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.
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany; Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Vay
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany; Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of General, Vascular, and Visceral Surgery, Ingolstadt Medical Center, Ingolstadt, Germany.
Stefan B
SB
Hosch
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany; Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Nikolas H
NH
Stoecklein
Division of Oncogenomics, Institute of Pathology, University of Regensburg, Regensburg, Germany.
Christoph A
CA
Klein
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany.
Daniel
D
Vallböhmer
Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Björn-Christian
BC
Link
Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Emre F
EF
Yekebas
Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jakob R
JR
Izbicki
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany; Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Wolfram T
WT
Knoefel
Department of Surgery (A), Heinrich-Heine-University and University Hospital Düsseldorf, Düsseldorf, Germany; Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Pediatric Surgery, University Hospital Rostock, Rostock, Germany.
Peter
P
Scheunemann
D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D016000:Cluster Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005455:Fluorescent Antibody Technique; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D021122:Protein Subunits / Q000378:metabolism; D012008:Recurrence
D016023:Integrins; D021122:Protein Subunits