WHY DOESN’T EVERYONE HAVE CANCER? THE DNA-DAMAGE RESPONSE

Majid Ali, M.D.

The human body has an estimated 50 to trillion cells in the body. All cells containing DNA are vulnerable to DNA-altering stresses. So, why doesn’t everyone have cancer? That is a legitimate question given the vulnerability of trillions of cells susceptible to gene mutations that could spark uncontrolled cell proliferation and clinical cancers. It has long been suspected that normal cells must have some robust mechanisms that can perceive the mutational damage and arrest aberrant cycles of cell divisions triggered by oncogenic stimuli.91 Experimental evidence for that view, however, was lacking until very recently when Bartkova et al.92 and Gorgoulis et al.93 published evidence for the existence of the phenomenon of DNA-damage response (DDR). Specifically, it was demonstrated that oncogene-driven cell-division cycles trigger DNA damage associated with DNA replication. That DNA-damage associated response raises a barrier to sustained cellular proliferation and the developmental of malignant tumors. Thus, progression towards clinical cancer requires the wayward cell to inactivate the mechanisms that monitor damage during DNA replication. Those findings help explain the close link between genomic instability and cancer evolution. Several genes are involved in DDR, including p53, ATM, ATR, Chk2, Fanconi anaemia proteins and the breast-cancer- susceptibility proteins BRCA1 and BRCA2.

How is that crucial DNA-damage response triggered and maintained? Direct experimental evidence implicating altered oxyecologic conditions in DDR is not yet forthcoming. However, it is note worthy in this context that oxidative stress is known to both interefere with tumor suppressive gene functions and trigger oncogenic elements. In previous columns on oxygen homeostasis, I have marshalled extensive evidence for my view that unrelenting oxidative stress exerts its pathogenic influences essentially through disruption of oxygen homeostasis. Thus, it seems safe to predict that the direct role of the oxyecologic conditions in DDR will be established with future investigations into this field.

WHY DOESN’T EVERYONE HAVE CANCER? THE DNA-DAMAGE RESPONSE

Why doesn’t everyone have cancer? That is a legitimate question given the vulnerability of trillions of cells susceptible to gene mutations that could spark uncontrolled cell proliferation and clinical cancers. It has long been suspected that normal cells must have some robust mechanisms that can perceive the mutational damage and arrest aberrant cycles of cell divisions triggered by oncogenic stimuli.91 Experimental evidence for that view, however, was lacking until very recently when Bartkova et al.92 and Gorgoulis et al.93 published evidence for the existence of the phenomenon of DNA-damage response (DDR). Specifically, it was demonstrated that oncogene-driven cell-division cycles trigger DNA damage associated with DNA replication. That DNA-damage associated response raises a barrier to sustained cellular proliferation and the developmental of malignant tumors. Thus, progression towards clinical cancer requires the wayward cell to inactivate the mechanisms that monitor damage during DNA replication. Those findings help explain the close link between genomic instability and cancer evolution. Several genes are involved in DDR, including p53, ATM, ATR, Chk2, Fanconi anaemia proteins and the breast-cancer- susceptibility proteins BRCA1 and BRCA2.

How is that crucial DNA-damage response triggered and maintained? Direct experimental evidence implicating altered oxyecologic conditions in DDR is not yet forthcoming. However, it is note worthy in this context that oxidative stress is known to both interefere with tumor suppressive gene functions and trigger oncogenic elements. In previous columns on oxygen homeostasis, I have marshalled extensive evidence for my view that unrelenting oxidative stress exerts its pathogenic influences essentially through disruption of oxygen homeostasis. Thus, it seems safe to predict that the direct role of the oxyecologic conditions in DDR will be established with future investigations into this field.

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