Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis.
Prostate, breast, and probably other epithelial tumors harbor inactivating mutations in the p53 tumor suppressor gene in the stromal cells, implying the nonautonomous action of p53 in carcinogenesis. We have tested this hypothesis by evaluating the tumorigenicity of MCF7 human breast cancer cells in severe combined immunodeficient mice that differ in their p53 status. Our results showed that, indeed, p53 ablation in the hosts reduced the latency for the development of MCF7 tumors. Furthermore, we show that heterozygous hosts frequently undergo loss of heterozygosity at the p53 locus in the tumor stroma tissue by mechanism that resembles the inactivation of p53 in primary tumors. To evaluate the impact of p53 ablation in the stromal fibroblasts, in tumorigenesis, tumors were reconstituted in mice bearing wild-type p53 alleles, by mixing MCF7 cells with fibroblasts isolated from mutant or wild-type p53 mice. Our results suggest that tumors containing p53-deficient fibroblasts developed faster and were more aggressive than their counterparts with wild-type fibroblasts, although their neoplastic component, namely MCF7 mammary carcinoma cells, was identical in both cases. These data strongly support the notion for the operation of a nonautonomous mechanism for p53 action in primary tumors and provide a mechanistic association between p53 mutations in the stromal component of epithelial tumors and carcinogenesis.
Kiaris
Hippokratis
H
Department of Biological Chemistry, Aretaieion Hospital, University of Athens Medical School, Athens, Greece. hkiaris@med.uoa.gr
Chatzistamou
Ioulia
I
Trimis
George
G
Frangou-Plemmenou
Matrisa
M
Pafiti-Kondi
Agatha
A
Kalofoutis
Anastasios
A
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016511:Severe Combined Immunodeficiency / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D016159:Tumor Suppressor Protein p53