Macrophage inhibitory cytokine-1 regulates melanoma vascular development.
Expression of macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-beta family, normally increases during inflammation or organ injury. MIC-1 is also expressed at higher levels in melanomas; however, its role in tumorigenesis is unknown. This report identifies a novel function for MIC-1 in cancer. MIC-1 was overexpressed in approximately 67% of advanced melanomas, accompanied by fivefold to six-fold higher levels of secreted protein in serum of melanoma patients compared with normal individuals. Constitutively active mutant (V600E)B-Raf in melanoma regulated downstream MIC-1 expression. Indeed, small-interfering RNA-mediated targeting of MIC-1 or (V600E)B-Raf reduced expression and secretion by three-fold to fivefold. This decrease in MIC-1 levels reduced melanoma tumorigenesis by approximately threefold, but did not alter cultured cell growth, suggesting a unique function other than growth control. Instead, inhibition of MIC-1 was found to mechanistically retard melanoma tumor vascular development, subsequently affecting tumor cell proliferation and apoptosis. This role in melanoma angiogenesis was confirmed by comparing MIC-1 and vascular endothelial growth factor (VEGF) function in chick chorioallantoic membrane and matrigel plug assays. Similar to VEGF in melanomas, MIC-1 stimulated directional vessel development, acting as a potent angiogenic factor. Thus, MIC-1 is secreted from melanoma cells together with VEGF to promote vascular development mediated by (V600E)B-Raf signaling.
Huh
Sung Jin
SJ
The Pennsylvania State College of Medicine, Department of Pharmacology, Hershey, PA 17033, USA.
Chung
Chin-Ying
CY
Sharma
Arati
A
Robertson
Gavin P
GP
D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D048493:Proto-Oncogene Proteins B-raf