Researchers from the Institute for Research in Biomedicine Barcelona have uncovered a mechanism behind the recurrence of colorectal cancer after chemotherapy treatment. The team, in a new study, identified a gene and a specific cell population that drives the recurrence behavior in colon cancer, paving the way for new therapeutics that could target the pathway and neutralize these cell populations, which could help improve the efficacy of chemotherapy treatment in the future.
The findings, reported in the journal Nature Cancer, describe a stem cell population in colon cancer that expresses a gene called Mex3a that causes the population of cells to remain in a latent state during chemotherapy treatment. These cells then become reactivated after treatment, resulting in the cancer relapsing.
Due to the action of the chemotherapy drugs, the specific cell population adopts a protective and naive state while the drugs are in circulation, however, once the chemo drugs clear out, the environment becomes more favorable and these cells are reactivated and can spur the tumor back into its full state, causing recurrence after treatment.
“Chemotherapy is effective and kills most of the tumour cells but not all of them. Our discovery reveals the identity of a group of persistent cells that are resistant to chemotherapy go on to regenerate the tumour after treatment. Our work paves the way for the development of drugs to eliminate these cells, which would make chemotherapy more effective and improve survival rates,” explains Dr Eduard Batlle in a press release.
The new study was conducted on organoids – three-dimensional cultured tumor masses derived from real patient tumors or from advanced collateral cancer tumors in animal models, which can be grown in complexity in the lab to observe a variety of different cell types.
"The organoids have allowed us to trace the evolution of the cells responsible throughout the process and observe their reaction to chemotherapy," explains Adrián Álvarez-Varela, the first author of the study.
The researchers took the observations in the organoids and animal data and compared the results with genetic data from samples of colon tumors from patients.
In addition to finding the mechanism for how these colon tumors relapse after chemotherapy, the team also discovered that the removal of the Mex3a gene from these cancer cells by genetic engineering techniques resulted in these cells being completely eliminated by chemotherapy treatments. Therefore, the Mex3a gene and protein product might be a useful drug target that could synergistically work with chemotherapy treatments to prevent colon cancer relapse.
In the future, the authors want to uncover the exact molecular mechanism that might explain how the Mex3a gene and protein keep colon cancer stem cells dormant. They also wish to address how chemotherapy treatment, specifically, triggers these cell-type populations to become naive and generate a state similar to that of an embryonic stem cell, which enables them to reactivate and become various different cell types after the chemo treatment has halted.