title: Fibroblasts from Werner syndrome patients: cancer cells derived by experimental introduction of oncogenes maintain malignant properties despite entering crisis.
abstract: Werner syndrome (WS) results from defects in the gene encoding WRN RecQ helicase. WS fibroblasts undergo premature senescence in culture. Because cellular senescence is a tumor suppressor mechanism, we examined whether WS fibroblasts exhibited reduced tumorigenicity, in comparison to control cells, in a model of experimental conversion of normal human cells to cancer cells. The combination of oncogenic Ras (Ha-Ras(V12G)) and SV40 large T antigen (SV40 LT) causes human cells to acquire neoplastic properties in the absence of telomerase. We found that WS cells could also be converted to a tumorigenic state by these oncogenes, as evidenced by invasion and metastasis of cells implanted in immunodeficient mice. Ras/SV40 LT-expressing cells retained invasiveness and malignant properties even when cells reached crisis in tumors in vivo. High levels of gelatinase were found by an in situ assay in Ras/SV40 LT-expressing cells undergoing crisis. We conclude that, despite evidence of accelerated senescence in WS cells, there is no evidence that the absence of active WRN acts as a barrier to neoplastic transformation. Moreover, we find that tumorigenic human cells retain malignant properties of the cells as they approach and reach crisis.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Furong
authors.initials: F
authors.lastname: Yuan
authors.forename: Meizhen
authors.initials: M
authors.lastname: Chen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hornsby
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D011905:Genes, ras / Q000502:physiology; D006085:Graft Survival; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D009857:Oncogenes / Q000502:physiology; D014183:Transplantation, Heterologous; D014898:Werner Syndrome / Q000473:pathology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; C499308:Rag2 protein, mouse