Yang Yiming, Sanders Andrew J, Ruge Fiona, Dong Xuefei, Cui Yuxin, Dou Qing Ping, Jia Shuqin, Hao Chunyi, Ji Jiafu, Jiang Wen G
Cardiff University School of Medicine Heath Park, Cardiff CF14 4XN, UK.
Barbara Ann Karmanos Cancer Institute, Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University Detroit, MI 48201, USA.
Am J Cancer Res. 2021 Dec 15;11(12):5917-5932. eCollection 2021.
Activated leukocyte cell adhesion molecule (ALCAM, or CD166) is a cell adhesion molecule and one of potential tumour metastasis 'soil' receptors that via homotypic and heterotypic interactions, mediates cancer cell adhesion. The present study investigated clinical, pathological and prognostic values of ALCAM in patients with pancreatic cancer. Human pancreatic cancer (PANC-1 and Mia PaCa-2) and human vascular endothelial cell lines were used to construct cell models differentially expressing levels of ALCAM. Tumour-endothelial interaction and tumour migration were assessed by a DiI-based method and electric cell-substrate impedance sensing (ECIS) assay. Pancreatic cancer tissues (n=223), collected immediately after surgery, were analysed for levels of the ALCAM transcripts, which were also analysed against clinical, pathological and clinical outcomes of the patients. ALCAM protein was assessed by immunohistochemistry on a tissue array. Our study demonstrate that pancreatic cancer tissues had significantly higher levels of ALCAM transcripts than normal tissues (P<0.00001). There were no significant differences with staging, differentiation and tumour locations. Tumours from patients who died of pancreatic cancer had significantly high levels of ALCAM compared with those who lived (P=0.018), and this finding was further supported by ROC analysis (P=0.016). Multivariant analysis showed that ALCAM is an independent prognosis factor for overall survival (HR=5.485), with both nodal status and TNM staging contributing to the model (HR=2.578 and 3.02, respectively). A surprising finding was the relationship between ALCAM expression and microvessel embolism of tumour cells (P=0.021, with vs without tumour embolism). Levels of ALCAM were found to be a determinant factor to adherence of the pancreatic cancer cells to vascular endothelial cells, as demonstrated by pancreatic cancer cell models genetically engineered to express differential levels of ALCAM. The tumour-endothelial interaction mediated by ALCAM was readily blocked by addition of soluble ALCAM. Our data supports the conclusion that ALCAM expression is aberrant in pancreatic cancer and its raised expression is an independent prognostic factor for the survival of the patients and the microvascular embolism by cancer cells. Our results suggest that ALCAM plays a key role in mediating tumour-endothelial cell interactions and enhancing tumour embolism in pancreatic cancer, and targeting ALCAM represents a potential therapeutic strategy for treating human pancreatic cancer.
活化白细胞细胞黏附分子（ALCAM，即CD166）是一种细胞黏附分子，是潜在的肿瘤转移“土壤”受体之一，通过同型和异型相互作用介导癌细胞黏附。本研究调查了ALCAM在胰腺癌患者中的临床、病理及预后价值。使用人胰腺癌细胞系（PANC-1和Mia PaCa-2）和人血管内皮细胞系构建差异表达ALCAM水平的细胞模型。通过基于DiI的方法和电场细胞基质阻抗传感（ECIS）分析评估肿瘤-内皮细胞相互作用和肿瘤迁移。对手术后立即收集的223例胰腺癌组织进行ALCAM转录本水平分析，并将其与患者的临床、病理及临床结局进行对照分析。通过组织芯片免疫组化评估ALCAM蛋白。我们的研究表明，胰腺癌组织中ALCAM转录本水平显著高于正常组织（P<0.00001）。在分期、分化程度和肿瘤位置方面无显著差异。死于胰腺癌患者的肿瘤中ALCAM水平显著高于存活患者（P=0.018），ROC分析进一步支持了这一发现（P=0.016）。多变量分析显示，ALCAM是总生存的独立预后因素（HR=5.485），淋巴结状态和TNM分期均对模型有贡献（HR分别为2.578和3.02）。一个令人惊讶的发现是ALCAM表达与肿瘤细胞微血管栓塞之间的关系（有肿瘤栓塞与无肿瘤栓塞相比，P=0.021）。通过基因工程构建表达不同水平ALCAM的胰腺癌细胞模型证明，ALCAM水平是胰腺癌细胞与血管内皮细胞黏附的决定因素。加入可溶性ALCAM可轻易阻断由ALCAM介导的肿瘤-内皮细胞相互作用。我们的数据支持以下结论：ALCAM在胰腺癌中表达异常，其表达升高是患者生存及癌细胞微血管栓塞的独立预后因素。我们的结果表明，ALCAM在介导胰腺癌肿瘤-内皮细胞相互作用及增强肿瘤栓塞中起关键作用，靶向ALCAM代表了一种治疗人类胰腺癌的潜在治疗策略。
