Macrophage inhibitory cytokine-1 regulates melanoma vascular development

Sung Jin Huh, Chin Ying Chung, Arati Sharma, Gavin P. Robertson

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Expression of macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-β 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 ∼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 V600EB-Raf in melanoma regulated downstream MIC-1 expression. Indeed, small-interfering RNA-mediated targeting of MIC-1 or V600EB-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 V600EB-Raf signaling.

Original languageEnglish (US)
Pages (from-to)2948-2957
Number of pages10
JournalAmerican Journal of Pathology
Volume176
Issue number6
DOIs
StatePublished - Jun 2010

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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