The incidence of pancreatic cancer is increasing significantly and will soon become the second leading cause of cancer-related deaths in the United States. We have previously shown that the gastrointestinal peptide gastrin, which is only expressed in the fetal pancreas and not in the adult pancreas, is activated during pancreatic carcinogenesis where it stimulates growth in an autocrine fashion. In this investigation, we used transgenic LSL-KrasG12D/+; P48-Cre mice that develop precancerous pancreatic intraepithelial neoplasia (PanIN) lesions and pancreatic cancer over time. Starting at 3 months of age, mice were either left untreated (control) or were treated with a gastrin-targeted vaccine, polyclonal antibody stimulator (PAS 250 μg) followed by a monthly booster until the mice reached 8 months of age when pancreata were excised, and analyzed by histology for PanIN grade in a blinded fashion. High-grade PanIN-3 lesions were significantly less in PAS-treated mice ( P = 0.0077), and cancers developed in 33% of the control mice but only in 10% of the PAS-treated mice. Compared with the control mice, fibrosis was reduced by >50%, arginase positive M2 macrophages were reduced by 74%, and CD8+ T cells were increased by 73% in the pancreas extracellular matrix in PAS-treated mice. Prevention Relevance: PAS vaccination significantly decreased high-grade PanIN lesions and altered the pancreas microenvironment, rendering it less carcinogenic.

中文翻译：

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多克隆抗体刺激剂 (PAS) 疫苗接种可预防 KRAS 小鼠模型中的胰腺癌发生

胰腺癌的发病率正在显着增加，并将很快成为美国癌症相关死亡的第二大原因。我们之前已经表明，仅在胎儿胰腺中而不在成人胰腺中表达的胃肠肽胃泌素在胰腺癌发生过程中被激活，它以自分泌方式刺激生长。在本次调查中，我们使用了转基因 LSL-KrasG12D/+；P48-Cre 小鼠随着时间的推移发展为癌前胰腺上皮内瘤变 (PanIN) 病变和胰腺癌。从 3 个月大开始，小鼠要么不接受治疗（对照），要么接受胃泌素靶向疫苗、多克隆抗体刺激剂（PAS 250 μg）治疗，然后每月加强一次，直到小鼠达到 8 个月大时切除胰腺, 并以盲法通过组织学分析 PanIN 等级。PAS 治疗小鼠的高级别 PanIN-3 病变显着减少 (P = 0.0077)，33% 的对照小鼠发生癌症，但只有 10% 的 PAS 治疗小鼠发生癌症。与对照小鼠相比，PAS 治疗小鼠胰腺细胞外基质中的纤维化减少了 >50%，精氨酸酶阳性 M2 巨噬细胞减少了 74%，CD8+ T 细胞增加了 73%。预防相关性：PAS 疫苗接种显着减少了高级别 PanIN 病变并改变了胰腺微环境，使其致癌性降低。与对照小鼠相比，PAS 治疗小鼠胰腺细胞外基质中的纤维化减少了 >50%，精氨酸酶阳性 M2 巨噬细胞减少了 74%，CD8+ T 细胞增加了 73%。预防相关性：PAS 疫苗接种显着减少了高级别 PanIN 病变并改变了胰腺微环境，使其致癌性降低。与对照小鼠相比，PAS 治疗小鼠胰腺细胞外基质中的纤维化减少了 >50%，精氨酸酶阳性 M2 巨噬细胞减少了 74%，CD8+ T 细胞增加了 73%。预防相关性：PAS 疫苗接种显着减少了高级别 PanIN 病变并改变了胰腺微环境，使其致癌性降低。