Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA.
Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA.
Science. 2020 Jul 17;369(6501). doi: 10.1126/science.aay1813.
Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33-responding FcεRIα macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33-TGF-β feedforward loop could potentially be exploited for cancer treatment.
靶向肿瘤起始细胞 (TICs) 与肿瘤微环境之间的串扰是癌症治疗的一个有吸引力的途径。我们在这里使用鳞状细胞癌的小鼠模型表明，TICs 在创建肿瘤进展和耐药所需的微环境中起着关键作用。转录因子 NRF2 介导的 TIC 中的抗氧化活性促进核细胞因子白细胞介素 33 (IL-33) 的释放。这种细胞因子促进表达高亲和力免疫球蛋白 E 受体 FcεRIα的巨噬细胞分化，并与 TICs 密切相关。反过来，这些对 IL-33 有反应的 FcεRIα 巨噬细胞向 TICs 发送旁分泌转化生长因子 β (TGF-β) 信号，诱导侵袭性和耐药性，并进一步上调 IL-33 表达。这种 TIC 驱动的、IL-33-TGF-β 正反馈回路可能被用于癌症治疗。
