Combating Colon Cancer through Modulation of the Tumor Microenvironment and Gut Microbiota (Abstract)

Orthodox anticancer strategies have been focused on targeting the tumor itself, which could result in unsatisfactory treatment outcome and drug resistance. Some cytotoxic tumoricidal agents may even cause major systemic toxicities. Our earlier research had revealed the synergistic anticancer effect of novel adjuvant agent with first-line chemotherapeutic drug in colon cancer therapy (Carcinogenesis 28:1347–55, 2007). We determined that such action is due to alleviation of the cytotoxic drug's hematologic toxicity through immunomodulation (Am J Chin Med 44:579–93, 2016). In order to effectively control cancer growth and progression, we need to consider carcinogenesis as a process involving complex heterotypic multi-cellular interactions within a tumor microenvironment, comprising tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), leukocytes, bone marrow-derived cells, vascular endothelial cells and mesenchymal stem cells. Investigation of drug actions in such tumor microenvironment could enable us to identify the way to cut off the connection between cancer cells and its microenvironment, providing a target-specific treatment that is free from major side effects in the host. Proliferation and migration of human colon cancer cells were markedly increased when they were cultured in activated macrophage-conditioned medium (CM). We demonstrate that novel chemotherapeutic agents attenuate the polarization and activation of TAM and CAF and inhibit colon cancer progression to be promoted by TAM and CAF. These include inhibition of growth inhibition and apoptosis, prevention of cell invasion and migration of colon cancer cells that used to be provoked when co-cultured with TAM or CAF. Besides, the overexpressed proangiogenic and metastatic factors (such as MMPs and VEGF) and altered signaling pathways in activated TAM and CAF as well as in colon cancer cells previously interacting with CM would be downregulated and rectified after drug modulation. Other than the tumor microenvironment, increasing evidences have shown that the gut microbiota is also important in the development of intestinal tumorigenesis. Their genotoxic metabolites could bind to specific intestinal cell surface receptors and consequently disturb intracellular signal transduction. Understanding the association between gut microbiota and the development of colon cancer will be crucial to rectify the altered molecular pathways during the carcinogenic process. We have explored the the restorative potential of novel chemotherapeutic agent on gut bacteria homeostasis in nude mice implanted with colon tumor, with maintenance of the commensal bacterial colonies such as lactobacillus. Such activity could bring along with antitumor effect of the drug, which may involve modulation of the tumor microenvironment during the course. These findings suggest that mediation of the tumor microenvironment and gut microbiota could serve as a potential therapeutic approach in the treatment of colon cancer.