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Integrin expression in esophageal squamous cell carcinoma: loss of the physiological integrin expression pattern correlates with disease progression.

Vay C, Hosch SB, Stoecklein NH, Klein CA, Vallböhmer D, Link BC, Yekebas EF, Izbicki JR, Knoefel WT, Scheunemann P - PLoS ONE (2014)

Bottom Line: In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis.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).

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Clustered display of integrin expression characteristics.Each tumor sample is represented by a single column of boxes; each integrin expression parameter is represented by a single row. The samples (columns) are grouped according to the similarity of their expression characteristics. The dendrogram above the cluster encloses subsets of samples reflecting the particular similarity among each other. The profiles of the various expression parameters (rows) are also arranged to each other according to their similarity. (A) Clustered display of the staining scores reflecting the expression quantities for the integrin subunits α2, α3, α6, β1, and β4 in distinct areas of the tumor samples (invasion front, marginal area, central area). In the majority of the cases, a uniform staining score was present in the marginal and central area of the individual tumor sample, which was reflected by the neighboring arrangement of the corresponding expression profiles. Notably, the expression profiles of the integrin subunits α6 and β4 at the invasion front were grouped adjacent to each other. (B) Clustered display of staining patterns representing the distribution of the integrin subunits α2, α3, α6, β1, and β4 in the tumor tissue (polarized, homogeneous and heterogeneous staining pattern). A subset of six patients possessed a polarized staining pattern for the integrin subunits α3, α6, and β4 at minimum (framed columns). The tumors of five of the six patients were well to moderately differentiated (G1-2), whereas only one patient had a poorly differentiated tumor (G3). The six patients showed a strong expression (+++) of the α6 subunit at the invasion front of their tumors which was statistically identified as the only independent prognostic factor for the collective.
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pone-0109026-g004: Clustered display of integrin expression characteristics.Each tumor sample is represented by a single column of boxes; each integrin expression parameter is represented by a single row. The samples (columns) are grouped according to the similarity of their expression characteristics. The dendrogram above the cluster encloses subsets of samples reflecting the particular similarity among each other. The profiles of the various expression parameters (rows) are also arranged to each other according to their similarity. (A) Clustered display of the staining scores reflecting the expression quantities for the integrin subunits α2, α3, α6, β1, and β4 in distinct areas of the tumor samples (invasion front, marginal area, central area). In the majority of the cases, a uniform staining score was present in the marginal and central area of the individual tumor sample, which was reflected by the neighboring arrangement of the corresponding expression profiles. Notably, the expression profiles of the integrin subunits α6 and β4 at the invasion front were grouped adjacent to each other. (B) Clustered display of staining patterns representing the distribution of the integrin subunits α2, α3, α6, β1, and β4 in the tumor tissue (polarized, homogeneous and heterogeneous staining pattern). A subset of six patients possessed a polarized staining pattern for the integrin subunits α3, α6, and β4 at minimum (framed columns). The tumors of five of the six patients were well to moderately differentiated (G1-2), whereas only one patient had a poorly differentiated tumor (G3). The six patients showed a strong expression (+++) of the α6 subunit at the invasion front of their tumors which was statistically identified as the only independent prognostic factor for the collective.

Mentions: Subjecting the integrin expression patterns to cluster analysis (Fig. 4), tumors with predominantly polarized expression of the integrin subunits could be clearly distinguished from tumors with mainly homogeneous or heterogeneous distribution.


Integrin expression in esophageal squamous cell carcinoma: loss of the physiological integrin expression pattern correlates with disease progression.

Vay C, Hosch SB, Stoecklein NH, Klein CA, Vallböhmer D, Link BC, Yekebas EF, Izbicki JR, Knoefel WT, Scheunemann P - PLoS ONE (2014)

Clustered display of integrin expression characteristics.Each tumor sample is represented by a single column of boxes; each integrin expression parameter is represented by a single row. The samples (columns) are grouped according to the similarity of their expression characteristics. The dendrogram above the cluster encloses subsets of samples reflecting the particular similarity among each other. The profiles of the various expression parameters (rows) are also arranged to each other according to their similarity. (A) Clustered display of the staining scores reflecting the expression quantities for the integrin subunits α2, α3, α6, β1, and β4 in distinct areas of the tumor samples (invasion front, marginal area, central area). In the majority of the cases, a uniform staining score was present in the marginal and central area of the individual tumor sample, which was reflected by the neighboring arrangement of the corresponding expression profiles. Notably, the expression profiles of the integrin subunits α6 and β4 at the invasion front were grouped adjacent to each other. (B) Clustered display of staining patterns representing the distribution of the integrin subunits α2, α3, α6, β1, and β4 in the tumor tissue (polarized, homogeneous and heterogeneous staining pattern). A subset of six patients possessed a polarized staining pattern for the integrin subunits α3, α6, and β4 at minimum (framed columns). The tumors of five of the six patients were well to moderately differentiated (G1-2), whereas only one patient had a poorly differentiated tumor (G3). The six patients showed a strong expression (+++) of the α6 subunit at the invasion front of their tumors which was statistically identified as the only independent prognostic factor for the collective.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232252&req=5

pone-0109026-g004: Clustered display of integrin expression characteristics.Each tumor sample is represented by a single column of boxes; each integrin expression parameter is represented by a single row. The samples (columns) are grouped according to the similarity of their expression characteristics. The dendrogram above the cluster encloses subsets of samples reflecting the particular similarity among each other. The profiles of the various expression parameters (rows) are also arranged to each other according to their similarity. (A) Clustered display of the staining scores reflecting the expression quantities for the integrin subunits α2, α3, α6, β1, and β4 in distinct areas of the tumor samples (invasion front, marginal area, central area). In the majority of the cases, a uniform staining score was present in the marginal and central area of the individual tumor sample, which was reflected by the neighboring arrangement of the corresponding expression profiles. Notably, the expression profiles of the integrin subunits α6 and β4 at the invasion front were grouped adjacent to each other. (B) Clustered display of staining patterns representing the distribution of the integrin subunits α2, α3, α6, β1, and β4 in the tumor tissue (polarized, homogeneous and heterogeneous staining pattern). A subset of six patients possessed a polarized staining pattern for the integrin subunits α3, α6, and β4 at minimum (framed columns). The tumors of five of the six patients were well to moderately differentiated (G1-2), whereas only one patient had a poorly differentiated tumor (G3). The six patients showed a strong expression (+++) of the α6 subunit at the invasion front of their tumors which was statistically identified as the only independent prognostic factor for the collective.
Mentions: Subjecting the integrin expression patterns to cluster analysis (Fig. 4), tumors with predominantly polarized expression of the integrin subunits could be clearly distinguished from tumors with mainly homogeneous or heterogeneous distribution.

Bottom Line: In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis.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).

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus