TY - JOUR
T1 - Macrophage inhibitory cytokine-1 regulates melanoma vascular development
AU - Huh, Sung Jin
AU - Chung, Chin Ying
AU - Sharma, Arati
AU - Robertson, Gavin P.
N1 - Funding Information:
Supported by NIH grant CA-127892, American Cancer Society grant RSG-04-053-01-GMC, and The Foreman Foundation for Melanoma Research.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.090963
DO - 10.2353/ajpath.2010.090963
M3 - Article
C2 - 20431030
AN - SCOPUS:77953217053
SN - 0002-9440
VL - 176
SP - 2948
EP - 2957
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -