Experimental Models

Initial studies of human cancer cells were limited to samples obtained from tumor biopsy specimens. To facilitate further study, cells from these tumors were frequently adapted into cell lines that grow in culture (18). These cell lines are useful for many purposes, however, it is impossible to determine the order or even a set of defined genetic or biochemical changes that lead to neoplastic development. Complicating matters further is the high likelihood that additional genetic alterations are acquired over time through propagation in culture.

Recently, transcriptional profiling has been helpful in evaluating the simultaneous expression of thousands of genes in particular cancers or cancer cell lines (19,20). Unfortunately, while these studies have provided us with tools to better classify cancers, they have not yet yielded insight into the functionally important gene expression changes required for cancer growth. It is still impossible from these analyses to determine which genes have true functional roles in the transformation to the malignant state. Thus, a complementary approach to studying the genetic alterations necessary to form a tumor is to transform normal cells, in vitro, by serially introducing multiple oncogenes. An alternative method of cancer modeling is through the production of genetically altered mice harboring specific alterations associated with human cancer.

Rodent cell transformation

In rodent systems, single oncogenes fail to transform primary cells without the presence of prior predisposing mutations (21,22). In contrast, two introduced oncogenes convert embryonic rodent cells to a tumorigenic phenotype (23,24). These observations indicated that the conversion of normal cells into cancer cells requires multiple genetic changes to occur.

Collaborating oncogenes that induced transformation in these cultured rodent primary cells included Myc/Ras or E1a/ ras (23,24). Further confirmation of this collaboration through transgenic mouse experiments occurred when a Ras or a Myc transgene was placed under the control of mammary- or prostate- specific promoters (25,26). Dysplasia in promoter specific organs developed at high rates in the transgenic mice expressing single oncogenes, but frank tumors did not develop unless mice expressed both transgenes. These findings support the concept that specific oncogenes collaborate to aid in tumor development in vivo, as well as in cultured cells.

Barriers to human cellular immortalization

While two oncogenes appeared to suffice to transform rodent cells, the transformation of primary human cell lines proved to be more complex. This difference is in part because human cells require more genetic alteration to bypass the barriers of immortalization (Figure 2). When normal human cells are grown in culture, their proliferative potential is limited and they eventually enter an irreversible, quiescent state, termed mortality stage 1 (M1) or replicative senescence (27). Although these cells are still viable, they can no longer be stimulated to divide. The exact trigger for entry into replicative

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