Scientists in the U.S. have identified a molecular pathway that appears to play a key role in the link between a high-fat diet (HFD) and the development of colorectal cancer. The research, led by the Cleveland Clinic’s Sheerlarani Karunanithi, and Matthew Kalady, suggests that it may one day be possible to develop drugs that reduce tumor growth associated with obesity and a diet that is high in fat. 

Their research is published today, in Stem Cell Reports, in a paper titled, “RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis.”

The Cleveland Clinic team’s review of published research indicated that high expression levels of two vitamin A signalling proteins—serum retinol binding protein (RPB4), stimulated by retinoic acid 6 (STRA6)—in colorectal cancer tumors is associated with poor prognosis, increased tumor metastasis and recurrence, and resistance to cancer therapy. The RBP4-STRA6 pathway triggers the JAK2-STAT3 signaling cascade.

The researchers engineered STRA6- or RBP4-knockdown cancer cells to demonstrate that the RBP4-STRA6 pathway is important for promoting cancer cell proliferation and survival and for maintaining the expression of core stem cell transcription factors. They also found that the RBP4-STRA6 pathway plays a key role in maintaining colon cancer stem cells (CSCs), both in cell lines and in patient-derived xenografts.

The team’s previous work had shown that knocking down STRA6 in a xenograft cancer model decreased tumor growth. In a new round of studies, they injected RBP4-knockdown cancer cells into experimental mice, and found that RBP4 deficiency resulted in the development of fewer tumors, and slower tumor growth and progression.

With evidence building for the role of RBPA4-STRA6 pathway in colorectal cancer development and progression, the team turned to look at diet-related cancer. A prior study had already suggested that HFD–induced obesity leads to increased intestinal stem cells and may impact colorectal cancer risk. This finding, combined with independent research establishing a role for the RBPA4-STRA6 pathway in diet-induced metabolic syndrome, prompted the Cleveland Clinic team to look at the relationship between HFD, cancer development, and the RBPA4-STRA6 pathway.

They injected either STRA6-deficient colorectal cancer cells or unmodified cancer cells into obesity-resistant mice fed either a normal diet or an HFD. HFD mice injected with unmodified cancer cells exhibited significantly increased tumor growth compared with mice fed a normal diet. In contrast, there was no relative increase in tumor growth among HFD animals receiving the STRA6-deficient tumor cells. 

“Our data clearly indicate that RBP4-STRA6 pathway is necessary for the optimal expression of stem cell markers such as NANOG, SOX2, and LGR5, and thereby for maintaining the colon CSC pool,” the authors conclude in their published paper. “We have known the influence of diet on colorectal cancer,” commented Matthew Kalady, M.D., colorectal surgeon, and co-director of the Cleveland Clinic Comprehensive Colorectal Cancer Program. “However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”

“The interesting finding here is that the high fat diet-induced effects appear to also involve the stem cell program, which is interesting for tumor growth and has implications on therapies, as tumor stem cells are also therapeutically resistant,” the authors told GEN. “In terms of treatments, what we might  envision is targeting a new component of the signaling axis we identified to reduce cancer growth. The pathways we have identified are known to control many aspects of cell behavior, but the input to these signaling programs is new and may represent a possible target. In terms of next steps, one would be to see whether this can be applied to other obesity-driven tumors. Can lessons from colon cancer be leveraged to other tumor types? We also are interested in inhibiting this new signaling axis as well as trying to understand more about this signaling program, as we may be able to identify signaling nodes that can be efficiently targeted.”

Dr. Karunanithi further explained to GEN that the team's study is one of the first to link the STRA6-driven pathway with high-fat induced colon cancer progression and cancer stem cell markers. “We are interested in studying this connection in other cancer models. Future studies will also entail the development of small molecule inhibitors towards STRA6. Considering that STRA6 is present on the cell surface, such inhibitors may function from the outside of the cells, bypassing the need to develop cell permeable agents, and thus reduce the time needed for translation in to the clinic.”

The published work was primarily carried out in the lab of the late Dr. Noa Noy at the Cleveland Clinic,Dr. Karunanithi pointed out. “Our new finding that STRA6 can provide the link between high-fat feeding and colon cancer can potentially be extended to other cancers in which STRA6 is highly upregulated. Interestingly, work from Dr. Noy’s lab had previously shown that STRA6 is also upregulated in breast cancer patients compared to normal breast. Breast cancer is also one of those highly influenced by high fat diet and other environmental factors. It will be important to study if STRA6 inhibition can prevent or mitigate breast cancer.” 



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