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Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

Tanizaki Y, Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K - Cancer Sci. (2014)

Bottom Line: This tumor-progressive effect was coincident with significantly reduced numbers of CD8(+) T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-β and interleukin-10 in ascites.Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-β secretion.These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.

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Pathogenic roles of indoleamine 2,3-dioxygenase (IDO) in the tumor progression of ovarian cancer in vivo. Stable clones of IDO-overexpressing (HM-1-IDO) or control vector-transfected (HM-1-mock) OV2944-HM-1 cells were i.p. transplanted into syngeneic B6C3F1 mice as a model of peritoneal dissemination of ovarian cancer. (a) Survival rate of mice transplanted with HM-1-IDO or HM-1-mock cells. There was a significant difference between the two groups by log–rank test (P = 0.042). (b) Macroscopic views of peritoneal dissemination in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Arrows indicate disseminated tumor nodules. Representative results from six independent mice in each group are shown. (c, d) Histopathological findings of disseminated tumors on the peritoneum in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Original magnification, ×100 (c) and ×400 (d). Bar = 500 μm (c) and 50 μm (d). (e, f) Total tumor weight and ascites volume were evaluated in mice transplanted with HM-1-mock and HM-1-IDO cells on days 11 and 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
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fig02: Pathogenic roles of indoleamine 2,3-dioxygenase (IDO) in the tumor progression of ovarian cancer in vivo. Stable clones of IDO-overexpressing (HM-1-IDO) or control vector-transfected (HM-1-mock) OV2944-HM-1 cells were i.p. transplanted into syngeneic B6C3F1 mice as a model of peritoneal dissemination of ovarian cancer. (a) Survival rate of mice transplanted with HM-1-IDO or HM-1-mock cells. There was a significant difference between the two groups by log–rank test (P = 0.042). (b) Macroscopic views of peritoneal dissemination in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Arrows indicate disseminated tumor nodules. Representative results from six independent mice in each group are shown. (c, d) Histopathological findings of disseminated tumors on the peritoneum in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Original magnification, ×100 (c) and ×400 (d). Bar = 500 μm (c) and 50 μm (d). (e, f) Total tumor weight and ascites volume were evaluated in mice transplanted with HM-1-mock and HM-1-IDO cells on days 11 and 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.

Mentions: In order to explore the pathogenic roles of IDO in the tumor progression of ovarian cancer in vivo, HM-1-IDO or HM-1-mock cells were i.p. transplanted into B6C3F1 syngeneic mice, and used as a model of peritoneal dissemination of ovarian cancer. In HM-1-IDO-transplanted mice (HM-1-IDO group), the survival rate was significantly impaired compared with that of HM-1-mock-transplanted mice (HM-1-mock group; Fig. 2a). Actually, on day 14 after tumor cell injection, macroscopic findings showed that the tumor peritoneal dissemination was more evident and widespread in the HM-1-IDO group than in the HM-1-mock group (Fig. 2b). In parallel, histological findings indicated deep invasion of tumor cells into the peritoneum, resulting in much thicker peritoneum in the HM-1-IDO group (Fig. 2c,d). Consistently, the total weight of disseminated tumors in the HM-1-IDO group was significantly increased on day 14 compared with that in the HM-1-mock group (Fig. 2e). Moreover, on days 11 and 14 after tumor cell injection, the ascites volume was significantly larger in the HM-1-IDO group than in the HM-1-mock group (Fig. 2f). These observations implied that tumor-derived IDO could promote the peritoneal dissemination and progression of ovarian cancer.


Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

Tanizaki Y, Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K - Cancer Sci. (2014)

Pathogenic roles of indoleamine 2,3-dioxygenase (IDO) in the tumor progression of ovarian cancer in vivo. Stable clones of IDO-overexpressing (HM-1-IDO) or control vector-transfected (HM-1-mock) OV2944-HM-1 cells were i.p. transplanted into syngeneic B6C3F1 mice as a model of peritoneal dissemination of ovarian cancer. (a) Survival rate of mice transplanted with HM-1-IDO or HM-1-mock cells. There was a significant difference between the two groups by log–rank test (P = 0.042). (b) Macroscopic views of peritoneal dissemination in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Arrows indicate disseminated tumor nodules. Representative results from six independent mice in each group are shown. (c, d) Histopathological findings of disseminated tumors on the peritoneum in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Original magnification, ×100 (c) and ×400 (d). Bar = 500 μm (c) and 50 μm (d). (e, f) Total tumor weight and ascites volume were evaluated in mice transplanted with HM-1-mock and HM-1-IDO cells on days 11 and 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
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Related In: Results  -  Collection

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fig02: Pathogenic roles of indoleamine 2,3-dioxygenase (IDO) in the tumor progression of ovarian cancer in vivo. Stable clones of IDO-overexpressing (HM-1-IDO) or control vector-transfected (HM-1-mock) OV2944-HM-1 cells were i.p. transplanted into syngeneic B6C3F1 mice as a model of peritoneal dissemination of ovarian cancer. (a) Survival rate of mice transplanted with HM-1-IDO or HM-1-mock cells. There was a significant difference between the two groups by log–rank test (P = 0.042). (b) Macroscopic views of peritoneal dissemination in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Arrows indicate disseminated tumor nodules. Representative results from six independent mice in each group are shown. (c, d) Histopathological findings of disseminated tumors on the peritoneum in mice transplanted with HM-1-mock and HM-1-IDO cells on day 14. Original magnification, ×100 (c) and ×400 (d). Bar = 500 μm (c) and 50 μm (d). (e, f) Total tumor weight and ascites volume were evaluated in mice transplanted with HM-1-mock and HM-1-IDO cells on days 11 and 14. All values represent mean ± SD. *P < 0.05, HM-1-mock versus HM-1-IDO.
Mentions: In order to explore the pathogenic roles of IDO in the tumor progression of ovarian cancer in vivo, HM-1-IDO or HM-1-mock cells were i.p. transplanted into B6C3F1 syngeneic mice, and used as a model of peritoneal dissemination of ovarian cancer. In HM-1-IDO-transplanted mice (HM-1-IDO group), the survival rate was significantly impaired compared with that of HM-1-mock-transplanted mice (HM-1-mock group; Fig. 2a). Actually, on day 14 after tumor cell injection, macroscopic findings showed that the tumor peritoneal dissemination was more evident and widespread in the HM-1-IDO group than in the HM-1-mock group (Fig. 2b). In parallel, histological findings indicated deep invasion of tumor cells into the peritoneum, resulting in much thicker peritoneum in the HM-1-IDO group (Fig. 2c,d). Consistently, the total weight of disseminated tumors in the HM-1-IDO group was significantly increased on day 14 compared with that in the HM-1-mock group (Fig. 2e). Moreover, on days 11 and 14 after tumor cell injection, the ascites volume was significantly larger in the HM-1-IDO group than in the HM-1-mock group (Fig. 2f). These observations implied that tumor-derived IDO could promote the peritoneal dissemination and progression of ovarian cancer.

Bottom Line: This tumor-progressive effect was coincident with significantly reduced numbers of CD8(+) T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-β and interleukin-10 in ascites.Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-β secretion.These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.

Show MeSH
Related in: MedlinePlus