Astragaloside IV Exerts Anti-tumor Effect on Murine Colorectal Cancer by Re-educating Tumor-Associated Macrophage
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ORIGINAL ARTICLE
Astragaloside IV Exerts Anti‑tumor Effect on Murine Colorectal Cancer by Re‑educating Tumor‑Associated Macrophage Feng Liu1 · Fang Ran2 · Hongqin He1 · Linyun Chen2 Received: 12 March 2020 / Accepted: 16 October 2020 © L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2020
Abstract Astragaloside IV (AS-IV) has shown anti-tumorigenic properties in certain cancers for its effect of boosting the body’s immune system, but its role in colorectal cancer (CRC) remains unclear. In this study, we investigated the therapeutic effect of AS-IV in CRC and explored its underlying mechanism. CT26 colon cancer cells and mouse model by injection of CT26 cells subcutaneously were used as in vitro and in vivo model. M1 and M2 macrophage-associated markers, mRNA and protein expression levels were analyzed after AS-IV treatment. Inflammatory factors and cytokines in the tumors from mouse model were detected. Repolarization effect of AS-IV in vitro on bone-marrow-derived macrophages was also detected. In vitro, AS-IV inhibited the proliferation of CT26 cells and induced cell apoptosis dose-dependently, and significantly reduced M2 macrophages and increased M1 macrophages. In mouse model, it suppressed tumor growth and decreased the production of anti-inflammatory factors such as TGF-β, IL-10 and VEGF-A, while increased the production of pro-inflammatory factors like IFN-γ, IL-12 and TNF-α in tumor. Combination of AS-IV and checkpoint inhibitor aPD-1 exhibited synergistic antitumor effect by inhibiting tumor growth and increasing T cell infiltration. AS-IV could induce M2 macrophages polarization to the M1 phenotype. Its combination with immune checkpoint inhibitors could be expected to become a potential new strategy for the treatment of CRC. Keywords Colon cancer · Tumor-associated macrophages · Macrophage polarization · Astragaloside IV · Tumor microenvironment
Introduction Colorectal cancer (CRC) is a common malignant tumor of the digestive system. There are about 1.2 million new cases every year worldwide (Mantovani et al. 2017). It has brought heavy economic and spiritual burdens to people around the world. At present, the treatment of CRC is mainly surgery, chemotherapy, and radiation therapy. There are about 75% of CRC patients who can be diagnosed at an early stage and they can be treated by surgery or/and chemotherapy. But * Linyun Chen [email protected] 1
Department of Anorectal Surgery, Medical College District of CANGZHOU People’s Hospital, Intersection of Chongqing Road and Jilin Avenue, Cangzhou 061000, Hebei, China
Division 2 of Neurology, CANGZHOU People’s Hospital Headquarters, Qingchi Avenue, Cangzhou 061000, Hebei, China
2
some patients are already in the advanced stage of inoperability at the time of diagnosis and can only get treatment like chemotherapy, radiotherapy and immunotherapy (Ciombor et al. 2015). Thus, it is very urgent to find effective therapeutic strategy for CRC treatment with less side effects for those who are diagnosed at
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