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Mathematical modeling of Interleukin-35 promoting tumor growth and angiogenesis.

Liao KL, Bai XF, Friedman A - PLoS ONE (2014)

Bottom Line: In the present paper we develop a mathematical model based on these experimental results.We include in the model an anti-IL-35 drug as treatment.We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8[Formula: see text] T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased.

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A network showing how IL-35 promotes tumor growth.M-CSF secreted by tumor cells promotes the differentiation of myeloid cells to MDSCs. M-CSF also attracts MDSCs to the tumor microenvironment by chemotaxis and promotes the secretion of VEGF by MDSCs. VEGF secreted by tumor cells and MDSCs attracts endothelial cells to trigger angiogenesis. IL-35 secreted by tumor cells, regulatory T cells and MDSCs promotes the secretion of VEGF by tumor cells and enhances the production of MDSCs. MDSCs promote Tregs, but also secrete MCP-1 to attract macrophages into the tumor microenvironment. Macrophages secrete IL-12 to activate CD4 T cells, and CD4 T cells secrete IL-2 which activates CD8 T cells. MDSCs also produce large amount of IL-10, which inhibits the chemotaxis and activation of CD4 T cells.
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pone-0110126-g001: A network showing how IL-35 promotes tumor growth.M-CSF secreted by tumor cells promotes the differentiation of myeloid cells to MDSCs. M-CSF also attracts MDSCs to the tumor microenvironment by chemotaxis and promotes the secretion of VEGF by MDSCs. VEGF secreted by tumor cells and MDSCs attracts endothelial cells to trigger angiogenesis. IL-35 secreted by tumor cells, regulatory T cells and MDSCs promotes the secretion of VEGF by tumor cells and enhances the production of MDSCs. MDSCs promote Tregs, but also secrete MCP-1 to attract macrophages into the tumor microenvironment. Macrophages secrete IL-12 to activate CD4 T cells, and CD4 T cells secrete IL-2 which activates CD8 T cells. MDSCs also produce large amount of IL-10, which inhibits the chemotaxis and activation of CD4 T cells.

Mentions: The mathematical model is based on the network schematically shown in Figure 1. Cancer cells secrete M-CSF which attracts MDSCs; cancer cells and MDSCs secrete VEGF which triggers angiogenesis by attracting endothelial cells and enhancing their proliferation. The additional roles of MDSC are described in the caption of Figure 1. In particular, MDSC, inhibits the activation CD8 T cells via IL-10 and a variety of other mechanisms.


Mathematical modeling of Interleukin-35 promoting tumor growth and angiogenesis.

Liao KL, Bai XF, Friedman A - PLoS ONE (2014)

A network showing how IL-35 promotes tumor growth.M-CSF secreted by tumor cells promotes the differentiation of myeloid cells to MDSCs. M-CSF also attracts MDSCs to the tumor microenvironment by chemotaxis and promotes the secretion of VEGF by MDSCs. VEGF secreted by tumor cells and MDSCs attracts endothelial cells to trigger angiogenesis. IL-35 secreted by tumor cells, regulatory T cells and MDSCs promotes the secretion of VEGF by tumor cells and enhances the production of MDSCs. MDSCs promote Tregs, but also secrete MCP-1 to attract macrophages into the tumor microenvironment. Macrophages secrete IL-12 to activate CD4 T cells, and CD4 T cells secrete IL-2 which activates CD8 T cells. MDSCs also produce large amount of IL-10, which inhibits the chemotaxis and activation of CD4 T cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214702&req=5

pone-0110126-g001: A network showing how IL-35 promotes tumor growth.M-CSF secreted by tumor cells promotes the differentiation of myeloid cells to MDSCs. M-CSF also attracts MDSCs to the tumor microenvironment by chemotaxis and promotes the secretion of VEGF by MDSCs. VEGF secreted by tumor cells and MDSCs attracts endothelial cells to trigger angiogenesis. IL-35 secreted by tumor cells, regulatory T cells and MDSCs promotes the secretion of VEGF by tumor cells and enhances the production of MDSCs. MDSCs promote Tregs, but also secrete MCP-1 to attract macrophages into the tumor microenvironment. Macrophages secrete IL-12 to activate CD4 T cells, and CD4 T cells secrete IL-2 which activates CD8 T cells. MDSCs also produce large amount of IL-10, which inhibits the chemotaxis and activation of CD4 T cells.
Mentions: The mathematical model is based on the network schematically shown in Figure 1. Cancer cells secrete M-CSF which attracts MDSCs; cancer cells and MDSCs secrete VEGF which triggers angiogenesis by attracting endothelial cells and enhancing their proliferation. The additional roles of MDSC are described in the caption of Figure 1. In particular, MDSC, inhibits the activation CD8 T cells via IL-10 and a variety of other mechanisms.

Bottom Line: In the present paper we develop a mathematical model based on these experimental results.We include in the model an anti-IL-35 drug as treatment.We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8[Formula: see text] T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased.

Show MeSH
Related in: MedlinePlus