Senescence as a mode of tumor suppression.
Two independent lines of experimental evidence are presented in support of the hypothesis that senescence is a normal mechanism of tumor suppression, a homeostatic device designed through evolution to limit cell proliferation irreversibly and thereby to protect the organism against cancer. One set of experiments uses normal human foreskin fibroblasts, transfected at early passage with SV40 DNA and subsequently infected with the K-ras virus. If the cells are immortal prior to infection, they become tumorigenic and make large tumors in nude mice, whereas if they are not immortal, though expressing SV40 T-antigen, they make tiny tumors that senesce in the test mouse after as many doublings as similar cells make in culture. This result demonstrates that immortalization is essential for progressive tumor growth in vivo. The second set of experiments demonstrate that normal human mammary epithelial cells can be immortalized by transfection with viral DNA from human papilloma virus 16 or 18, although these viruses have not been associated with breast cancer. The effective immortalization and other premalignant changes induced by human papilloma virus transfection are accompanied by chromosome changes that may contribute to the partially transformed phenotypes. None of the cloned or pooled transfectants have been tumorigenic in the nude mouse assay. Here, too, immortalization is experimentally separable from tumor-forming ability.
Sager
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Dana-Farber Cancer Institute, Boston, MA 02115.
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000502:physiology; D001940:Breast / Q000166:cytology; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D004268:DNA-Binding Proteins; D004848:Epithelium; D005347:Fibroblasts; D005799:Genes, Dominant; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006801:Humans; D007708:Kirsten murine sarcoma virus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection
D000952:Antigens, Polyomavirus Transforming; D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16