Cell cycle aberrations in the pathogenesis of squamous cell carcinoma of the uterine cervix

Cancer cells are characterized by limitless proliferative autonomy and immu nity to inhibitory and apoptotic signals, thus ensuring growth and metastas is [1]. Epidemiological studies have long implicated human papillomavirus ( HPV) as a pathogenic agent in cervical cancer. Progress in cancer research now provides an understanding of how these characteristics are achieved by the interaction of BPV proteins with the cell cycle machinery. Expression o f oncoproteins E7 and E6 induces immortalization of cells through their inh ibitory effects on tumor suppressor proteins pRb and p53, respectively. Und ermining of pRb's growth-inhibitory role with release of E2F transcription factors renders the cells independent of mitogenic stimuli. The abundance o f growth transcription factors grants limitless proliferative potential by allowing expression of products such as cyclins A, E, and B, dihydrofolate reductase, and DNA polymerase which fuel the various stages of the cell cyc le. There is subsequent disruption of both the G(1)-S and G(2)-M cell cycle checkpoints. Overexpression of cyclin E results in chromosomal instability and possible unmasking of genetic mutations, allowing disease progression. Cyclin A grants anchorage-independent growth, facilitating tissue invasion and tumor spread. Apoptotic and growth-inhibitory mechanisms are also evad ed. p53 is degraded by E6 and its own downstream protein mdm2. Its other do wnstream protein, p21 is rendered ineffective against cyclin-cyclin-depende nt kinase units by E7, as is p27. The understanding of the molecular pathol ogy of disease will provide us with the ability to prognosticate and treat patients more effectively. (C) 2001 Academic Press.