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MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status.

Grimm M, Lazariotou M, Kircher S, Stuermer L, Reiber C, Höfelmayr A, Gattenlöhner S, Otto C, Germer CT, von Rahden BH - J Transl Med (2010)

Bottom Line: No expression of MMP-13 was found in these specimens.On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results.Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Oberduerrbacher Strasse 6, 97080 Wuerzburg, Germany.

ABSTRACT

Background: Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Matrix metalloproteinases (MMPs) might play a role during the multistep carcinogenetic process.

Methods: Expression of MMP-1 and -13 was analyzed in esophageal cancer (n = 41 EAC with BE, n = 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC), furthermore in BE without intraepithelial neoplasia (IN) (n = 18), and the cell line OE-33. MMP-1 was co-labelled with Ki-67 (proliferation), Cdx-2 (marker for intestinal metaplasia, BE) and analyzed on mRNA level. MMP-1 staining results were correlated with clinicopathological parameters.

Results: On protein level, MMP-1 expression was found in 39 of 41 (95%) EAC with BE, in 19 of 19 (100%) EAC without BE, in 6 of 10 (60%) ESCC, and in 10 of 18 (56%) BE without IN. No expression of MMP-13 was found in these specimens. Quantification showed 48% MMP-1 positive cells in EAC with BE, compared to 35% in adjacent BE (p < 0.05), 44% in EAC without BE, 32% in ESCC, and 4% in BE without IN. Immunofluorescence double staining experiments revealed increased MMP-1 expressing in proliferating cells (MMP-1+/Ki-67+) (r = 0.943 for BE and r = 0.811 for EAC). On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results. High MMP-1 levels were associated with lymph node metastases but not with poorer survival (p = 0.307).

Conclusions: Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC. Expression of MMP-1 in proliferating BE and EAC cells suggest malignant proliferation following the clonal expansion model.

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Correlation and co-expression of Ki-67 with MMP-1. Correlation from quantified immunohistochemical staining results of MMP-1+ in BE (n = 41) and EAC (n = 60) with proliferating cells (Ki-67+) showed that Ki-67+ expression in BE (a) and EACs (b) had a strong direct correlation with the expression of MMP-1+ (r = 0.943 for BE and r = 0.811 for EAC). (c) Images demonstrate a representative example of Ki-67 co-expression with MMP-1+ by an immunofluorescent double staining in early BE showing the majority of proliferating (Ki-67+) cells with MMP-1+ (big arrows). Small arrows indicate goblet cells. FITC green Fluoresceinisothiocyanat, Cy3 red, and DAPI 4',6-Diamidino-2-phenylindoldihydrochlorid blue. Top, Calibration bar represents 50 μm. Bottom, calibration bar represents 25 μm. The square box at the bottom demonstrates the area which is also shown in larger magnification.
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Figure 3: Correlation and co-expression of Ki-67 with MMP-1. Correlation from quantified immunohistochemical staining results of MMP-1+ in BE (n = 41) and EAC (n = 60) with proliferating cells (Ki-67+) showed that Ki-67+ expression in BE (a) and EACs (b) had a strong direct correlation with the expression of MMP-1+ (r = 0.943 for BE and r = 0.811 for EAC). (c) Images demonstrate a representative example of Ki-67 co-expression with MMP-1+ by an immunofluorescent double staining in early BE showing the majority of proliferating (Ki-67+) cells with MMP-1+ (big arrows). Small arrows indicate goblet cells. FITC green Fluoresceinisothiocyanat, Cy3 red, and DAPI 4',6-Diamidino-2-phenylindoldihydrochlorid blue. Top, Calibration bar represents 50 μm. Bottom, calibration bar represents 25 μm. The square box at the bottom demonstrates the area which is also shown in larger magnification.

Mentions: For investigation of proliferating cells in BE and EAC and its relation to multi-step carcinogenesis, we analyzed MMP-1 expression in early Barrett cells, adjacent EAC, EAC without BE and ESCC. Evaluation of immunohistochemically stained serial sections showed a strong positive correlation of MMP-1 expression with proliferating cells (Figure 3a and 3b: MMP-1+/Ki-67+: r = 0.943 for BE, n = 41 and r = 0.811 for EAC, n = 60). As shown in Figure 3c by an immunofluorescence double staining, MMP-1 was co-expressed with great amounts of proliferating (Ki-67+) cells in areas which were associated with early BE (goblet cells as well as Cdx-2 positivity were observed in serial sections) (Figure 3c, representative example of n = 41 BE). IF double staining confirmed correlation analysis evaluated in IHC serial sections. We found a dominant population of proliferating MMP-1+/Ki-67+ cells in BE and EAC. Proliferation status (Ki-67+) itself did not have had any impact on survival (data not shown).


MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status.

Grimm M, Lazariotou M, Kircher S, Stuermer L, Reiber C, Höfelmayr A, Gattenlöhner S, Otto C, Germer CT, von Rahden BH - J Transl Med (2010)

Correlation and co-expression of Ki-67 with MMP-1. Correlation from quantified immunohistochemical staining results of MMP-1+ in BE (n = 41) and EAC (n = 60) with proliferating cells (Ki-67+) showed that Ki-67+ expression in BE (a) and EACs (b) had a strong direct correlation with the expression of MMP-1+ (r = 0.943 for BE and r = 0.811 for EAC). (c) Images demonstrate a representative example of Ki-67 co-expression with MMP-1+ by an immunofluorescent double staining in early BE showing the majority of proliferating (Ki-67+) cells with MMP-1+ (big arrows). Small arrows indicate goblet cells. FITC green Fluoresceinisothiocyanat, Cy3 red, and DAPI 4',6-Diamidino-2-phenylindoldihydrochlorid blue. Top, Calibration bar represents 50 μm. Bottom, calibration bar represents 25 μm. The square box at the bottom demonstrates the area which is also shown in larger magnification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2967517&req=5

Figure 3: Correlation and co-expression of Ki-67 with MMP-1. Correlation from quantified immunohistochemical staining results of MMP-1+ in BE (n = 41) and EAC (n = 60) with proliferating cells (Ki-67+) showed that Ki-67+ expression in BE (a) and EACs (b) had a strong direct correlation with the expression of MMP-1+ (r = 0.943 for BE and r = 0.811 for EAC). (c) Images demonstrate a representative example of Ki-67 co-expression with MMP-1+ by an immunofluorescent double staining in early BE showing the majority of proliferating (Ki-67+) cells with MMP-1+ (big arrows). Small arrows indicate goblet cells. FITC green Fluoresceinisothiocyanat, Cy3 red, and DAPI 4',6-Diamidino-2-phenylindoldihydrochlorid blue. Top, Calibration bar represents 50 μm. Bottom, calibration bar represents 25 μm. The square box at the bottom demonstrates the area which is also shown in larger magnification.
Mentions: For investigation of proliferating cells in BE and EAC and its relation to multi-step carcinogenesis, we analyzed MMP-1 expression in early Barrett cells, adjacent EAC, EAC without BE and ESCC. Evaluation of immunohistochemically stained serial sections showed a strong positive correlation of MMP-1 expression with proliferating cells (Figure 3a and 3b: MMP-1+/Ki-67+: r = 0.943 for BE, n = 41 and r = 0.811 for EAC, n = 60). As shown in Figure 3c by an immunofluorescence double staining, MMP-1 was co-expressed with great amounts of proliferating (Ki-67+) cells in areas which were associated with early BE (goblet cells as well as Cdx-2 positivity were observed in serial sections) (Figure 3c, representative example of n = 41 BE). IF double staining confirmed correlation analysis evaluated in IHC serial sections. We found a dominant population of proliferating MMP-1+/Ki-67+ cells in BE and EAC. Proliferation status (Ki-67+) itself did not have had any impact on survival (data not shown).

Bottom Line: No expression of MMP-13 was found in these specimens.On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results.Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Oberduerrbacher Strasse 6, 97080 Wuerzburg, Germany.

ABSTRACT

Background: Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Matrix metalloproteinases (MMPs) might play a role during the multistep carcinogenetic process.

Methods: Expression of MMP-1 and -13 was analyzed in esophageal cancer (n = 41 EAC with BE, n = 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC), furthermore in BE without intraepithelial neoplasia (IN) (n = 18), and the cell line OE-33. MMP-1 was co-labelled with Ki-67 (proliferation), Cdx-2 (marker for intestinal metaplasia, BE) and analyzed on mRNA level. MMP-1 staining results were correlated with clinicopathological parameters.

Results: On protein level, MMP-1 expression was found in 39 of 41 (95%) EAC with BE, in 19 of 19 (100%) EAC without BE, in 6 of 10 (60%) ESCC, and in 10 of 18 (56%) BE without IN. No expression of MMP-13 was found in these specimens. Quantification showed 48% MMP-1 positive cells in EAC with BE, compared to 35% in adjacent BE (p < 0.05), 44% in EAC without BE, 32% in ESCC, and 4% in BE without IN. Immunofluorescence double staining experiments revealed increased MMP-1 expressing in proliferating cells (MMP-1+/Ki-67+) (r = 0.943 for BE and r = 0.811 for EAC). On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results. High MMP-1 levels were associated with lymph node metastases but not with poorer survival (p = 0.307).

Conclusions: Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC. Expression of MMP-1 in proliferating BE and EAC cells suggest malignant proliferation following the clonal expansion model.

Show MeSH
Related in: MedlinePlus