Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice.
We investigated whether blocking of monocyte chemoattractant-1 (MCP-1) function would inhibit recruitment of tumor-associated macrophages (TAMs) and prevent tumor angiogenesis and tumor growth of human malignant melanoma. B16-F1 melanoma cells were implanted onto the back of C57BL/6 mice (Day 0). At Day 7, a dominant negative MCP-1 mutant (7ND) gene was transfected in the thigh muscle to make overexpressed 7ND protein secreted into systemic circulation. 7ND treatment inhibited TAM recruitment and partially reduced tumor angiogenesis and tumor growth. Also, 7ND treatment attenuated inductions of tumor necrosis factor-alpha (TNFalpha), interleukin-1alpha (IL-1alpha), and vascular endothelial growth factor (VEGF) in the stroma and tumor. Melanoma cells expressed not only MCP-1 but also its receptor CCR2. Accordingly, it was suggested that MCP-1 would enhance tumor angiogenesis and early tumor growth in the early stages by inducing TNFalpha, IL-1alpha, and VEGF through TAM recruitment and probably the direct autocrine/paracrine effects on melanoma cells.
Koga
Mitsuhisa
M
Department of Internal Medicine, Division of Cardio-Vascular Medicine and Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan.
Kai
Hisashi
H
Egami
Kimiyasu
K
Murohara
Toyoaki
T
Ikeda
Ayami
A
Yasuoka
Suguru
S
Egashira
Kensuke
K
Matsuishi
Toyojiro
T
Kai
Mamiko
M
Kataoka
Yasufumi
Y
Kuwano
Michihiko
M
Imaizumi
Tsutomu
T
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000517:prevention & control*
C111835:CCL2 protein, human; D018932:Chemokine CCL2