Immortalization of Normal Human Cells

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Cellular senescence was originally described as phenomenon observed in cultured human cells. Accumulating lines of evidence now indicate that the same processes also take place in vivo, with important implications for tumour development. Most cancer cells can devide indifinitely by escaping this senescence program. The E6 and E7 genes of HPV16, which is most frequently found in cervical cancer, can cooperatively immortalize normal human epithelial cells originated from skin and mammary gland. Both inactivation of the RB pathway by E7 and activation of telomerase by E6 are required for immortalization of these cell types. Most human cell types in culture senese by accumulating p16INK4a (Fig.). Indeed, supression of p16 by either Bmi-1 or p16-shRNA can inhibit the premature senescence of skin keratinocytes, mammary epithelial cells and bronchial epithelial cells, and additional transduction of hTERT can immortalize these cell types (Cancer Sci, 98:147-154, 2007). Inactivation of p16 and telomerase activation are frequently found in cancer cells. Thus inactivation of normal senescence program is required for carcinogenesis. Indeed, oncogenes such as myc, bmi-1, cyclin D and cdk4 are involved in immortalization of human cells. Understanding of the immortalization might be applied to cancer therapy by reactivating the senescence program in cancer cells (Expert Opin Ther Targets. 11:1623-37, 2007. for review).