| First Author | Huh SJ | Year | 2010 |
| Journal | Am J Pathol | Volume | 176 |
| Issue | 6 | Pages | 2948-57 |
| PubMed ID | 20431030 | Mgi Jnum | J:161327 |
| Mgi Id | MGI:4457994 | Doi | 10.2353/ajpath.2010.090963 |
| Citation | Huh SJ, et al. (2010) Macrophage inhibitory cytokine-1 regulates melanoma vascular development. Am J Pathol 176(6):2948-57 |
| abstractText | 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. |
