PO.PR02.03 · 预防研究
长期高脂饮食摄入增加胰腺上皮内瘤变向癌症的进展
Prolonged high fat dietary intake increases pancreatic intraepithelial neoplasia to cancer progression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：新兴证据表明，膳食宏量营养素构成是胰腺肿瘤发生的关键调节因素。虽然高脂饮食（HFD）在Kras G12D小鼠中驱动腺泡-导管化生（ADM）和胰腺上皮内瘤变（PanIN）的进展，但生酮饮食（KD）的影响仍存在争议。为确定KD如何影响早期Kras驱动的瘤变，我们利用Ptf1a CreERT2 Kras G12V（KC Acinar）小鼠模型，研究了KD、HFD和低脂饮食（LFD）对胰腺疾病发生和进展的影响。
方法：将6至8周龄的KC Acinar小鼠和野生型（WT）小鼠维持在标准饲料（SD）上，或在他莫昔芬诱导Kras G12V激活之前，改换为LFD、HFD或KD喂养四周。监测小鼠的存活率、体重和葡萄糖耐量。采集胰腺组织进行组织病理学评估、三色染色和免疫组织化学。对胰腺裂解物进行反相蛋白质阵列（RPPA）分析并进行血清细胞因子谱分析，以评估信号传导和全身性变化。
结果：与SD（87±29天；p=0.02）和LFD（57±27天；p=0.02）相比，KD喂养的KC Acinar小鼠存活时间最短（中位26±7天），而HFD与SD相比也降低了存活率（35±25天；p=0.05）。KD喂养在WT和KC Acinar小鼠中均诱导了葡萄糖不耐受。组织学分析显示，KD和HFD喂养的KC Acinar小鼠均发生了更高发生率的伴纤维化的侵袭性PDAC，同时相对于肿瘤区室，CD8⁺ T细胞浸润减少且基质CD39表达增加。蛋白质组学分析显示，KD和HFD喂养的KC Acinar小鼠中Akt、phospho-S6、Paxillin和YTHDF2表达升高，而PUMA、STAT5A、PHGDH、FASN和ASNS表达降低。通路富集分析确定了EGFR酪氨酸激酶抑制剂耐药、趋化因子、PI3K-Akt-mTOR、Rap1和VEGF信号通路的上调。血清细胞因子谱分析进一步显示，KD喂养的KC Acinar小鼠中Ang-2、CCL6、LDLR、MMP-9、PAI-1、PTX3、TNFSF13B和OPG的全身水平升高。
结论：致癌性Kras激活之前的膳食脂质含量关键性地塑造了胰腺癌的发展。生酮饮食和高脂饮食均加速了从PanIN向侵袭性PDAC的进展，同时伴有纤维化、免疫抑制以及PI3K-Akt-mTOR和EGFR信号通路的激活。这些发现揭示了富含脂质的饮食可增强胰腺中的致癌和炎症通路，并警示在预防环境或胰腺癌早期阶段使用生酮饮食。
查看英文原文 English abstract
Background: Emerging evidence implicates dietary macronutrient composition as a key modulator of pancreatic tumorigenesis. While the high-fat diet (HFD) drives acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) progression in Kras G12D mice, the impact of ketogenic diet (KD) remains controversial. To determine how KD affects early Kras -driven neoplasia, we investigated the effects of KD, HFD, and low-fat diet (LFD) on pancreatic disease initiation and progression using the Ptf1a CreERT2 Kras G12V (KC Acinar ) mouse model.
Methods : Six- to eight-week-old KC Acinar and wild-type (WT) mice were maintained on standard chow (SD) or switched to LFD, HFD, or KD for four weeks before tamoxifen-induced Kras G12V activation. Mice were monitored for survival, body weight, and glucose tolerance. Pancreatic tissues were collected for histopathological evaluation, trichrome staining, and immunohistochemistry. Reverse-phase protein array (RPPA) of pancreatic lysates and serum cytokine profiling were performed to assess signaling and systemic changes.
Results: KD-fed KC Acinar mice showed the shortest survival (median 26 ± 7 days) compared with SD (87 ± 29; p = 0.02) and LFD (57 ± 27; p = 0.02), while HFD also reduced survival compared with SD (35 ± 25; p = 0.05). KD feeding induced glucose intolerance in both WT and KC Acinar mice. Histological analysis revealed that both KD- and HFD-fed KC Acinar mice developed a higher incidence of invasive PDAC with fibrosis, accompanied by reduced CD8⁺ T-cell infiltration and increased stromal CD39 expression relative to tumor compartments. Proteomic profiling showed increased Akt, phospho-S6, Paxillin, and YTHDF2, and decreased PUMA, STAT5A, PHGDH, FASN, and ASNS expression in KD- and HFD-fed KC Acinar mice. Pathway enrichment analysis identified upregulation of EGFR tyrosine kinase inhibitor resistance, chemokine, PI3K-Akt-mTOR, Rap1, and VEGF signaling pathways. Serum cytokine profiling further revealed elevated systemic levels of Ang-2, CCL6, LDLR MMP-9, PAI-1, PTX3, TNFSF13B, and OPG in KD-fed KC Acinar mice.
Conclusions: Dietary lipid content before oncogenic Kras activation critically shapes pancreatic cancer development. Both ketogenic and high-fat diets accelerated progression from PanIN to invasive PDAC, accompanied by fibrosis, immune suppression, and activation of PI3K-Akt-mTOR and EGFR signaling. These findings reveal that lipid-rich diets can potentiate oncogenic and inflammatory pathways in the pancreas and caution against the use of ketogenic diets in prevention settings or early stages of pancreatic cancer.
利益披露 Disclosure
U. Sardarni, None..
E. Faraoni, None..
A. Waller, None..
L. Strickland, None..
B. O'Brien, None..
J. Cox, None..
F. McAllister, None..
J. Bailey-Lundberg, None.