Interleukin 10 suppresses tumor growth and metastasis of human melanoma cells: potential inhibition of angiogenesis.
Interleukin 10 (IL-10) inhibits the production of a wide range of cytokines in various cell types. The purpose of this study was to determine whether the expression of the IL-10 gene can influence tumor growth and metastatic properties of human melanoma cells. The human melanoma cell line, A375P, which does not produce endogenous IL-10, was transfected with a hygromycin expression vector (control) or a vector containing full-length murine IL-10 cDNA. A375P parental cells, A375P-Hygro, and A375P-IL-10-positive cells were injected s.c. and i.v. into nude mice. A375P-IL-10 cells produced significantly slower growing s.c. tumors and fewer lung metastases than control cells. The tumorigenicity of the human melanoma A375SM and the murine melanoma B16-BL6 cells was also significantly inhibited when they were admixed with A375P-IL-10 but not with A375P-Hygro before s. c. injection into nude mice. The suppression of tumor growth and metastasis was directly correlated with a decrease in neovascularity determined by immunostaining with anti-factor VIII. Because tumor-associated macrophages are the major source of angiogenic molecules in melanoma, we used reverse transcription-PCR to demonstrate that IL-10 down-regulates the production of vascular endothelial growth factor, the most potent angiogenic factor in activated macrophages. Other factors involved in angiogenesis such as IL-1beta, tumor necrosis factor-alpha, IL-6, and the proteinase matrix metalloproteinase-9 were also inhibited in activated macrophages by supernatants from A375P-IL-10 cells. Collectively, these data suggest that the production of IL-10 by tumor cells inhibits macrophages-derived angiogenic factors, and hence, tumor growth and metastasis.
Huang
S
S
Departments of Cell Biology and Immunology, The University of Texas Anderson Cancer Center, Houston, Texas 77030, USA.
Xie
K
K
Bucana
C D
CD
Ullrich
S E
SE
Bar-Eli
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015197:Carcinogenicity Tests; D017364:Collagenases / Q000096:biosynthesis; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008222:Lymphokines / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D007375:Interleukin-1; D015850:Interleukin-6; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016753:Interleukin-10; D017364:Collagenases; D020780:Matrix Metalloproteinase 9