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

Abstract

BackgroundEsophageal 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.MethodsExpression 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 clinicopatholocical parameters.ResultsOn 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).ConclusionsOur 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.

Barrett’s to Oesophageal Cancer Sequence: A Model of Inflammatory-Driven Upper Gastrointestinal Cancer

“…They are involved in the processes of inflammation and carcinogenesis, as many are produced by inflammatory and stromal cells, and so may have a role in inflammatory-driven cancers. In the oesophagus, MMP-1 has been found to be increased in BO and Barrett's-derived cancers and in OAC cell lines; it also correlates with lymph-node metastasis and poor prognosis [49][50][51]. Another study found that MMP-1, -3, -7 and -10 along with TIMP-1 were increased along the sequence from BO to OAC [19].…”

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

“…48 Hence, this MMP may be related to another mechanism than the PA-system, coming at onset of invasion. It has also been reported that a low host inflammatory response in the vicinity of the adenocarcinoma cells indicates a poor prognosis.…”

The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

“…Esophageal adenocarcinoma is related to gastroesophageal reflux and Barrett's esophagus, which is regarded as a precancerous lesion. Expression of MMP-1 was found in 95% of cases of ACE with BE and in 100% of cases of ACE without BE, whereas no expression of MMP-13 was found in these specimens [52]. Moreover, increased MMP-1 expression was observed in tumor cells positive for Ki-67 (the marker of cells' proliferation) whereas high MMP-1-mRNA levels were associated with lymph node metastases [52].…”