Abstract
Epidermal growth factor receptor (EGFR) is a target of colon cancer therapy, but the effects of this therapy on the tumor microenvironment remain poorly understood. Our in vivo studies showed that cetuximab, an anti-EGFR monoclonal antibody, effectively inhibited AOM/DSS-induced, colitis-associated tumorigenesis, downregulated M2-related markers, and decreased F4/80+/CD206+ macrophage populations. Treatment with conditioned medium of colon cancer cells increased macrophage expression of the M2-related markers arginase-1 (Arg1), CCL17, CCL22, IL-10 and IL-4. By contrast, conditioned medium of EGFR knockout colon cancer cells inhibited expression of these M2-related markers and induced macrophage expression of the M1-related markers inducible nitric oxide synthase (iNOS), IL-12, TNF-α and CCR7. EGFR knockout in colon cancer cells inhibited macrophage-induced promotion of xenograft tumor growth. Moreover, colon cancer-derived insulin-like growth factor-1 (IGF-1) increased Arg1 expression, and treatment with the IGF1R inhibitor AG1024 inhibited that increase. These results suggest that inhibition of EGFR signaling in colon cancer cells modulates cytokine secretion (e.g. IGF-1) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth.
Highlights
Colorectal cancer (CRC) is the fifth and fourth most commonly diagnosed cancer in males and females, respectively, and is the fifth most common cause of cancer-related death in China [1]
These results suggest that inhibition of Epidermal growth factor receptor (EGFR) signaling in colon cancer cells modulates cytokine secretion (e.g. insulin-like growth factor-1 (IGF-1)) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth
These results suggest that cetuximab effectively protected against AOM/ Dextran sodium sulfate (DSS)-induced, colitis-associated tumorigenesis
Summary
Colorectal cancer (CRC) is the fifth and fourth most commonly diagnosed cancer in males and females, respectively, and is the fifth most common cause of cancer-related death in China [1]. Colitis associated cancer (CAC) is a type of CRC that results from inflammatory bowel disease (IBD) [2, 3]. Traditional colorectal cancer therapies include surgical resection, chemotherapy, and radiotherapy [4]. Tumor-associated macrophages (TAMs) that infiltrate tumors are abundant in the tumor microenvironment. TAMs play important roles in chronic inflammation and in the tumor microenvironment and promote tumor cell growth, and affect the efficacy of different antineoplastic therapies [7,8,9,10]
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