基隆長庚醫院 外科部 泌尿科；1嘉義長庚醫院 外科部，2放射治療科；3林口長庚醫院 核子醫學科
TGF-β1 mediates the radiation response of prostate cancer
Chun-Te Wu, Ching-Chuan Hsieh, Tzu-Chen Yen, Wen-Cheng Chen, Miao-Fen Chen
Divisions of Urology, Department of Surgery, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; Department of General Surgery2, Nuclear Medicine3, Radiation Oncology4, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
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.