Colorectal cancer is the third most common cancer globally but ranks as the second leading cause of cancer-related deaths.
Growing research highlights the impact of colorectal cancer stem cells, and making the condition significantly more difficult to treat. These “stem-like” cancer cells describe cells within tumors able to self-renew and differentiate, which drives tumor metastasis, recurrence, and therapy resistance.
Certain cell signaling pathways likely play a crucial role in the maintenance of these cancer stem cells. Therefore, targeting these pathways may provide a viable strategy for treating resistant colorectal cancer.
Now, a new study highlights a protein, known as BEX2, which may be able to disrupt a key molecular signaling pathway.
The findings, which appear in Cancer Biology & Medicine, suggest this protein may suppress the aggressive, treatment-resistant behavior of these cells, raising the possibility of new therapies aimed at preventing tumors from returning.
Despite advances in cancer therapy, relapse remains common in colorectal cancer, with a recurrence rate of roughly 30% after surgery. A major reason for recurrence is the presence of cancer stem cells, which can survive treatment and regenerate tumors.
Characteristic features of cancer stem cells are their ability to self-renew, resist drugs, and drive tumor growth, making them a promising target for the treatment
The research team investigated the role of BEX2. This is a protein that has a context-dependent role in cancer development, which can range from tumour-suppressive functions to pro-oncogenic activities.
The study findings suggest that BEX2 acts as a “brake” on stem-like behavior in colorectal cancer cells. When BEX2 levels were low, cancer cells act more like stem cells. In contrast, high BEX2 levels make the cells responsive to treatment.
Ketan Thanki, MD, board-certified colorectal surgeon who specializes in benign and malignant disease of the colon, rectum, and anus with the MemorialCare Todd Cancer Institute at Long Beach Medical Center in Long Beach, CA, who was not involved in the study, explained how BEX2 may influence cancer stem cell behavior.
“BEX2 taps the brakes on pathways that allow cancer cells to revert to more primitive, aggressive stem-like states. When BEX2 levels are high, cancer cell behaviors are more controlled. When BEX2 is low or absent, cancer cells become more like stem cells: harder to kill, more invasive, and more resistant to chemotherapy,” Thanki told Medical News Today.
“BEX2 taps the brakes on pathways that allow cancer cells to revert to more primitive, aggressive stem-like states. When BEX2 levels are high, cancer cell behaviors are more controlled. When BEX2 is low or absent, cancer cells become more like stem cells: harder to kill, more invasive, and more resistant to chemotherapy.”
– Ketan Thanki, MD
Notably, the team also identified that BEX2 interacted with another molecule, known as MCL1, which supports cancer cell survival and is often overexpressed in colorectal cancer.
BEX2 promoted the breakdown of MCL1, which in turn dampened the activity in the Hedgehog signaling pathway, a pathway closely associated with maintaining cancer stem cells in colorectal cancer.
“BEX2 acts like a tag on MCL1, marking it for destruction so that it can no longer activate the Hedgehog (Hh) signaling pathway,” Thanki explained to MNT.
“The Hh pathway is a growth accelerator that fuels aggressive, stem-like cancer cells. In colorectal cancer, this pathway is one of the most well-studied drivers of treatment resistance and recurrence, so keeping it switched off could be transformational to our treatment practices,” he detailed.
When BEX2 was absent, MCL1 became more stable, activating Hedgehog signaling and enhancing stem-like traits. Importantly, blocking either MCL1 or Hedgehog signaling reversed these effects in experimental models. These findings were supported by analyses of patient datasets, laboratory experiments, and mouse models.
Tumor samples showed that BEX2 levels were lower in colorectal cancer tissue compared with normal tissue, and lower levels were associated with worse disease-free survival.
In cell experiments, removing BEX2 increased markers linked to stemness, such as CD133 and CD44, and made cells more resistant to chemotherapy drugs like oxaliplatin. Animal studies further confirmed that reduced BEX2 led to stronger tumor growth.
The researchers suggest their findings highlight a potential new strategy of targeting the mechanisms that sustain cancer stem cells, rather than focusing solely on shrinking tumors.
“The data from this study are promising,” Thanki told MNT. “They show a link between low BEX2 expression and worse outcomes in [colorectal cancer] patients, but we are years away from using BEX2 as a biomarker in clinical practice. This would require large, standardized studies, and evidence that measuring it actually changes treatment decisions in a meaningful way.”
If confirmed in larger clinical studies, BEX2 could serve both as a biomarker to identify high-risk tumors, and a therapeutic target to weaken the cells responsible for relapse. Thus, potential approaches could include restoring BEX2 activity to destabilize MCL1 or inhibit Hedgehog signaling.
“The most exciting implication is that patients whose tumors show low BEX2 levels might be identified as having higher Hh pathway activity and being high-risk for recurrence and chemotherapy resistance,” Thanki added.
“Clinicians can utilize this knowledge to pursue more aggressive treatment or enroll them in trials targeting the Hedgehog pathway,” he suggested.
As cancer stem cells are thought to underpin treatment resistance and disease recurrence, targeting them is becoming an increasingly important area of research.
While the current findings are still at an early stage, they offer a clearer picture of how stem-like cells are regulated in colorectal cancer and how they might be disrupted.
