Abstract
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.
Highlights
Esophageal cancer is a highly aggressive tumor entity characterized by late diagnosis and early metastasis [1,2]
The strongest integrin expression was observed in the basal keratinocytes, while staining intensities gradually diminished with an increasing distance to the substratum in terms of a polarized expression pattern (Supplementary Table S2)
Using a novel immunofluorescence staining approach, we have investigated a panel of esophageal squamous cell carcinomas (ESCC) and evaluated both the level of expression and the distribution of the subunits constituting the integrins a2b1, a3b1, a6b1, and a6b4
Summary
Esophageal cancer is a highly aggressive tumor entity characterized by late diagnosis and early metastasis [1,2]. As the eighth most common cancer worldwide with over 480,000 new cases estimated in 2008, and the sixth most common cause of death from cancer worldwide with 407,000 deaths (5.4% of the total) in 2008, esophageal carcinoma is one of the leading causes of malignancy-associated death [3,4]. Even though the incidence of esophageal adenocarcinoma has been rising in most western industrial countries like no other malignancy since the mid-1970s, globally squamous cell carcinoma (SCC) still represents a predominant type of esophageal cancer and accounts for the a high number of fatal outcomes [5]. Survival rates remain unsatisfactory and continue to lag behind those of other gastrointestinal malignancies [9]. Postoperative clinicopathological staging is still the most relevant factor to estimate disease recurrence and patient survival [10]
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