Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner
Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner
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DOI：
10.1158/1078-0432.ccr-11-1354
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发表时间：
2011-12-01
影响因子：
11.5
通讯作者：
Luo, Yongzhang
中科院分区：
文献类型：
--
作者：
Chen, Peiwen;Huang, Yujie;Luo, Yongzhang
目的：肿瘤微环境中肿瘤相关巨噬细胞（TAM）数量的增加通常与黑色素瘤的预后不良相关。然而，TAM调节黑色素瘤生长的机制仍然知之甚少。本研究旨在探讨TAM衍生的肾上腺髓质素（adrenomedullin，ADM）在黑色素瘤血管生成和生长中的作用和机制。实验设计：建立体外和体内模型，研究TAM和ADM在黑色素瘤中的关系，探讨ADM在TAM诱导的血管生成和黑色素瘤生长中的作用和机制。ADM及其受体的临床意义进行了评估，使用黑色素瘤组织微阵列。结果：ADM的表达浸润TAMs在人黑色素瘤，其分泌的巨噬细胞与黑色素瘤细胞，或与黑色素瘤细胞条件培养基后上调。同时，TAM促进内皮细胞迁移和小管形成，也促进B16/F10肿瘤生长。中和ADM抗体和ADM受体拮抗剂AMA分别在体外和体内减弱TAM诱导的血管生成和黑色素瘤生长。此外，ADM促进血管生成和黑色素瘤的生长，通过旁分泌效应，介导的内皮型一氧化氮合酶信号通路，和自分泌效应，刺激极化的巨噬细胞向交替激活（M2）表型。最后，对人类黑色素瘤的免疫荧光分析表明，ADM在TAMs及其受体的表达大大增加相比，相邻的正常skin.Conclusion：我们的研究揭示了一个新的机制，TAMs通过ADM促进血管生成和黑色素瘤的生长，并提供了潜在的黑色素瘤治疗的目标。临床癌症研究; 17（23）; 7230-9。（C）2011年《非洲标准化评论》。
Purpose: Elevated numbers of tumor-associated macrophages (TAM) in the tumor microenvironment are often correlated with poor prognosis in melanoma. However, the mechanisms by which TAMs modulate melanoma growth are still poorly understood. This study was aimed at examining the function and mechanism of TAM-derived adrenomedullin (ADM) in angiogenesis and melanoma growth.Experimental Design: We established in vitro and in vivo models to investigate the relationship between TAMs and ADM in melanoma, the role and mechanism of ADM in TAM-induced angiogenesis and melanoma growth. The clinical significance of ADM and its receptors was evaluated using melanoma tissue microarrays.Results: ADM was expressed by infiltrating TAMs in human melanoma, and its secretion from macrophages was upregulated upon coculture with melanoma cells, or with melanoma cells conditioned media. Meanwhile, TAMs enhanced endothelial cell migration and tubule formation and also increased B16/F10 tumor growth. Neutralizing ADM antibody and ADM receptor antagonist, AMA, attenuated TAM-induced angiogenesis in vitro and melanoma growth in vivo, respectively. Furthermore, ADM promoted angiogenesis and melanoma growth via both the paracrine effect, mediated by the endothelial nitric oxide synthase signaling pathway, and the autocrine effect, which stimulated the polarization of macrophages toward an alternatively activated (M2) phenotype. Finally, immunofluorescence analysis on human melanomas showed that the expression of ADM in TAMs and its receptors was greatly increased compared with adjacent normal skins.Conclusion: Our study reveals a novel mechanism that TAMs enhance angiogenesis and melanoma growth via ADM and provides potential targets for melanoma therapies. Clin Cancer Res; 17(23); 7230-9. (C)2011 AACR.