Immortalization of human cells and its mechanisms.

One of the contributions of in vitro neoplastic transformation studies on human cells is the confirmation that cells become malignant by a multistep process. In this review, we use the term "neoplastic transformation" to indicate that the cells become capable of forming a histologically malignant tumor, that is, one that invades and/or erodes normal tissue and is serially transplantable in a susceptible animal host. Phenotypically, the cells first become immortalized and then neoplastic. If normal human cells do not overcome aging by becoming immortalized, they cannot be neoplastically transformed. However, normal human cells are stringently destined to cellular aging and very rarely become immortalized by oncogenic DNA viruses (SV40, papillomavirus types 16 and 18, adenovirus types 5 and 12), chemicals, X-rays, or spontaneously. Once human cells get immortalized, they relatively easily become neoplastic. Evidence shows that immortalization is a critical step in the neoplastic transformation process of human cells. Therefore, investigation of the mechanisms of immortalization is indispensable in understanding the multistep carcinogenesis of human cells. Although the precise mechanisms of immortalization are unknown at present, data indicate that the p53 cascade appears to be important for the immortalization of human cells. The loss of functions of normal p53 may induce genomic instability, resulting in mutations of some other unknown genes that are more directly involved in the immortalization of human cells. These unknown genes, which are presumably located at chromosomes 1, 4, 6, 7, 9, 11, 13, 17, 18, and X are now under extensive investigation.