Research conducted by the group of Marikki Laiho, M.D., Ph.D., a Professor at the University of Helsinki, Finland, in collaboration with Donna Peehl, Ph.D., an Associate Professor (Research) at Stanford University, US, points to absence of critical mechanisms protecting prostate cells from DNA damage as a key contributor to the development of prostate cancer.
Results of the study will be published in the online Early Edition of the Proceedings of the National Academy of Sciences, USA, during the week of April 9-13.
The investigators used primary cultures of normal epithelial cells derived from patients’ surgical specimens to examine responses to DNA damage induced by irradiation or chemicals. These cultured cells are the “progenitor” cells in the prostate in which cancer may originate, and therefore provide a realistic experimental model in which to study carcinogenic processes.
After exposure to DNA damaging agents, cells typically mount several types of defensive mechanisms to allow repair of DNA damage prior to cell division. These mechanisms prevent the passage of damaged genetic material to daughter cells, which would contribute to the conversion of those damaged cells to cancer. One of these protective mechanisms is cell cycle checkpoint arrest, which is mediated by a series of molecular events triggered by DNA damage.
Surprisingly, normal prostate cells were unable to enforce cell cycle checkpoint arrest and continued to proliferate following DNA damage. Early events involving cellular recognition of DNA damage were intact, so lack of checkpoint arrest in these cells was not due to inability to recognize DNA damage. Rather, inability to enforce cell cycle arrest was linked to low levels of the protein Wee1A, a tyrosine kinase that phosphorylates and inhibits cyclin dependent kinase 2 (cdk2). In the absence of Wee1A activity, cdk2 remained active and continued to drive the prostate cells to undergo cell division. In conjunction, slower clearance of DNA damage foci suggested persistent DNA damage. When Wee1A protein was restored in these cells, checkpoint control was rescued, showing that Wee1A was indeed critical to this important pathway.
When using cultured cells, there is always a concern that the in vitro environment may alter cellular behavior. To confirm that the observed results were not an artifact of cell culture, the investigators used a novel model system of “tissue slice cultures”, developed by Peehl. Cores of fresh tissue were bored from surgical specimens, then were precision-cut to thicknesses of only a few hundred microns. These slices were incubated and retained their structure and function for several days. The value of tissue slice cultures is that all elements of the whole tissue remain intact, permitting realistic experiments that are not feasible to perform directly in humans. The responses to DNA damage of the normal epithelial cells in these tissues were similar to those of the cell cultures, signifying that defensive mechanisms against DNA damage are indeed lacking in the human prostate.
The lack of Wee1A-mediated DNA damage-induced checkpoint enforcement is not the only defective protective mechanism in prostate cells. In 1995, Peehl in collaboration with another investigator at Stanford, Amato Giaccia, Ph.D., reported in Cancer Research that normal prostatic epithelial cells lacked the p53 response to DNA damage. The p53 protein is a major tumor suppressor and lack of p53 function leads to genomic instability and malignancy. The defects in the two checkpoint enforcement pathways, mediated by p53 in one and by Wee1A in the other, are unrelated, since correcting the Wee1A pathway did not restore p53 function in prostate cells.
The use of human cells and tissues in these studies was key to the medical relevance of the findings. The human prostate is almost unique among mammals in having a high incidence of prostate cancer. Rodents, most commonly used in the laboratory to study mechanisms of cancer, do not develop prostate cancer spontaneously. The absence of at least two key checkpoint elements in the DNA damage response pathways may predispose human prostatic epithelial cells to accrual of DNA lesions and provide a mechanistic basis for the high incidence of cancer in the prostate.
Why prostate cells lack these mechanisms is unknown, but discovery of ways to restore these checkpoints controls might protect against prostate cancer.
The study was funded by the Department of Defense Prostate Cancer Research Program, the Academy of Finland, Biocentrum Helsinki, the Finnish Cancer Organizations and the Finnish Cultural Foundation.
Paivi Lehtinen | alfa
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