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Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.

Lin HH, Chiang MT, Chang PC, Chau LY - Cancer Sci. (2015)

Bottom Line: Whether HO-1 has an effect on cancer progression through stromal compartments is less clear.Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling.These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, China.

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Myeloid heme oxygenase-1 (HO-1)-induced vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) promote transendothelial migration and STAT3 activation of tumor cells. (a) Representative micrograph of CMFDA labeled-B16F10 cells transmigrated through endothelium-coated transwell filters in response to control medium or indicated bone marrow-derived macrophage conditional medium (BMDM-CM). Bar = 500 μm. The quantitative data are mean ± SE of three independent experiments. *P < 0.02 versus control medium. (b) B16F10 cell transendothelial migrations induced by various BMDM-CM were performed in the absence or presence of indicated antibodies. Data are mean ± SE of four independent experiments. *P < 0.02 versus control medium; †P < 0.05 versus WT-CM without antibody pretreatment. (c) B16F10 cells were treated with WT or HO-1+/− BMDM-CM for indicated times. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. (d) WT BMDM-CM pre-incubated with or without indicated antibody (1 μg/mL) for 30 min was used to treat B16F10 cells for 15 min. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. CM, conditional medium.
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fig06: Myeloid heme oxygenase-1 (HO-1)-induced vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) promote transendothelial migration and STAT3 activation of tumor cells. (a) Representative micrograph of CMFDA labeled-B16F10 cells transmigrated through endothelium-coated transwell filters in response to control medium or indicated bone marrow-derived macrophage conditional medium (BMDM-CM). Bar = 500 μm. The quantitative data are mean ± SE of three independent experiments. *P < 0.02 versus control medium. (b) B16F10 cell transendothelial migrations induced by various BMDM-CM were performed in the absence or presence of indicated antibodies. Data are mean ± SE of four independent experiments. *P < 0.02 versus control medium; †P < 0.05 versus WT-CM without antibody pretreatment. (c) B16F10 cells were treated with WT or HO-1+/− BMDM-CM for indicated times. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. (d) WT BMDM-CM pre-incubated with or without indicated antibody (1 μg/mL) for 30 min was used to treat B16F10 cells for 15 min. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. CM, conditional medium.

Mentions: The vascular permeability is crucial for tumor cell extravasation at the metastatic site. VEGF, a potent inducer of endothelial permeability, is induced by HO-1 in macrophages.20 We confirmed the previous finding that VEGF gene expression was significantly higher in WT-BMDM than HO-1+/−-BMDM (Fig. S5). To test whether macrophage-derived VEGF impacts tumor cell extravasation, we performed an in vitro transendothelial migration assay. As shown in Figure6(a), WT BMDM-CM induced significantly greater transendothelial migration of CMFDA-labeled B16F10 cells than HO-1+/− BMDM-CM. Cotreatment with VEGF neutralizing antibody, but not control IgG, resulted in the reduction of increased transendothelial migration of tumor cells induced by BMDM-CM (Fig.6b). These observations support the involvement of HO-1-induced VEGF in macrophage-mediated tumor cell extravasation at the metastatic site.


Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.

Lin HH, Chiang MT, Chang PC, Chau LY - Cancer Sci. (2015)

Myeloid heme oxygenase-1 (HO-1)-induced vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) promote transendothelial migration and STAT3 activation of tumor cells. (a) Representative micrograph of CMFDA labeled-B16F10 cells transmigrated through endothelium-coated transwell filters in response to control medium or indicated bone marrow-derived macrophage conditional medium (BMDM-CM). Bar = 500 μm. The quantitative data are mean ± SE of three independent experiments. *P < 0.02 versus control medium. (b) B16F10 cell transendothelial migrations induced by various BMDM-CM were performed in the absence or presence of indicated antibodies. Data are mean ± SE of four independent experiments. *P < 0.02 versus control medium; †P < 0.05 versus WT-CM without antibody pretreatment. (c) B16F10 cells were treated with WT or HO-1+/− BMDM-CM for indicated times. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. (d) WT BMDM-CM pre-incubated with or without indicated antibody (1 μg/mL) for 30 min was used to treat B16F10 cells for 15 min. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. CM, conditional medium.
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Related In: Results  -  Collection

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fig06: Myeloid heme oxygenase-1 (HO-1)-induced vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) promote transendothelial migration and STAT3 activation of tumor cells. (a) Representative micrograph of CMFDA labeled-B16F10 cells transmigrated through endothelium-coated transwell filters in response to control medium or indicated bone marrow-derived macrophage conditional medium (BMDM-CM). Bar = 500 μm. The quantitative data are mean ± SE of three independent experiments. *P < 0.02 versus control medium. (b) B16F10 cell transendothelial migrations induced by various BMDM-CM were performed in the absence or presence of indicated antibodies. Data are mean ± SE of four independent experiments. *P < 0.02 versus control medium; †P < 0.05 versus WT-CM without antibody pretreatment. (c) B16F10 cells were treated with WT or HO-1+/− BMDM-CM for indicated times. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. (d) WT BMDM-CM pre-incubated with or without indicated antibody (1 μg/mL) for 30 min was used to treat B16F10 cells for 15 min. The levels of phospho-STAT3 and STAT3 examined by western blot analysis. CM, conditional medium.
Mentions: The vascular permeability is crucial for tumor cell extravasation at the metastatic site. VEGF, a potent inducer of endothelial permeability, is induced by HO-1 in macrophages.20 We confirmed the previous finding that VEGF gene expression was significantly higher in WT-BMDM than HO-1+/−-BMDM (Fig. S5). To test whether macrophage-derived VEGF impacts tumor cell extravasation, we performed an in vitro transendothelial migration assay. As shown in Figure6(a), WT BMDM-CM induced significantly greater transendothelial migration of CMFDA-labeled B16F10 cells than HO-1+/− BMDM-CM. Cotreatment with VEGF neutralizing antibody, but not control IgG, resulted in the reduction of increased transendothelial migration of tumor cells induced by BMDM-CM (Fig.6b). These observations support the involvement of HO-1-induced VEGF in macrophage-mediated tumor cell extravasation at the metastatic site.

Bottom Line: Whether HO-1 has an effect on cancer progression through stromal compartments is less clear.Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling.These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, China.

Show MeSH
Related in: MedlinePlus