Although it is the second most common cause of cancer-related deaths worldwide, colorectal cancer is the third most common type of cancer.
The effect of colorectal cancer stem cells is being highlighted by growing studies, which makes treating the disease much more challenging. The ability of these “stem-like” cancer cells to self-renew and differentiate is what causes tumor spread, recurrence, and resistance to treatment.
These cancer stem cells are probably maintained in large part by certain cell signaling pathways. As a result, treating resistant colorectal cancer may be possible by focusing on these pathways.
According to a recent study, a protein called BEX2 may be able to interfere with an important molecular signaling system.
According to the research published in Cancer Biology & Medicine, this protein may inhibit these cells’ aggressive, treatment-resistant nature, opening the door to novel treatments meant to stop cancers from coming back.
BEX2’s function in cancer “stemness”
With a recurrence risk of about 30% following surgery, colorectal cancer relapse is still frequent despite advancements in cancer treatment. The existence of cancer stem cells, which may withstand therapy and create tumors, is a significant contributing factor to recurrence.
Cancer stem cells are an attractive target for treatment because of their capacity to self-renew, withstand medication, and promote tumor growth.
The research team looked at BEX2’s function. This protein plays a context-dependent role in the development of cancer, ranging from pro-oncogenic to tumor-suppressive.
According to the study’s findings, BEX2 “brakes” colorectal cancer cells’ stem-like function. Cancer cells behave more like stem cells when BEX2 levels are low. High BEX2 levels, on the other hand, cause the cells to respond to therapy.
BEX2 may affect the behavior of cancer stem cells, according to Ketan Thanki, MD, a board-certified colorectal surgeon with expertise in benign and malignant diseases of the colon, rectum, and anus at the MemorialCare Todd Cancer Institute at Long Beach Medical Center in Long Beach, CA. Thanki was not involved in the study.
“BEX2 inhibits pathways that permit cancer cells to revert to more aggressive, primitive stem-like states.” The actions of cancer cells are more regulated when BEX2 levels are high. Cancer cells become more like stem cells when BEX2 is reduced or absent, making them more invasive, difficult to eradicate, and resistant to treatment, Thanki told Medical News Today.
An important signaling route was discovered
Interestingly, the team also found that BEX2 interacted with MCL1, a protein that promotes cancer cell survival and is frequently overexpressed in colorectal cancer.
The Hedgehog signaling pathway, which is strongly linked to the maintenance of cancer stem cells in colorectal cancer, was less active as a result of BEX2’s promotion of MCL1 breakdown.
Thanki told MNT that “BEX2 functions like a tag on MCL1, marking it for death so that it can no longer stimulate the Hedgehog (Hh) signaling pathway.”
“Aggressive, stem-like cancer cells are fueled by the Hh pathway, a growth accelerator.” This route is one of the most thoroughly researched causes of therapy resistance and recurrence in colorectal cancer, so turning it off could revolutionize our therapeutic approaches,” he explained.
MCL1 became more stable in the absence of BEX2, which enhanced stem-like characteristics and triggered Hedgehog signaling. Crucially, in experimental models, these effects were reversed by blocking either MCL1 or Hedgehog signaling. Analyses of patient databases, lab tests, and mouse models corroborated these conclusions.
BEX2 levels were lower in colorectal cancer tissue than in normal tissue, according to tumor samples, and lower levels were linked to a worse disease-free survival.
What implications might this have for upcoming therapies?
Instead of concentrating only on tumor shrinkage, the researchers propose that their findings point to a possible new approach that targets the systems that support cancer stem cells.
“We are years away from utilizing BEX2 as a biomarker in clinical practice, but the data from this study are interesting,” Thanki told MNT. “They suggest a relationship between low BEX2 expression and worse outcomes in [colorectal cancer] patients.” This would necessitate extensive, standardized research as well as proof that assessing it genuinely influences treatment choices in a significant way.
BEX2 may be used as a biomarker to detect high-risk cancers and as a therapeutic target to reduce the cells that cause relapse if it is validated in more extensive clinical trials. Therefore, restoring BEX2 activity to destabilize MCL1 or block Hedgehog signaling are possible strategies.
Thanki continued, “The most interesting implication is that patients whose tumors have low BEX2 levels may be identified as having increased Hh pathway activity and being high-risk for recurrence and treatment resistance.”
He proposed that “clinicians can use this knowledge to pursue more aggressive treatment or enroll patients in studies targeting the Hedgehog pathway.”
Targeting cancer stem cells is becoming a more significant topic of research because it is believed that these cells underlie therapy resistance and disease recurrence.