Limits...
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.

Show MeSH

Related in: MedlinePlus

Non-dimensional raw intensities for Rhodamine Red-X (RRX) fluorescence were measured in at least three low power fields (100fold magnification) representative for each tissue section in three different areas of the tumor cell formations: Invasion front, marginal areas, and central areas.Predominant raw intensity values were classified below 150 as negative (−), from 150 to 500 as weak (+), from 500 to 1000 as moderate (++), and above 1000 as strong (+++) expression of the respective integrin subunit.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4232252&req=5

pone-0109026-g001: Non-dimensional raw intensities for Rhodamine Red-X (RRX) fluorescence were measured in at least three low power fields (100fold magnification) representative for each tissue section in three different areas of the tumor cell formations: Invasion front, marginal areas, and central areas.Predominant raw intensity values were classified below 150 as negative (−), from 150 to 500 as weak (+), from 500 to 1000 as moderate (++), and above 1000 as strong (+++) expression of the respective integrin subunit.

Mentions: In each digitalized CCD-image of a low power field mean raw intensities were determined separately by scanning the range of luminance values in three different areas of the tumor cell formations: (1) At the direct invasion front (stromal surfaces of basal tumor cells constituting the invasive tumor margin), (2) in the marginal areas (basal cell layers adjacent to the surrounding tissue), and (3) in the central areas of tumor cell formations. In addition, if tumor sections contained adjacent normal esophageal mucosa, distribution and intensity of integrin expression intensities were determined in an analogous manner (1) at the border of the epithelium to the basement mebrane (basal epithelial surface), (2) in the basal cell layers (stratum basale), (3) in the suprabasal cell layers (stratum spinosum), and (4) in the luminal cell layers (stratum squamosum) of the squamous epithelium (Fig. 1). The mean staining intensities of the integrin subunits measured in the stratum basale of the epithelia served as a reference to evaluate the integrin expression in the suprabasal and central tumor tissue. Furthermore, the average staining intensities at the basal surface of the keratinocytes directly attached to the substratum provided the reference to evaluate the integrin expression at the invasion front of the tumors.


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)

Non-dimensional raw intensities for Rhodamine Red-X (RRX) fluorescence were measured in at least three low power fields (100fold magnification) representative for each tissue section in three different areas of the tumor cell formations: Invasion front, marginal areas, and central areas.Predominant raw intensity values were classified below 150 as negative (−), from 150 to 500 as weak (+), from 500 to 1000 as moderate (++), and above 1000 as strong (+++) expression of the respective integrin subunit.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0109026-g001: Non-dimensional raw intensities for Rhodamine Red-X (RRX) fluorescence were measured in at least three low power fields (100fold magnification) representative for each tissue section in three different areas of the tumor cell formations: Invasion front, marginal areas, and central areas.Predominant raw intensity values were classified below 150 as negative (−), from 150 to 500 as weak (+), from 500 to 1000 as moderate (++), and above 1000 as strong (+++) expression of the respective integrin subunit.
Mentions: In each digitalized CCD-image of a low power field mean raw intensities were determined separately by scanning the range of luminance values in three different areas of the tumor cell formations: (1) At the direct invasion front (stromal surfaces of basal tumor cells constituting the invasive tumor margin), (2) in the marginal areas (basal cell layers adjacent to the surrounding tissue), and (3) in the central areas of tumor cell formations. In addition, if tumor sections contained adjacent normal esophageal mucosa, distribution and intensity of integrin expression intensities were determined in an analogous manner (1) at the border of the epithelium to the basement mebrane (basal epithelial surface), (2) in the basal cell layers (stratum basale), (3) in the suprabasal cell layers (stratum spinosum), and (4) in the luminal cell layers (stratum squamosum) of the squamous epithelium (Fig. 1). The mean staining intensities of the integrin subunits measured in the stratum basale of the epithelia served as a reference to evaluate the integrin expression in the suprabasal and central tumor tissue. Furthermore, the average staining intensities at the basal surface of the keratinocytes directly attached to the substratum provided the reference to evaluate the integrin expression at the invasion front of the tumors.

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