Tumor cells sometimes evade the destructive effect of radiation by damaging their own DNA in certain places. For example, they temporarily stop their cell division, so that radiation has less effect. That explains why cancer sometimes comes back after radiation treatment, writes a group of international researchers Thursday in the scientific magazine science†
They conducted research on cultured human colon cancer cells and other human tumor cell lines. The discovery offers leads for the search for a better treatment.
Radiotherapy is one of the most commonly used treatments against tumors. Targeted X-rays or radioactive radiation destroy the DNA in cancer cells. As a result, they can no longer divide and die. Rapidly dividing cells, such as cancer cells, are extra sensitive to radiation.
Unfortunately, it often happens that not all tumor cells are killed after radiation, and the cancer comes back later. The chance of this differs per cancer type and stage. “Soft tissue cancer and renal cell tumors are more often resistant to radiotherapy, lymphoma is very sensitive to it,” says Martijn Lolkema, internist-oncologist at Erasmus MC in Rotterdam, and not involved in the study. “You sometimes see problems arising, especially at the edges of a tumor.” It was not yet well known why some cancer cells can protect themselves from radiation damage.
The researchers, led by geneticist Claus Sorensen from the University of Copenhagen, found that cancer cells activate an enzyme in response to radiation: nuclease caspase-activated DNase (abbreviated CAD). This enzyme temporarily causes extra breaks in the DNA of the cancer cell, in specific places. This self-inflicted DNA damage stops the division of the cell for a while, and thus prevents the radiation damage from killing the cancer cell.
Natural repair processes
Every healthy cell regularly sustains DNA damage. That’s no problem, that damage is repaired under normal circumstances by natural repair processes. During the cycle of growth and division that every cell goes through, there are different moments, check points, which is checked for DNA breaks. Thus, those errors can be repaired before the cell makes copies of them and divides into two new cells. And if the mistakes cannot be repaired, the cell dies. In a normal cell this is the so-called G1 checkpoint.
In cancer cells, this first checkpoint often no longer works. But the self-inflicted DNA breaks do activate the next checkpoint in the cancer cell, G2, the authors discovered. The cell, as it were, remains suspended in this phase for a while. This temporarily prevents the cancer cell from dividing and the cell from dying.
Only the cancer cells in which the CAD enzyme was active survived the radiation. The homemade DNA damage is easily repaired by the tumor cell. After that DNA repair, the cancer cell simply divides again.
Lolkema sees two possibilities for application in treatment practice. “You could measure the enzyme, CAD, in patients. Patients in whom this is strongly elevated could be at a higher risk that the radiation is not sufficient, and you could then devise a different strategy for them.” Another option is to develop drugs that can inhibit CAD. These drugs are not yet available, but they could have a very specific effect on tumor cells, because normal cells do not express that enzyme.
“A very interesting study into the deep mechanisms”, says Roland Kanaar, molecular geneticist at Erasmus MC in Rotterdam. “We always look for a difference between normal cells and cancer cells, so that we can intervene. This is such a difference.” He expects that cancer cells in which the enzyme, CAD, is active may be very sensitive to existing drugs against, among other things, hereditary breast cancer: PARP1 inhibitors. “They inhibit the repair of the type of DNA breaks that CAD makes. If they can no longer be repaired, the cancer cell will still die.”
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