Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner

Abstract

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.

Organ-Specific Microenvironment Modifies Diverse Functional and Phenotypic Characteristics of Leukemia-Associated Macrophages in Mouse T Cell Acute Lymphoblastic Leukemia

“…Research over the past decades revealed the remarkably diverse roles of macrophages in the growth and metastasis of solid tumors (8). In most cases, tumor cells secrete a variety of chemoattractants that attract macrophages and cause their accumulation in tumor tissues, wherein the macrophages become TAMs and play protumor roles (14,38,39). Compared with solid tumors, hematopoietic malignancies have unique features, and leukemia is characterized by impaired production of normal blast cells and the proliferation of leukemia blast cells principally in the BM (spleen in acute lymphoblastic leukemia) without solid mass (17).…”

Autophagy-mediated regulation of macrophages and its applications for cancer

“…77 ADM/adrenomedullin , an antagonist of ADM receptors, suppresses tumor growth by skewing TAMs polarization to the M1 phenotype through downregulation of ADM in an autocrine-dependent manner. 75 These findings suggest that the identification of potential targets that polarize TAMs toward the M1 phenotype should be a promising anticancer strategy. By sensing the stimulation from the tumor microenvironment, macrophages are polarized to specific phenotypes through different signaling pathways, including the induction of autophagy.…”

“…16,21,75,76 TAMs are mainly polarized toward the M2 phenotype, that promotes tumor angiogenesis, growth, and metastasis. 16,21 However, it should be noted that some exceptions to this pattern exist.…”

“…16,21 However, it should be noted that some exceptions to this pattern exist. For instance, TAMs are biased toward the M1 phenotype in nonprogressing, regressing, and early-stage tumors, 16,21,75,77 suggesting that the phenotype of TAMs can be polarized by the local tumor microenvironment. Interestingly, recent studies demonstrated that HRG (histidine-rich glycoprotein) inhibits tumor growth and metastasis by inducing TAM polarization toward the M1 phenotype through downregulation of PGF (placental growth factor).…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Interestingly, it has been recently reported that in melanomas, TAMderived adrenomedullin is involved in angiogenesis and tumor growth. It was found that the adrenomedullin derived from TAMs interacts with its receptors on endothelial cells to promote tumor growth via a paracrine loop through the activation of the eNOS signaling pathway similar to the angiogenesis cytokine VEGF [90]. On the other hand, TAM-derived adrenomedullin can influence macrophages themselves in an autocrine manner, and, probably, may render immunosuppressive phenotype of tumor-associated DCs as well.…”