Sci. STKE, 19 April 2005
CANCER Checking Cancer Development
Bartkova et al. and Gorgoulis et al. have uncovered evidence suggesting that, early in the process of cancer development, the DNA damage response (DDR)--which elicits cell death or cell senescence--acts as a barrier to uncontrolled cell proliferation. This could create a selection pressure to inactivate genes involved in the DDR, such as p53, leading to increased genomic instability and tumor progression. Bartkova et al. used immunohistochemistry to show that two components of the DDR, Chk2 and ataxia telangiectasia mutated (ATM), were activated and that the ATM substrates p53 and histone H2AX were phosphorylated in early stages of bladder cancer development. Phosphorylation of Chk2 and ATM was apparent before the development of pronounced genomic instability or the appearance of mutations in p53 and other genes involved in DDR. Chk2 and ATM were activated in premalignant lesions of the breast, colon, and lung but not in normal proliferating cells or inflammatory tissues. Overexpression of oncogenes that promote S phase entry in U-2-OS-derived cells led to DDR activation, suggesting that deregulated DNA replication elicited the response. Consistent with this notion, various premalignant lesions showed abnormalities associated with deregulated entry into S phase, allelic imbalances at genomic sequences that are difficult to replicate, and a functional DDR.
Gorgoulis et al. found that premalignant human lung lesions expressed wild-type p53 and showed evidence of the DDR [focal nuclear localization of p53 binding protein 1 (53BP1, a sensor of DNA double-strand breaks), H2AX phosphorylation, Chk2 phosphorylation, enhanced p53 abundance, and apoptotic cells]. Normal tissue did not exhibit a DDR, whereas non-small cell lung carcinomas showed 53BP1 nuclear foci and H2AX and Chk2 phosphorylation with suppression of apoptosis, generally associated with p53 mutation or decreased p53 abundance. Similarly, the DDR was apparent in premalignant skin lesions from patients with malignant melanoma and in a model of hyperplasia in which human skin grafted onto immunodeficient mice was stimulated with growth factors. Again, preneoplastic lesions showed allelic imbalances at genomic sequences prone to DNA double-strand breaks, and the hyperplastic grafts developed allelic imbalances at these sites within a few weeks. Thus, like Bartkova et al., Gorgoulis et al. concluded that the DDR, driven by replicative stress, is an early anticancer response. Venkitaraman discusses both articles and provides context for this research.
J. Bartkova, Z. Hoeji, K. Koed, A. Krämer, F. Tort, K. Zieger, P. Guldberg, M. Sehested, J. M. Nesland, C. Lukas, T. Ørntoft, J. Lukas, J. Bartek, DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870 (2005). [PubMed]
V. G. Gorgoulis, L.-V. Vassiliou, P. Karakaidos, P. Zacharatos, A. Kotsinas, T. Liloglou, M. Venere, R. A. DiTullio Jr., N. G. Kastrinakis, B. Levy, D. Kletsas, A. Yoneta, M. Herlyn, C. Kittas, T. D. Halazonetis, Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907-913 (2005). [PubMed]
A. R. Venkitaraman, Aborting the birth of cancer. Nature 434, 829-830 (2005). [PubMed]
Citation: Checking Cancer Development. Sci. STKE 2005, tw145 (2005).
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