| Abstract: |
Recent evidence has implied that disruption of a limited number of defined cellular pathways is necessary and sufficient for neoplastic conversion of a variety of normal human cell types in tissue culture.We show instead that malignancy in such models results from an iterative process of clonal selection in vitro and/or in vivo. Normal human fibroblasts underwent malignant transformation after transduction with telomerase, cyclin-dependent kinase 4, dominant-negative p53, and activated Ras or MEK. Furthermore, culture conditions favoring overgrowth resulted in clonal selection, which with added Ras or MEK oncogenes led to the emergence of tumorigenic clones. Such tumors showed variable degrees of malignancy with some even exhibiting metastasis. SV40 small t antigen (ST) has been reported to be necessary and sufficient to convert human fibroblasts with these pathway aberrations to a polyclonal tumor. However, we observed that clonal tumors emerged even with ST addition. Genomic instability was markedly increased by p53and Rb pathway abrogation. Under the same conditions, fibroblasts with these alterations failed to induce tumors, implying that genomic instability may be necessary but not sufficient for malignant transformation. These findings indicate that the minimum number of events required for malignant transformation of human fibroblasts is greater than has been enumerated by such oncogene addition strategies and support a stochastic cancer progression model initiated by four defined cellular alterations. ©2008 American Association for Cancer Research. |
| Keywords: |
mitogen activated protein kinase; controlled study; human cell; cancer growth; nonhuman; neoplasms; mouse; cells, cultured; models, biological; animal experiment; animal model; in vivo study; in vitro study; cell line, tumor; protein p53; telomerase; cell transformation, neoplastic; oncogene; kinetics; genomic instability; fibroblast; simian virus 40; fibroblasts; tumor suppressor protein p53; ras protein; ras proteins; cell clone; malignant transformation; retinoblastoma protein; protein p21; cell adhesion; karyotyping; stochastic model; cyclin dependent kinase 4; dna, complementary; tissue culture; virus small t antigen; map kinase kinase kinase 1
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