The Role of Itaconate in the Advancement of Colorectal Cancer: A Mathematical Modeling Perspective

Colorectal cancer (CRC), ranking as the second most common cancer in women and the third in men, remains a significant global health concern. While the immune system is inherently designed to combat cancer, recent studies have revealed that certain immune components can paradoxically promote tumor growth. One such factor is itaconate, a metabolite produced by macrophages. Itaconate exerts its pro-tumorigenic effects by modulating gene expression within the tumor microenvironment. Specifically, it downregulates the expression of interleukin-۱۰ (IL-۱۰), an anti-inflammatory cytokine. This reduction in IL-۱۰ intensifies inflammation within the tumor, leading to increased blood vessel formation and nutrient supply, thereby fostering tumor progression and metastasis. To delve deeper into the complex interplay between itaconate, the immune system, and tumor cells, we developed a mathematical model using ordinary differential equations. This model simulated the dynamics of key biological processes, including itaconate production, immune cell activation, tumor cell (human colorectal adenocarcinoma cell line HT-۲۹) proliferation, and IL-۱۰ secretion. By incorporating experimental data, we were able to calibrate the model and assess the impact of varying itaconate concentrations on tumor growth. The findings from the model simulation reveal that higher levels of itaconate are associated with lower levels of the anti-inflammatory cytokine interleukin-۱۰ (IL-۱۰), which in turn supports tumor growth. Additionally, the sensitivity analysis of the model pinpointed the rates at which itaconate decreases IL-۱۰ and its influence on tumor reduction as crucial elements impacting the model’s results. By targeting itaconate-related pathways, we may be able to develop novel therapeutic strategies to combat CRC. This study provides a mechanistic understanding of itaconate's pro-tumorigenic role in CRC by modulating IL-۱۰ signaling and highlights the utility of mathematical modeling in deciphering complex biological interactions in cancer.

کلیدواژه ها:

colorectal cancer ، Interleukin-۱۰ ، Itaconate ، mathematical modeling