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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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Overall survival curves calculated by Kaplan-Meier method in Barrett associated adenocarcinomas. High levels of MMP-1 expression in EAC (n = 60) were not found to be associated with poorer survival (p = 0.307). The times of the censored data are indicated by short vertical lines.
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Figure 4: Overall survival curves calculated by Kaplan-Meier method in Barrett associated adenocarcinomas. High levels of MMP-1 expression in EAC (n = 60) were not found to be associated with poorer survival (p = 0.307). The times of the censored data are indicated by short vertical lines.

Mentions: To analyze survival differences of patients after successful (R0) curative surgical resection for EAC with and without BE, patients were divided into two subgroups as described above (dichotomous variables). Lymph node metastasis (pN+, Table 3, pT-category (pT3/4, Table 3) and grading (G3/4, Table 3) were shown to be unfavorable factors in univariate analysis of all (n = 60) EACs. Moreover, we found a strong association between high MMP-1 expression and positive lymph node metastases (p = 0.016136582, Fisher's exact test, Table 1) in EAC patients (n = 60). To analyze differences in tumor related survival dependent on MMP-1-expression in EAC we divided the patients in two subgroups as described above (dichotomous variables). Survival in subgroup with high MMP-1 expression of all EACs (n = 60; Figure 4, Table 1) was not significantly worse in comparison to the subgroup of patients with low expression of MMP-1 (Figure 4, Table 1). Data show that MMP-1 expression in BE and adjacent EACs is associated with clinicopathologic features which may predict worse clinical outcome of adjacent EACs. Multivariate analysis using the Cox Proportional Hazards Model demonstrate lymph node metastases and grading as independent prognostic factors in all (n = 60) EACs (Table 4).


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)

Overall survival curves calculated by Kaplan-Meier method in Barrett associated adenocarcinomas. High levels of MMP-1 expression in EAC (n = 60) were not found to be associated with poorer survival (p = 0.307). The times of the censored data are indicated by short vertical lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Overall survival curves calculated by Kaplan-Meier method in Barrett associated adenocarcinomas. High levels of MMP-1 expression in EAC (n = 60) were not found to be associated with poorer survival (p = 0.307). The times of the censored data are indicated by short vertical lines.
Mentions: To analyze survival differences of patients after successful (R0) curative surgical resection for EAC with and without BE, patients were divided into two subgroups as described above (dichotomous variables). Lymph node metastasis (pN+, Table 3, pT-category (pT3/4, Table 3) and grading (G3/4, Table 3) were shown to be unfavorable factors in univariate analysis of all (n = 60) EACs. Moreover, we found a strong association between high MMP-1 expression and positive lymph node metastases (p = 0.016136582, Fisher's exact test, Table 1) in EAC patients (n = 60). To analyze differences in tumor related survival dependent on MMP-1-expression in EAC we divided the patients in two subgroups as described above (dichotomous variables). Survival in subgroup with high MMP-1 expression of all EACs (n = 60; Figure 4, Table 1) was not significantly worse in comparison to the subgroup of patients with low expression of MMP-1 (Figure 4, Table 1). Data show that MMP-1 expression in BE and adjacent EACs is associated with clinicopathologic features which may predict worse clinical outcome of adjacent EACs. Multivariate analysis using the Cox Proportional Hazards Model demonstrate lymph node metastases and grading as independent prognostic factors in all (n = 60) EACs (Table 4).

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