In a groundbreaking discovery, scientists at MUSC Hollings Cancer Center have identified a potential reason why cancer often returns in patients after chemotherapy or radiotherapy. This revelation centers on polyploid giant cancer cells (PGCCs), which are monstrously oversized cells containing multiple nuclei.
Breakthrough in understanding cancer recurrence
Cancer therapies such as chemotherapy and radiotherapy aim to stress cancer cells into self-destruction. However, these treatments often lack long-term effectiveness as cancer cells can adapt, escape, and enable the tumor to rebound after a short period. Researchers have long observed PGCCs in cancerous tissues but their exact role in cancer recurrence remained unknown until now.
A team led by Christina Voelkel-Johnson, Ph.D., at MUSC Hollings Cancer Center, reported in the Journal of Biological Chemistry that they have identified select genes that prostate cancer cells manipulate to become PGCCs, which helps them survive therapy stress. These PGCCs later regain their capacity for cell division, paving the way for cancer recurrence.
Unexpected discoveries in lab experiments
The discovery emerged from studies on an inhibitor, a drug designed to block a biological mechanism, associated with durable cures after radiotherapy. Initially, Voelkel-Johnson’s lab believed the combination of radiation and the inhibitor killed cancer cells more effectively. However, extended observation periods revealed a different story.
During short-term experiments, researchers noticed giant, abnormal-looking cells they presumed were “doomed.” When the observation period was extended, these cells surprisingly produced small offspring. “They looked really funky,” said Voelkel-Johnson. Without the inhibitor, the giant cancer cells generated daughter cells, forming colonies with smaller cells surrounding the large one.
These PGCCs, visually distinct from other cancer cells, could copy their genetic information, increasing the number of nuclei without cytoplasmic division, resulting in monstrous, multi-nucleated cells. This unexpected finding suggested that the inhibitor stopped cancer recurrence not by killing the cells better, but by preventing PGCCs from producing offspring.
Genetic insights and therapeutic implications
Voelkel-Johnson’s team identified cell-signaling pathways that cancer cells manipulate to become PGCCs in response to therapy stress, and later transition back to cells capable of producing daughter cells. A key protein involved is p21, induced by p53 when normal cells are stressed. In normal cells, p21 prevents duplication of damaged DNA, leading to cell suicide if damage is irreparable.
However, in cancer cells lacking p53, p21 does not prevent DNA duplication, aiding the formation of PGCCs. Blocking increases in p21 in stressed cancer cells prevented the transformation into PGCCs. Furthermore, interfering with p21 in existing PGCCs stopped them from producing daughter cells, potentially responsible for tumor relapse.
These findings suggest new targets for improving patient outcomes post-cancer therapy. While blocking p21 directly may not be feasible, drugs like the breast cancer drug tamoxifen and cholesterol-lowering statins have shown potential in interfering with the identified pathways. Further research is necessary to evaluate whether these drugs can reduce recurrence rates by blocking PGCCs from generating daughter cells.
The findings also indicate the importance of the timing of drug administration. Voelkel-Johnson emphasizes that treatment should coincide with chemotherapy or radiotherapy to prevent PGCCs from generating daughter cells. Administering these drugs post-therapy would be too late.
Future research directions
Voelkel-Johnson plans to continue exploring ways to prevent the generation of daughter cells from PGCCs to enhance therapy efficacy. She also aims to assess how various combination treatment regimens delivered during cancer therapy affect recurrence rates across different cancers.
This research opens new avenues for cancer treatment strategies, offering hope for more durable cures and reduced recurrence rates by targeting the overlooked yet significant role of polyploid giant cancer cells.
