Targeted Cancer Therapy Illustration (© Riz - stock.adobe.com)
CHARLESTON, S.C. — Cancer can sometimes come back, even after undergoing chemotherapy or radiation treatments. Why does this happen? Researchers at the MUSC Hollings Cancer Center may have unlocked part of the mystery. They discovered that cancer cells can transform into monstrous “polyploid giant cancer cells” or PGCCs when under extreme stress from treatment. With that in mind, scientists believe targeting these cells could be the key to preventing recurrences of cancer.
The findings, in a nutshell
Study authors, who published their work in the Journal of Biological Chemistry, found that these bizarre, monster-like cells have multiple nuclei crammed into a single, enlarged cell body. At first, the researchers thought PGCCs were doomed freaks headed for cellular destruction. However, they realized PGCCs could actually spawn new “offspring” cancer cells after the treatment ended. It's these rapidly dividing daughter cells that likely drive cancer's resurgence in some patients. Blocking PGCCs from reverting and generating these daughter cells could be the strategy that keeps the disease from returning.
The scientists identified specific genes that cancer cells crank up to become PGCCs as a survival mechanism against harsh therapy. One gene called p21 seems particularly important. In healthy cells it stops DNA replication if damage occurs, but in cancer cells lacking p53 regulation, p21 allows replication of damaged DNA to continue, facilitating PGCC formation.
How did scientists make the discovery?
Originally, the Hollings team was studying whether an experimental drug inhibitor could boost cancer cell death when combined with radiation therapy. However, their initial experiments showed no extra killing benefit from the combination treatment. Discouraged, they extended the experiment timeline, and that's when they noticed something very strange.
While the inhibitor made no difference in the short term, over a longer period, the scientists observed the emergence of bizarre, bloated “monster” cancer cells containing multiple nuclei. At first, they assumed these polyploid giant cancer cells (PGCCs) were doomed mutations that would naturally die off in the patient's body. Then, researchers saw the PGCCs were generating rapidly dividing offspring cells around themselves, mimicking tumor recurrence.
This made the team rethink the inhibitor's effects. It didn't increase cancer cell killing, but it did seem to stop PGCCs from reverting to a state where they could spawn proliferating daughter cells. Blocking this reversion to divisible cells could potentially prevent cancer relapse after treatment.
The researchers analyzed gene expression changes as cancer cells transformed into PGCCs and then back into dividing cells. They identified molecular pathways involved, like p21 overexpression, which allows duplication of damaged DNA. Ultimately, combining their inhibitor with radiation prevented PGCC reversion and daughter cell generation, providing a possible novel strategy against treatment-resistant cancers.
What do the researchers say?
“We initially thought that combination of radiation with the inhibitor killed cancer cells better,” says research leader Christina Voelkel-Johnson, Ph.D., in a media release. “It was only when the inhibitor failed to make a difference in short-term experiments that the time frame was extended, which allowed for an unusual observation.”
“One of the questions we had was, ‘At what point of the therapy do you treat?’” Voelkel-Johnson explains. “Our findings suggest that treatment should occur at the same time as chemotherapy or radiotherapy. It is important to administer one of these drugs in conjunction with therapy stress to prevent PGCCs from generating the daughter cells. Once they are generated, it is too late.”
