Tumor-associated macrophages (TAMs) have been shown to be associated with poor prognosis of cancer and are predominately localized in the hypoxia regions of tumor. We demonstrated in this study that hypoxia increases the synthesis and secretion of galectin-3 by TAMs. The increased expression of galectin-3 in TAMs was seen to be associated with nucleation of transcription factor NF-κB through generation and activation of ROS and promoted tumor growth and metastasis in vitro and in mice through multiple molecular mechanisms. It was found that the TAMs-mediated promotion of tumor growth and metastasis in hypoxia was inhibited by administration of macrophage-depletion agent clodronate liposomal (CL) or galectin-3 inhibitor modified citric pectin (MCP) in orthotopic syngeneic mammary adenocarcinoma model and metastasis model. Co-administration of anti-angiogenesis agent sorafenib or bevacizumab with CL and MCP showed to cause stronger inhibition of tumor growth and metastasis than administration of each agent alone. These results indicate that hypoxia-induced galectin-3 expression and secretion from TAMs promotes tumor growth and metastasis. Targeting the actions of galectin-3 in hypoxia may be a potential therapeutic strategy for cancer treatment.
Keywords: Bevacizumab; Galectin-3; Hypoxia; Modified citrus pectin; TAMs.
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