Background/Objectives: The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) is highly complex, influencing both vascular function and therapy response. P21-activated kinases (PAKs) are key regulators of the cellular and immune system, but the specific roles of PAK1 and PAK4 in pancreatic tumour vasculature and chemotherapy sensitivity are unclear. This study investigated the effects of PAK1 and PAK4 on tumour vasculature and therapeutic response in an immunocompromised mouse model.Methods: KPC-derived wild type (WT), PAK1 knockout (KO), PAK4KO, or PAK1&4KO pancreatic cancer cells were injected subcutaneously into SCID mice, followed by gemcitabine treatment. Tumour growth, vessel density, pericyte coverage, and endothelial adhesion molecule expression were analysed by histology and immunostaining. A proteomic study was used to identify protein changes.Results: PAK1KO significantly reduced tumour growth, enhanced vascular normalisation, upregulated stromal ICAM-1 and VCAM-1, but reduced gemcitabine efficacy. PAK4KO did not inhibit tumour growth but increased vessel diameter and enhanced gemcitabine efficacy. Proteomics study indicated that PAK1KO downregulated proteins involved in the VEGF pathway, while PAK4KO upregulated most proteins involved in the VEGF pathway and downregulated DNA repair proteins, contributing to improved chemotherapy sensitivity. The double knockout of PAK1 and PAK4 did not inhibit tumour growth, although it stimulated vascular normalisation, indicating an outcome balanced between PAK1 and PAK4.Conclusions: PAK1 and PAK4 differentially regulated pancreatic tumour vasculature and chemotherapy response. PAK1KO suppressed tumour growth by reducing angiogenesis and enhancing vascular normalisation, whereas PAK4KO enhanced gemcitabine efficacy through vessel dilation.
背景/目的：胰腺导管腺癌（PDA）的肿瘤微环境高度复杂，影响血管功能及治疗反应。P21激活激酶（PAKs）是细胞与免疫系统的关键调节因子，但PAK1和PAK4在胰腺肿瘤血管系统及化疗敏感性中的具体作用尚不明确。本研究在免疫缺陷小鼠模型中探讨了PAK1和PAK4对肿瘤血管系统及治疗反应的影响。 方法：将KPC来源的野生型（WT）、PAK1敲除（KO）、PAK4敲除或PAK1&4双敲除的胰腺癌细胞皮下注射至SCID小鼠，随后进行吉西他滨治疗。通过组织学与免疫染色分析肿瘤生长、血管密度、周细胞覆盖及内皮黏附分子表达。采用蛋白质组学研究鉴定蛋白变化。 结果：PAK1敲除显著抑制肿瘤生长，促进血管正常化，上调基质ICAM-1与VCAM-1表达，但降低了吉西他滨疗效。PAK4敲除未抑制肿瘤生长，但增加血管直径并增强吉西他滨疗效。蛋白质组学分析表明，PAK1敲除下调VEGF通路相关蛋白，而PAK4敲除上调多数VEGF通路蛋白并下调DNA修复蛋白，从而提升化疗敏感性。PAK1与PAK4双敲除虽能促进血管正常化，但未抑制肿瘤生长，提示其效应介于PAK1与PAK4单独作用之间。 结论：PAK1与PAK4对胰腺肿瘤血管系统及化疗反应具有差异性调控作用。PAK1敲除通过抑制血管生成、促进血管正常化来抑制肿瘤生长，而PAK4敲除则通过扩张血管增强吉西他滨疗效。
The Effects of PAK-Regulated Tumour Vasculature on Gemcitabine Response of Pancreatic Cancer
肿瘤(癌症)患者之家