Leuk Res. 2021 Sep 20;110:106709.doi: 10.1016/j.leukres.2021.106709. Online ahead of print.

Tumor-associated macrophages modulate angiogenesis and tumor growth in a xenograft mouse model of multiple myeloma

Miaomiao Sun  1 Qiankun Xiao  2 Xiaoqian Wang  3 Chenbo Yang  4 Chao Chen  4 Xiangyu Tian  4 Shuaiyuan Wang  4 Hui Li  4 Sen Qiu  5 Jiao Shu  1 Yuwei Shou  4 Yinghao Liang  4 Tong Xue  4 Kuisheng Chen  6 Affiliations

Abstract

Tumor-associated macrophages (TAMs) are closely associated with poor multiple myeloma (MM) prognosis. Therefore, in-depth understanding of the mechanism by which TAM supports MM progression may lead to its effective treatment. We used the MM nude mouse subcutaneous xenograft model to evaluate the efficacy of the macrophage-depleting agent clodronate liposome (Clo) against MM and elucidate the mode of action of this therapy. At the same time, observe whether the elimination of TAM in vivo while silencing the expression of VEGFA has the same effect as in vitro experiments. We also used Clo to eliminate macrophages and reinjected M1 or M2 TAM through mouse tail veins to investigate the effects of various macrophage subtypes on MM xenograft tumor growth. We applied qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay to quantify VEGFA, CD31, and CD163 expression in tumor tissues and sera. Removal of TAMs from the tumor microenvironment impeded tumor growth. The combination of Clo plus VEGFA siRNA had a stronger inhibitory effect on tumor growth than Clo alone, and M2 and M1 macrophages promoted and inhibited tumor growth, respectively. Macrophage depletion combined with cytokine blocking is a promising MM treatment. Targeted M2 macrophage elimination together with cytokine block may be more effective at inhibiting MM growth than either treatment alone. The results of the present study lay an empirical foundation for the development of novel therapeutic strategies for MM.

Keywords: Angiogenesis; Clodronate liposome; Multiple myeloma; Tumor-associated macrophage; Vascular endothelial growth factor A; siRNA.

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