Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Cell Oncol (Dordr). 2024 Feb;47(1):229-244. doi: 10.1007/s13402-023-00865-y. Epub 2023 Aug 29.
Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear.
PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity.
Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis.
Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion.
肥胖是胰腺导管腺癌（PDAC）的一个风险因素和预后不良因素，但潜在机制尚不清楚。
使用 PDAC 细胞和来自小鼠和人类的肥胖内脏脂肪细胞（O-Ad）来分析两种细胞类型之间的相互作用，并使用人微血管内皮细胞进行血管生成测定。使用皮下注射 PDAC 细胞的异种移植小鼠模型进行动物研究。使用有和没有肥胖的 PDAC 患者的切除组织分析内脏脂肪与预后的关系。
O-Ad 的条件培养基（CM）显著增加了人源和鼠源 PDAC 细胞的生长、迁移和血管生成能力，而在鼠源和人源细胞中阻断骨桥蛋白（OPN）则消除了 O-Ad 诱导的作用。此外，O-Ad 直接增加了内皮细胞的迁移和管状形成能力，而阻断 OPN 则消除了这些作用。O-Ad 增加了 PDAC 和内皮细胞中 AKT 的磷酸化和 VEGFA 的表达，而 OPN 在 O-Ad 中的抑制作用则消除了这些 OPN 诱导的作用。在异种移植模型中，与瘦小鼠相比，肥胖小鼠的 PDAC 肿瘤体积明显增大，而阻断 OPN 则显著抑制了肥胖加速的肿瘤生长。与非肥胖患者相比，肥胖患者 PDAC 肿瘤周围脂肪组织中的 OPN 表达明显更高。在肥胖的 PDAC 患者中，脂肪组织中 OPN 的高表达与预后不良显著相关。
肥胖脂肪细胞通过 OPN 分泌触发 PDAC 细胞的侵袭性转化，从而诱导 PDAC 进展并加速血管生成。
