Regulation of tumor growth and metastasis by interleukin-10: The melanoma experience

Because interleukin-10 (IL-10) has potent immunosuppressive and anti-inflam matory properties and is produced by some cancers, including melanoma, we h ypothesized that its production by tumor cells may contribute to the escape from immune surveillance. To test this hypothesis, we transfected human A3 75P melanoma cells that do not express IL-10 with the murine IL-10 gene and subsequently analyzed for changes in tumor growth and metastasis in nude m ice. Surprisingly, IL-10 gene transfer resulted in a loss of metastasis and significant inhibition of tumor growth. In addition, the growth of other m urine or human melanoma cells was also inhibited when they were admired wit h IL-10-transfected cells before injection into nude mice. We provide evide nce that IL-10 exerts its antitumor and antimetastatic activity by inhibiti ng angiogenesis in vivo. The in vivo decrease in neovascularization found i n IL-10-secreting tumors is most likely due to the ability of IL-10 to down regulate the synthesis of vascular endothelial growth factor (VEGF), interl eukin-la (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and ma trix metalloproteinase-9 (MMP-9) in tumor-associated macrophages, Other stu dies have shown that IL-10 inhibits tumor metastasis through a natural kill er (NK) cell-dependent mechanism. The inhibitory effects of IL-10 on tumor growth and metastasis were also demonstrated in other tumor models, includi ng breast cancers. Furthermore, administration of rIL-10 into mice resulted in inhibition of tumor metastasis. Because IL-10 has little toxicity when given systemically to human volunteers, its efficacy as an antimetastatic a gent should be further explored, both as an independent and in combination with other inhibitors of neovascularization.