line, FRO, prompted us to investigate the in vivo effect of exogenous wt-p53 and TSP1 expression on tumor growth and angiogenesis of FRO xenografts in nude mice. Overexpression of TSP1, which did not affect the in vitro cell growth, significantly inhibited the in vivo tumor growth and neovascularization but not tumorigenesis; all the mice inoculated with FRO cells expressing TSP1 developed tumors, which were smaller and less vascularized than those derived from FRO cells. In contrast, restoration of wt-p53 expression, which reduced the in vitro cell growth rate, inhibited tumorigenesis and induced a state of "dormancy". Thus, approximately 40% of mice inoculated with FRO cells expressing wt-p53 (FRO-p53) were tumor free and the remaining mice developed hypovascular tumors which remained small (< or = 5 mm in size) for up to 60 days. Of interest, the phenotype of FRO-p53 tumors reverted to a well vascularized, progressively expanding tumor by exogenous expression of vascular endothelial growth factor (a proangiogenic factor). Our data demonstrated wt-p53 inhibition of tumorigenesis and induction of dormancy by suppression of neovascularization in FRO cells. The results suggest that p53 gene therapy for thyroid carcinoma harboring p53 mutation may be more efficacious than we had expected from previous in vitro data.
Nagayama
Y
Y
Department of Pharmacology 1, Nagasaki University School of Medicine, Japan. ngayama@net.nagasaki-u.ac.p
Shigematsu
K
K
Namba
H
H
Zeki
K
K
Yamashita
S
S
Niwa
M
M
D000818:Animals; D004285:Dogs; D016158:Genes, p53 / Q000502:physiology*; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019700:Thrombospondin 1 / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000517:prevention & control*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D019700:Thrombospondin 1