Therapeutic Treatment of Colorectal Cancer through Eph/Ephrin System Modulation

Throughout history, it has been well known that wealthier, more developed countries tend to struggle with maintaining a healthy lifestyle and diet. To demonstrate this idea further, there is an apt comparison to be made between the number of cases of colorectal cancer in America versus Uganda. The highest rates of colorectal cancer seen globally happen to be in Connecticut, while the lowest in Kampala, Uganda (Greger 2018). This distinction is so drastic that many physicians in Uganda have never even come across one case. According to Dr. Denis Burkitt, this seems to be correlated with the amount the fiber intake of Ugandans (Greger 2018). In contrast, in the United States, less than 3% of Americans meet the recommended daily intake of fiber (Greger 2018). This severe lack of fiber intake has placed colorectal cancer as number two on the list of top cancers for Americans. While advances in medicine have produced better diagnoses, more efficient surgeries, and better medications to combat colorectal cancer, further improvements are needed to reduce this drastic, yet very preventable disease. 

In Dr. William Rochlin's 2016 paper, "Ephrin-B/EphB Signaling is Required for Normal Innervation of Lingual Gustatory Papillae," the role of the Eph/Ephrin signaling system in axon guidance was thoroughly explored. Rochlin et al. found that Eph-B/Ephrin-B signaling was deemed necessary for the normal innervation of gustatory papillae. In addition to axon guidance, the Eph/Ephrin signaling system seems to play a large role in bone and intestinal homeostasis, platelet aggregation, glucose balance, immune system functions, inflammation, and angiogenesis (Tognolini et al. 2014). Given the widespread expression of the Eph/Ephrin system in many stem cell cultures, it is only logical to assume that when this system becomes deregulated, cancer can arise (Tognolini et al. 2014). Further, the deregulation of this system has been implicated in diseases such as Alzheimer's, ALS, Cancer, Atherosclerosis, and diabetes. As such, Dr. Tognolini and colleagues have spent years investigating the therapeutic measures in which to regulate and/or inhibit the Eph/Ephrin system when gone awry. 

     

Figure 1 & 2: Highlighting the Eph/Ephrin receptor system and the small molecules shown to have inhibitory effects. 

In their 2014 paper, Tognolini et al. laid out many different means by which the Eph/Ephrin connection could be disrupted via small molecules, kinase inhibitors, peptides, and antibodies. Interestingly, many of the small molecules that have been shown to regulate this system are naturally occurring in the body and whole plant foods. For example, Salicylic acid derivatives are found in almonds, cherries, berries, apples, and grapes and these have been shown to inhibit the binding of Ephrin to Eph A2 and Eph A4 (Tognolini et al. 2014). Eph A2 activation has been linked to tumor necrosis factor angiogenesis while Eph A4 activation via ephrin A1 has shown to recruit immunological and inflammatory cells to blood vessels leading to the formation of atherosclerotic plaque (Tognolini et al. 2014). Among the small molecules presented, the bile acid derivative, UniPR129, has shown the most promise in Tognolini's most recent paper as the most potent inhibitor of the Eph/Ephrin system (Tognolini et al. 2020). This paper's main finding found that this 8-week pharmacological intervention significantly reduced the number, diameter, and progression of adenomas in the ileum of Colorectal cancer mice. All things considered, this information provides great evidence for the intrinsic healing and regulatory nature of healthy food molecules. Implementing these molecules in a pharmacological manner presents immense promise as a novel means to slow many cancers and diseases mentioned prior. 

References:

Corrado, Miriam & Giorgio, Carmine & Barocelli, Elisabetta & Vittucci Marzetti, Giuseppe & Cantoni, Anna & Lecce, Rosanna & Incerti, Matteo & Castelli, Riccardo & Lodola, Alessio & Tognolini, Massimiliano. (2020). Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice. Pharmaceuticals. 13. 69. 10.3390/ph13040069. 

"How Not to Die from Brain Diseases." How Not to Die: Discover the Foods Scientifically Proven to Prevent and Reverse Disease, by Michael Greger and Gene Stone, Pan Books, 2018, pp. 51-57. 

Tognolini M, Hassan-Mohamed I, Giorgio C, Zanotti I, Lodola A. Therapeutic perspectives of Eph-ephrin system modulation. Drug Discov Today. 2014 May;19(5):661-9. doi: 10.1016/j.drudis.2013.11.017. Epub 2013 Nov 26. PMID: 24291785.

Treffy RW, Collins D, Hoshino N, Ton S, Katsevman GA, Oleksiak M, Runge EM, Cho D, Russo M, Spec A, Gomulka J, Henkemeyer M, Rochlin MW. Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae. Dev Neurosci. 2016;38(2):124-38. DOI: 10.1159/000444748. Epub 2016 Apr 2. PMID: 27035151; PMCID: PMC4927353.