Integrin Expression in Esophageal Squamous Cell Carcinoma: Loss of the Physiological Integrin Expression Pattern Correlates with Disease Progression

The integrins are a family of heterodimeric transmembrane signaling receptors that mediate the adhesive properties of epithelial cells affecting cell growth and differentiation. In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis. However, only few studies have investigated the role of integrin expression in esophageal squamous cell carcinoma (ESCC). Using a novel quantifying immunofluorescence-staining assay, we investigated the expression of the integrins α2β1, α3β1, α6β1, and α6β4 in primary ESCC of 36 patients who underwent surgical resection. Magnitude and distribution of expression were analyzed in primary tumor samples and autologous esophageal squamous epithelium. The persistence of the physiologically polarized expression of the subunits α6, β1, and β4 in the tumor tissue was significantly associated with prolonged relapse-free survival (p = 0.028, p = 0.034, p = 0.006). In contrast, patients with reduced focal α6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong α6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001). Multivariate regression analysis identified the maintenance of strong α6 immunoreactivity at the invasion front as an independent prognostic factor for increased relapse-free and disease-specific survival (p = 0.003; p = 0.003). Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients. Particularly, the distinct expression of the integrins α6β4 and α6β1 at the invasion front as well as the maintenance of a polarized integrin expression pattern in the tumor tissue may serve as valuable new markers to assess the aggressiveness of ESCC.整合素（integrins）是一类异二聚体跨膜信号受体，可介导上皮细胞的黏附特性，进而影响细胞生长与分化。在诸多上皮源性恶性肿瘤中，整合素表达异常与肿瘤进展密切相关，且常与不良预后存在关联。然而，目前针对整合素表达在食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）中作用的研究寥寥无几。本研究采用新型定量免疫荧光染色检测法，对36例接受手术切除的原发性食管鳞状细胞癌患者的整合素α2β1、α3β1、α6β1及α6β4表达情况进行了分析，并对原发肿瘤样本及自体食管鳞状上皮的表达强度与分布模式展开评估。结果显示，肿瘤组织中α6、β1及β4亚基维持生理性极化表达的患者，其无复发生存期显著延长（p=0.028、p=0.034、p=0.006）。与之相反，肿瘤侵袭前沿α6表达呈局灶性减弱的患者，相较于基质表面α6表达强阳性（该表型在正常食管上皮中较为常见）的患者，其无复发生存期显著缩短（p=0.001）。多因素回归分析表明，侵袭前沿维持α6强免疫反应性是延长无复发生存期及疾病特异性生存期的独立预后因素（p=0.003；p=0.003）。本研究结果提示，整合素表达模式与表达强度的异常可能在食管鳞状细胞癌患者的疾病进展中发挥关键作用。其中，整合素α6β4与α6β1在侵袭前沿的特异性表达，以及肿瘤组织中整合素极化表达模式的维持，或可作为评估食管鳞状细胞癌侵袭性的新型潜在有效标志物。