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The role of IL-6 in the radiation response of prostate cancer.

Wu CT, Chen MF, Chen WC, Hsieh CC - Radiat Oncol (2013)

Bottom Line: IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior.Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.These data demonstrate that IL-6 is important in the biological sequelae following irradiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan. wucgmh@gmail.com

ABSTRACT

Background: Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.

Material and methods: The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.

Results: HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.

Conclusion: These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer.

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IL-6 is linked to MDSC recruitment. Effects of IL-6 and irradiation on MDSC recruitment in tumors were evaluated by (a) FACS of spleen using GrI-CD11b staining, and (b) immunofluorescence of tumor (DAPI, blue; CD11b, red) in mice bearing tumors (tumor size 300 ~ 350 mm3) with or without IL-6–silencing vectors or 48 h after 15-Gy irradiation or sham-irradiation. Representative images are shown. Quantification of CD11b expression was calculated as the number of cells positive for CD11b immunofluorescence divided by the total number of cells for each condition. Y-axis represents the ratio normalized to the value of TRAMP-C1 cells. Columns are the means of three independent experiments; bars, SD. *, P < 0.05. The effect of IL-6 on MDSC recruitment was further evaluated by (c) FACS of the spleen and (d) immunofluorescence of tumor specimens in pre-irradiated mice bearing tumors (with or without IL-6 stimulation) for 2 weeks.
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Figure 5: IL-6 is linked to MDSC recruitment. Effects of IL-6 and irradiation on MDSC recruitment in tumors were evaluated by (a) FACS of spleen using GrI-CD11b staining, and (b) immunofluorescence of tumor (DAPI, blue; CD11b, red) in mice bearing tumors (tumor size 300 ~ 350 mm3) with or without IL-6–silencing vectors or 48 h after 15-Gy irradiation or sham-irradiation. Representative images are shown. Quantification of CD11b expression was calculated as the number of cells positive for CD11b immunofluorescence divided by the total number of cells for each condition. Y-axis represents the ratio normalized to the value of TRAMP-C1 cells. Columns are the means of three independent experiments; bars, SD. *, P < 0.05. The effect of IL-6 on MDSC recruitment was further evaluated by (c) FACS of the spleen and (d) immunofluorescence of tumor specimens in pre-irradiated mice bearing tumors (with or without IL-6 stimulation) for 2 weeks.

Mentions: We reported previously that MDSC contributes to tumor promotion in IL-6–positive prostate cancer, at least in part. Moreover, the increase in MDSC induced by local irradiation facilitates tumor regrowth after irradiation [18]. Therefore, we examined the correlation between IL-6 and MDSC recruitment after irradiation by analyzing MDSC levels in tumor-bearing mice 48 h after irradiation [10,22], with or without IL-6-silencing vectors. The recruitment of CD11b + Gr1+ myeloid cells increased significantly in mice bearing a HR tumor, compared to that in TRAMP-C1 tumor, by FACS and immunofluorescence analyses, and recruitment of CD11b + Gr1+ cells to tumors were augmented by irradiation (Figure 5a-b). Furthermore, the IL-6 silencing vector significantly abrogated the recruitment of MDSC with or without irradiation. To determine further whether MDSC accumulation was driven by IL-6 stimulation, we examined MDSC levels in tumors in pre-irradiated mice with or without IL-6 stimulation. As determined by FACS and immunofluorescence, IL-6 stimulation increased MDSC accumulation (Figure 5c-d). These results suggested that IL-6 plays an important role in the induction of MDSC recruitment, which might subsequently contribute to the increased invasiveness of tumors that regrow after irradiation.


The role of IL-6 in the radiation response of prostate cancer.

Wu CT, Chen MF, Chen WC, Hsieh CC - Radiat Oncol (2013)

IL-6 is linked to MDSC recruitment. Effects of IL-6 and irradiation on MDSC recruitment in tumors were evaluated by (a) FACS of spleen using GrI-CD11b staining, and (b) immunofluorescence of tumor (DAPI, blue; CD11b, red) in mice bearing tumors (tumor size 300 ~ 350 mm3) with or without IL-6–silencing vectors or 48 h after 15-Gy irradiation or sham-irradiation. Representative images are shown. Quantification of CD11b expression was calculated as the number of cells positive for CD11b immunofluorescence divided by the total number of cells for each condition. Y-axis represents the ratio normalized to the value of TRAMP-C1 cells. Columns are the means of three independent experiments; bars, SD. *, P < 0.05. The effect of IL-6 on MDSC recruitment was further evaluated by (c) FACS of the spleen and (d) immunofluorescence of tumor specimens in pre-irradiated mice bearing tumors (with or without IL-6 stimulation) for 2 weeks.
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Related In: Results  -  Collection

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Show All Figures
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Figure 5: IL-6 is linked to MDSC recruitment. Effects of IL-6 and irradiation on MDSC recruitment in tumors were evaluated by (a) FACS of spleen using GrI-CD11b staining, and (b) immunofluorescence of tumor (DAPI, blue; CD11b, red) in mice bearing tumors (tumor size 300 ~ 350 mm3) with or without IL-6–silencing vectors or 48 h after 15-Gy irradiation or sham-irradiation. Representative images are shown. Quantification of CD11b expression was calculated as the number of cells positive for CD11b immunofluorescence divided by the total number of cells for each condition. Y-axis represents the ratio normalized to the value of TRAMP-C1 cells. Columns are the means of three independent experiments; bars, SD. *, P < 0.05. The effect of IL-6 on MDSC recruitment was further evaluated by (c) FACS of the spleen and (d) immunofluorescence of tumor specimens in pre-irradiated mice bearing tumors (with or without IL-6 stimulation) for 2 weeks.
Mentions: We reported previously that MDSC contributes to tumor promotion in IL-6–positive prostate cancer, at least in part. Moreover, the increase in MDSC induced by local irradiation facilitates tumor regrowth after irradiation [18]. Therefore, we examined the correlation between IL-6 and MDSC recruitment after irradiation by analyzing MDSC levels in tumor-bearing mice 48 h after irradiation [10,22], with or without IL-6-silencing vectors. The recruitment of CD11b + Gr1+ myeloid cells increased significantly in mice bearing a HR tumor, compared to that in TRAMP-C1 tumor, by FACS and immunofluorescence analyses, and recruitment of CD11b + Gr1+ cells to tumors were augmented by irradiation (Figure 5a-b). Furthermore, the IL-6 silencing vector significantly abrogated the recruitment of MDSC with or without irradiation. To determine further whether MDSC accumulation was driven by IL-6 stimulation, we examined MDSC levels in tumors in pre-irradiated mice with or without IL-6 stimulation. As determined by FACS and immunofluorescence, IL-6 stimulation increased MDSC accumulation (Figure 5c-d). These results suggested that IL-6 plays an important role in the induction of MDSC recruitment, which might subsequently contribute to the increased invasiveness of tumors that regrow after irradiation.

Bottom Line: IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior.Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.These data demonstrate that IL-6 is important in the biological sequelae following irradiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology, Chang Gung Memorial Hospital, Keelung, Taiwan. wucgmh@gmail.com

ABSTRACT

Background: Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.

Material and methods: The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.

Results: HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.

Conclusion: These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer.

Show MeSH
Related in: MedlinePlus