The incidence of pancreatic cancer increases with age, suggesting that chronological aging is a significant risk factor for this disease. Fibroblasts are the major nonmalignant cell type in the stroma of human pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether the chronological aging of normal human fibroblasts (NHFs), a previously underappreciated area in pancreatic cancer research, influences the progression and therapeutic outcomes of PDAC. Results from experiments with murine xenografts and 2D and 3D co-cultures of NHFs and PDAC cells revealed that older NHFs stimulate proliferation of and confer resistance to radiation therapy of PDAC. MS-based metabolite analysis indicated that older NHFs have significantly increased arachidonic acid 12-lipoxygenase (ALOX12) expression and elevated levels of its mitogenic metabolite, 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-(S)-HETE) compared with their younger counterparts. In co-cultures with older rather than with younger NHFs, PDAC cells exhibited increases in mitogen-activated protein kinase signaling and cellular metabolism, as well as a lower oxidation state that correlated with their enhanced proliferation and resistance to radiation therapy. Expression of ALOX12 was found to be significantly lower in PDAC cell lines and tumor biopsies, suggesting that PDAC cells rely on a stromal supply of mitogens for their proliferative needs. Pharmacological (hydroxytyrosol) and molecular (siRNA) interventions of ALOX12 in older NHFs suppressed their ability to stimulate proliferation of PDAC cells. We conclude that chronological aging of NHFs contributes to PDAC progression and that ALOX12 and 12-(S)-HETE may be potential stromal targets for interventions that seek to halt progression and improve therapy outcomes.

中文翻译：

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花生四烯酸12-脂氧合酶和12-羟基二十碳四烯酸有助于基质老化诱导的胰腺癌的进展。

胰腺癌的发生率随年龄增长而增加，这表明按时间顺序排列的衰老是该疾病的重要危险因素。成纤维细胞是人胰腺导管腺癌（PDAC）基质中的主要非恶性细胞类型。在这项研究中，我们调查了正常人成纤维细胞（NHFs）的按时间顺序老化（胰腺癌研究中先前未被重视的区域）是否影响PDAC的进展和治疗效果。鼠异种移植以及NHF和PDAC细胞的2D和3D共培养的实验结果表明，较老的NHF刺激PDAC的增殖并赋予其抗放射治疗的能力。基于质谱的代谢物分析表明，较老的NHF具有明显的花生四烯酸12-脂氧合酶（ALOX12）表达，且其促有丝分裂代谢物12-（S）-羟基-5,8,10,14-二十碳四烯酸（12- （S）-HETE）与年轻同龄人相比。在与较老的NHF而不是较年轻的NHF一起培养的情况下，PDAC细胞显示出促分裂原激活的蛋白激酶信号传导和细胞代谢增加，并且氧化态较低，这与其增强的增殖和对放射疗法的抵抗力有关。发现在PDAC细胞系和肿瘤活检组织中ALOX12的表达明显较低，这表明PDAC细胞依赖于有丝分裂原的基质供应来满足其增殖需求。在较老的NHF中，ALOX12的药理（羟基酪醇）和分子（siRNA）干预抑制了它们刺激PDAC细胞增殖的能力。我们得出的结论是，NHF的按时间顺序的老化有助于PDAC的发展，而ALOX12和12-（S）-HETE可能是试图阻止进展和改善治疗结果的干预措施的潜在基质靶标。