C.E. Hsieh

Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells

Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. A better understanding of the molecular mechanisms involved in HR should lead to more rational approaches to therapy. The role of IL-6/STAT3 signaling in the transition of HR with aggressive tumor behavior and its possible link with myeloid-derived suppressor cells (MDSCs) were identified. In the present study, murine prostate cancer cell line (TRAMP-C1) and a hormone-resistant cell sub-line (TRAMP-HR) were used. Changes in tumor growth, invasion ability, and the responsible pathway were investigated in vitro and in vivo. We also examined the role of IL-6 in HR tumor progression and the recruitment of MDSCs. As seen in both in vitro and in vivo experiments, HR had aggressive tumor growth compared to TRAMP-C1. From mRNA and protein analysis, a higher expression of IL-6 associated with a more activated STAT3 was noted in HR tumor. When IL-6 signaling in prostate cancer was blocked, aggressive tumor behavior could be overcome. The underlying changes included decreased cell proliferation, less epithelial–mesenchymal transition, and decreased STAT3 activation. In addition to tumor progression, circulating IL-6 levels were significantly correlated with MDSC recruitment in vivo. Inhibition of IL-6 abrogated the recruitment of MDSCs in tumor- bearing mice, associated with slower tumor growth and attenuated angiogenesis. In conclusion, altered IL-6/STAT3 signaling is crucial in HR transition, aggressive behavior, and MDSC recruitment. These findings provide evidence for therapeutically targeting IL-6 signaling in prostate cancer.

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

BackgroundHormone-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 methodsThe 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.ResultsHR 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.ConclusionThese 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.

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)–induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial–mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO–induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO–induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC. Mol Cancer Ther; 14(6); 1365–75. ©2015 AACR.

Role of Interleukin-6 in the Radiation Response of Liver Tumors

PURPOSE To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. METHODS AND MATERIALS The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. RESULTS Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. CONCLUSION These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

TGF-β1 mediates the radiation response of prostate cancer.

Radiotherapy is the main treatment modality for prostate cancer. This study investigated the role of TGF-β1 in biological sequelae and tumor regrowth following irradiation, which are critical for the clinical radiation response of prostate cancer. Human and murine prostate cancer cell lines, and corresponding hormone-refractory (HR) cells, were used to examine the radiation response by clonogenic assays in vitro and tumor growth delay in vivo. Biological changes after irradiation, including cell death and tumor regrowth, were examined by experimental manipulation of TGF-β1 signaling. The correlations among tumor radiation responses, TGF-β1 levels, and regulatory T cells (Tregs) recruitment were also evaluated using animal experiments. HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1 compared to hormone-sensitive (HS) cells. TGF-β1 expression was positively linked to irradiation and radioresistance, as demonstrated by in vitro and in vivo experiments. Inhibition of TGF-β1 increased tumor inhibition and DNA damage after irradiation. When mice were irradiated with a sub-lethal dose, the regrowth of irradiated tumors was significantly correlated with TGF-β1 levels and Tregs accumulation in vivo. Furthermore, blocking TGF-β1 clearly attenuated Tregs accumulation and tumor regrowth following treatment. These data demonstrate that TGF-β1 is important in determining the radiation response of prostate cancer, including tumor cell killing and the tumor microenvironment. Therefore, concurrent treatment with a TGF-β1 inhibitor is a potential therapeutic strategy for increasing the radiation response of prostate cancer, particularly for more aggressive or HR cancer cells.Key message• HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1.• TGF-β1 was positively linked to the radiation resistance of prostate cancer.• Tumor regrowth following irradiation was significantly correlated with TGF-β1 and Tregs levels.• Blocking TGF-β1 significantly attenuated RT-induced DNA repair and Tregs.• TGF-β1 inhibitor increases the radiation response of HR cancer cells.

Intensity-Modulated Proton Therapy Reduces Acute Treatment-Related Toxicities for Patients with Nasopharyngeal Cancer: A Case-Control Propensity Score Match Study with Volumetric Modulated Arc Therapy

To evaluate the differences in the treatment-related toxicity between patients with nasopharyngeal cancer treated between IMPT and VMAT. To compare the clinical oncologic outcomes of these two treatment modalities. Intensity-modulated proton therapy reduces acute treatment-related toxicities for patients with nasopharyngeal cancer: A case-control propensity score match study with volumetric modulated arc therapy