New research shows that polyploid giant cell carcinoma cells (PGCCs), which can adapt and survive after treatment, are key to cancer recurrence. These cells change genes to protect themselves from treatment, then divide and cause the tumor to grow back. Targeting these cells during therapy with specific inhibitors such as p21 may improve cancer treatment outcomes.
Scientists have discovered that polyploid giant cancer cells may be responsible for the development of disease after cancer treatment.
Researchers at the MUSC Hollings Cancer Center have made a discovery that may explain why cancer returns in patients who have received chemotherapy or radiotherapy.
Both types of treatment aim to pressure cancer cells into self-destruction. However, these treatments often lack long-term efficacy because cancer cells can adapt to the stress, escape, and cause the tumor to regenerate after a short period of time.
Recently, scientists have begun to look at the role of polyploid giant cell carcinomas, or PGCCs, in cancer recurrence. Although these cells have been known by scientists since the invention of the microscope and observed by pathologists in cancer tissues, the exact function of cancer recurrence is unknown.
In a recent article by Journal of Biological ChemistryA research team at the MUSC Hollings Cancer Center, led by Christina Voelkel-Johnson, PhD, has identified select genes that cause prostate cancer cells to become PGCCs, thereby protecting themselves from treatment stress. Hollings’ group also established that PGCCs later regained their ability to divide, setting the stage for cancer recurrence.
Unexpected findings in laboratory experiments
Voelkel-Johnson and her lab made this discovery while studying a drug inhibitor, or drug, designed to block the biological mechanism involved in long-lasting cures after radiotherapy. “We thought that combining radiation with inhibitors would kill cancer cells better,” Voelkel-Johnson said. “It was only when the inhibitors failed to make a difference in short-term trials that the time limit was extended, which allowed for an unusual observation.”
In short-term experiments, the lab members observed large, abnormal-looking cells but dismissed them as “disaster.” When the time frame was extended, they were surprised to see that these cells formed small seeds.
This time-lapse video shows PGCC formation in ovarian cancer cells in response to therapeutic stress. Credit: Video courtesy of Joe. R. Delaney, Medical University of South Carolina
“They looked really funny,” Voelkel-Johnson said. When we didn’t use the inhibitors, those giant cancer cells produced daughter cells, forming a colony of smaller cells surrounding the larger one.
These funny-looking PGCCs were visually distinct from other cancer cells. By increasing the number of nuclei, they were able to make copies of their genetic information. However, the cytoplasm was not divided, and therefore the cells grew significantly, containing not only one, but several nuclei.
MUSC Hollings Cancer Center researcher Dr. Christina Voelkel-Johnson. Credit: Medical University of South Carolina. Photo by Sarah Pack.
The surprising finding that the monster cells were not “stunned” led Voile-Johnson and her team to suspect that they had stopped the cancer from coming back in a different way than its defenders had assumed.
“The drug didn’t kill the cancer cells the best way,” Voelkel-Johnson said. “Instead, it prevented the formation of progeny from giant polyploid cancer cells.”
The team also continued to divide the PGCC daughter cells, mimicking the recurrence of tumors that some patients experience after treatment. It became clear that this inhibitor was producing lasting cures not by inducing cell death, but by preventing PGCCs from transforming into mononuclear cancer cells capable of dividing.
To understand what differentiates PGCCs and their daughter cells from their parent cancer cells, Voelkel-Johnson, along with other collaborators, began examining gene expression changes between the different cells that occurred during their experiments. This information may help explain how cancer cells transition to and exit the PGCC state after exposure to therapeutic stress.
Genetic insights and therapeutic implications
Voelkel-Johnson and her team were able to identify the cell signaling pathways that help cancer cells to become PGCCs in response to medical stress and later to transition into cells capable of producing daughter cells.
One protein that particularly interested them was p21, which is produced by a protein called p53 when normal cells are stressed. In normal cells, p21 prevents defective replication DNARepairing DNA damage. Cells that cannot be repaired will destroy themselves.
Hollings’ research team found that stress in cancer cells lacking p53 increased p21, but the protein did not stop the replication of damaged DNA as it did in normal cells. As a result, p21 helped set the stage for the generation of PGCCs.
When increases in p21 were blocked, the depressed cancer cells did not transform into these dreaded cells. Interfering with p21 in already malignant cells prevented them from generating daughter cells that could cause tumor recurrence.
The team’s findings provide insights into new strategies that could be targeted to improve patient outcomes after cancer treatment. Although it is not possible to block p21 as a treatment, both the breast cancer drug tamoxifen and cholesterol-lowering statins have been shown to interfere with the pathways identified by the team. Further study is needed to assess whether PGCCs can reduce the recurrence rate by preventing daughter cells from regaining their reproductive potential.
The findings provide new insight into the optimal timing of administration of these drugs.
“One of our questions is, ‘What level of treatment are you treating?'” Voelkel-Johnson said. It was saying. “Our findings suggest that treatment should occur at the same time as chemotherapy or radiotherapy. To prevent PGCCs from producing daughter cells, it is important to administer one of these drugs in conjunction with medical stress. Once they develop, it is too late,” he said.
Voelkel-Johnson plans to continue researching ways to protect the daughter’s cells from PGCCs to increase the effectiveness of the treatment. She is also interested in evaluating how different combination therapies given during cancer treatment affect recurrence rates in different types of cancer.
Reference: “Transcriptome Analysis of Polyploid Giant Cancer Cells and Their Progeny Reveals a Functional Role for p21 in Polyploidization and Polyploidization” by Shai White-Gilbertson, Ping Lu, Ozge Saatchi, Ozgur Sahin, Joe R. Delaney, Bessim Ogretman, and Christina Voelkel-Johnson, March 4 , 2024, Journal of Biological Chemistry.
DOI: 10.1016/j.jbc.2024.107136
The study was funded by the National Cancer Institute National Institutes of Healthand the American Cancer Society.