title: Tumor-associated macrophages promote angiogenesis and melanoma growth via adrenomedullin in a paracrine and autocrine manner.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Our study reveals a novel mechanism that TAMs enhance angiogenesis and melanoma growth via ADM and provides potential targets for melanoma therapies.
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.
authors: Peiwen
authors: P
authors: Chen
authors: Yujie
authors: Y
authors: Huang
authors: Rosabel
authors: R
authors: Bong
authors: Yanping
authors: Y
authors: Ding
authors: Nan
authors: N
authors: Song
authors: Xiaofeng
authors: X
authors: Wang
authors: Xiaomin
authors: X
authors: Song
authors: Yongzhang
authors: Y
authors: Luo
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019898:Autocrine Communication; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019899:Paracrine Communication; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D017077:Culture Media, Conditioned; D053607:Adrenomedullin; D052250:Nitric Oxide Synthase Type III