MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status.
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.
Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Oberduerrbacher Strasse 6, 97080 Wuerzburg, Germany.
Martin
M
Grimm
Maria
M
Lazariotou
Stefan
S
Kircher
Luisa
L
Stuermer
Christoph
C
Reiber
Andreas
A
Höfelmayr
Stefan
S
Gattenlöhner
Christoph
C
Otto
Christoph T
CT
Germer
Burkhard H A
BH
von Rahden
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000473:pathology*; D001706:Biopsy; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis
D020781:Matrix Metalloproteinase 1