Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages.
Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages.
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吸烟是胰腺癌 (PC) 的一个确定的危险因素，但晚期诊断限制了对其在 PC 进展中的机制作用的评估。我们使用成熟的 PC 基因工程小鼠模型 (LSL-K-rasG12D) 来阐明吸烟在胰腺上皮内瘤变 (PanIN) 发生和发展过程中的作用。将 10 周大的 floxed 小鼠 (K-rasG12D; Pdx-1cre) 及其对照未 floxed 小鼠 (LSL-K-rasG12D) 暴露于香烟烟雾（总悬浮颗粒：150 mg/m3）中 20 周。烟雾暴露显着加速了 floxed 小鼠 PanIN 病变的发展，这与细胞角蛋白表达增加十倍相关。与未接触烟雾的对照组相比，接触烟雾的小鼠体内骨髓源性抑制细胞（MDSC）的全身积累显着减少（P<0.01），同时巨噬细胞（P<0.05）和树突状细胞（DC）（P<0.01）数量增加。此外，吸烟引起的炎症（IFN-γ、CXCL2；P<0.05）伴随着胰腺星状细胞活化增强和血清视黄酸结合蛋白4水平升高，表明视黄酸生物利用度增加，有助于MDSC分化为肿瘤相关巨噬细胞（TAM）和DC。 TAM 主要促进暴露于烟雾的 floxed 小鼠肿瘤前病变中肝素结合表皮生长因子样生长因子（EGFR 配体）表达的增加，从而促进腺泡导管化生（ADM）。此外，在 PC 进展过程中，接触烟雾还会导致免疫系统受到部分抑制。总体而言，本研究提供了在存在组成型活性 K-ras 突变的情况下吸烟诱导 ADM 增加的新机制。
Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-rasG12D) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-rasG12D; Pdx-1cre) and their control unfloxed (LSL-K-rasG12D) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m3) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.
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