The multistep process in skin carcinogenesis

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Normal keratinocytes in human epidermis can convert to Squamous cell carcinoma (SCC) through the multistep process that involves activation of proto-oncogenes. However, the process in SCC is currently unknown. To elucidate the process, we tried keratinocytes. Using high efficiebcy retrovial transductions in primary keratinocytes, we expressed RasV12, P53w248, CDK (Cyclin dependent kinase) 4, and Htert either singly or in combination and used these cells to regenerate human skin on SCID mine. Within 3 weeks Ras-CDK4 produced human skin tumors with histologic features of SCC. Ras-CDK4 tumors, similar to human SCC, express increased levels of Cyclin D1, MMP2, and VEGF. Cyclin D1 was necessary but not sufficient for Ras-CDK4 neoplasia as CDK4-D1 failed to induce tumors while an anti-sense D1 retrovector that suppressed D1 tissue protein expression abolished Ras-CDK4 neoplasia. CDK4 synergy with Ras is dependent on intrinsic CDK4 kinase function as the kinase-dead N158 CDK4 point mutant failed to induce neoplasia when co-expressed with Ras. These data identify Ras and CDK4 as capable of converting normal human epidermal tissue into invasive neoplasia and indicate that functional CDK4-D1 is necessary for this process.