Background and purpose: The occurrence of colorectal cancer is associated with a variety of factors. Accumulating evidence shows that peripheral differentiation of regulatory T cells (Tregs) is critical in controlling tumorigenesis. Our previous studies demonstrated that the Yi Yi Fu Zi Bai Jiang San extract exerted potent anticancer activities by significantly enhancing immunosuppression in ApcMin/+ mice. However, there is limited knowledge on the effect of Yi Yi Fu Zi Bai Jiang San in the prevention of colorectal cancer and the underlying mechanisms of action.
Methods: In this study, we investigated the effect of oral administration of Yi Yi Fu Zi Bai Jiang San in preventing azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. We found that Yi Yi Fu Zi Bai Jiang San treatment decreased tumor load, tumor number, histology, and the severity of disease activity index (DAI) scores.
To investigate if Yi Yi Fu Zi Bai Jiang San inhibited tumorigenesis by regulating regulatory T cells, we depleted Tregs in AOM/DSS mice. We then analyzed the effect of intragastric administration of Yi Yi Fu Zi Bai Jiang San on tumorigenesis and the regulation of tumor microenvironment.
Results: As expected, intragastric administration of Yi Yi Fu Zi Bai Jiang San in AOM/DSS mice model significantly increased immune responses in the tumor microenvironment through its hypoxia-associated anti-cancer activities. Additionally, Yi Yi Fu Zi Bai Jiang San regulated the polarization of peripheral Treg (pTreg) to suppress colorectal cancer cell proliferation and infiltration.
This was demonstrated by the decrease in tumor proliferation-related proteins including p-STAT3, p-NF-κB and MMPs in a dose-dependent manner. Clinically, the increase in the levels of Tregs in human tissues during colorectal cancer progression was associated with low expression of HIF-1α in the stroma, and correlated with colorectal cancer survival and prognosis.
Conclusion: Altogether, we demonstrated that HIF-1α may promote pTreg -induced carcinogenesis and progression of colorectal cancer cells, indicating that Yi Yi Fu Zi Bai Jiang San is a promising protective agent against HIF-1α-mediated Treg activation in colorectal cancer.
This study is the first to imply a novel clinical significance of a traditional Chinese herbal medicine from Synopsis of Golden Chamber in the cancer treatment and clarify the important role of tumor microenvironment in preventing tumorigenesis.