While inflammation is associated with pancreatic cancer, the underlying mechanisms leading to cancer initiation are still being delineated. Eosinophils may promote or inhibit tumor growth, although the specific role in pancreatic cancer has yet to be determined. Eosinophil-supporting cytokine interleukin-5 and receptor are likely to have a role, but the significance in the pancreatic cancer microenvironment is unknown. Genetically engineered Akt1Myr/KRasG12D and KRasG12D mice were used to model changes induced by chronic inflammation. Tissue samples were collected to analyze the tumor microenvironment and infiltration of immune cells, whereas serum was collected to analyze cytokine and amylase activity in the inflammatory model. The expression of IL-5R and the effects of IL-5 were analyzed in human and murine tumor cells. Compound Akt1Myr/KRasG12D mice, compared to single KRasG12D or Akt1Myr mice, exhibited increased tissue damage after repeat inductions of inflammation, and had accelerated tumor development and metastasis. M2 macrophages and newly identified eosinophils co-localized with fibrotic regions rather than infiltrating into tumors, consistent with immune cell privilege. The majority of eosinophils found in the pancreas of Akt1Myr/KRasG12D mice with chronic inflammation lacked the cytotoxic NKG2D marker. IL-5 expression was upregulated in pancreatic cells in response to inflammation, and then diminished in advanced lesions. Although not previously described in pancreatic tumors, IL-5Rα was increased during mouse pancreatic tumor progression and expressed in human pancreatic ductal adenocarcinomas (7 of 7 by immunohistochemistry). IL-5 stimulated tumor cell migration and activation through STAT5 signaling, thereby suggesting an unreported tumor-promoting role for IL-5Rα in pancreatic cancer. Chronic inflammation induces increased pancreatic cancer progression and immune cells such as eosinophils are attracted to areas of fibrosis. Results suggest that IL-5 in the pancreatic compartment stimulates increased IL-5Rα on ductal tumor cells to increase pancreatic tumor motility. Collectively, IL-5/IL-5Rα signaling in the mouse and human pancreatic tumors microenvironment is a novel mechanism to facilitate tumor progression.

中文翻译：

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慢性胰腺炎中新的 IL-5 信号通路的鉴定和与胰腺肿瘤细胞的串扰。

虽然炎症与胰腺癌有关，但仍在阐明导致癌症发生的潜在机制。嗜酸性粒细胞可能促进或抑制肿瘤生长，但在胰腺癌中的具体作用尚未确定。支持嗜酸性粒细胞的细胞因子白细胞介素 5 和受体可能起作用，但在胰腺癌微环境中的意义尚不清楚。基因工程的 Akt1Myr/KRasG12D 和 KRasG12D 小鼠用于模拟慢性炎症引起的变化。收集组织样本以分析肿瘤微环境和免疫细胞的浸润，而收集血清以分析炎症模型中的细胞因子和淀粉酶活性。在人和鼠肿瘤细胞中分析了 IL-5R 的表达和 IL-5 的作用。与单个 KRasG12D 或 Akt1Myr 小鼠相比，复合 Akt1Myr/KRasG12D 小鼠在重复诱导炎症后表现出增加的组织损伤，并加速了肿瘤的发展和转移。M2 巨噬细胞和新发现的嗜酸性粒细胞与纤维化区域共定位，而不是浸润到肿瘤中，这与免疫细胞特权一致。在患有慢性炎症的 Akt1Myr/KRasG12D 小鼠的胰腺中发现的大多数嗜酸性粒细胞缺乏细胞毒性 NKG2D 标记物。IL-5 表达在胰腺细胞中响应炎症而上调，然后在晚期病变中减少。尽管以前没有在胰腺肿瘤中描述过，但 IL-5Rα 在小鼠胰腺肿瘤进展过程中增加，并在人胰腺导管腺癌中表达（免疫组织化学 7 中的 7 个）。IL-5 通过 STAT5 信号传导刺激肿瘤细胞迁移和激活，从而表明 IL-5Rα 在胰腺癌中具有未报告的促肿瘤作用。慢性炎症会导致胰腺癌进展加快，并且免疫细胞（如嗜酸性粒细胞）会被吸引到纤维化区域。结果表明，胰腺隔室中的 IL-5 刺激导管肿瘤细胞上增加的 IL-5Rα，从而增加胰腺肿瘤的运动性。总的来说，小鼠和人胰腺肿瘤微环境中的 IL-5/IL-5Rα 信号传导是一种促进肿瘤进展的新机制。慢性炎症会导致胰腺癌进展加快，并且免疫细胞（如嗜酸性粒细胞）会被吸引到纤维化区域。结果表明，胰腺隔室中的 IL-5 刺激导管肿瘤细胞上增加的 IL-5Rα，从而增加胰腺肿瘤的运动性。总的来说，小鼠和人胰腺肿瘤微环境中的 IL-5/IL-5Rα 信号传导是一种促进肿瘤进展的新机制。慢性炎症会导致胰腺癌进展加快，并且免疫细胞（如嗜酸性粒细胞）会被吸引到纤维化区域。结果表明，胰腺隔室中的 IL-5 刺激导管肿瘤细胞上增加的 IL-5Rα，从而增加胰腺肿瘤的运动性。总的来说，小鼠和人胰腺肿瘤微环境中的 IL-5/IL-5Rα 信号传导是一种促进肿瘤进展的新机制。