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Matrix Metalloproteinase 2 and Thrombospondin 1: Their Potential As Biomarkers and Their Association in the Development of Esophageal Adenocarcinoma
Daniel Vallböhmer, Department of Surgery, University of Southern California, Los Angeles, CA; Jeffrey H. Peters, Department of Surgery, University of Rochester, Rochester, NY; Hidekazu Kuramochi, Daisuke Shimizu, Department of Biochemistry, University of Southern California, Los Angeles, CA; Daniel Oh, Departmnet of surgery, University of Southern California, Los Angeles, CA; Steven R. DeMeester, Dpertment of Surgery, University of Southern California, Los Angeles, CA; Jeffrey A. Hagen, Department of Surgery, University of Southern California, Los Angeles, CA; Parakrama T. Chandrasoma, Department of Pathology, University of Southern California, Los Angeles, CA; Kathleen D. Danenberg, Response Genetics, Inc., Los Angeles, Los Angeles, CA; Peter V. Danenberg, Department of Biochemistry, University of Southern California, Los Angeles, CA; Tom R. DeMeester, Dpartment of Surgery, University of Southern California, Los Angeles, CA

Matrix metalloproteinase 2 (MMP-2) is a key protease in tumor growth, invasion and metastatic spread. Studies suggest that thrombospondin-1 (TSP-1), a platelet and matrix glycoprotein, is the main regulator of the production of matrix metalloproteinase's. These enzymes have not been studied as potential biomarkers in Barrett's associated adenocarcinoma. We investigated the gene expression levels of MMP-2 and TSP-1 in the Barrett's metaplasia-dysplasia-carcinoma sequence.

Methods: Three tissue types were analyzed: 1) biopsies containing specialized intestinal metaplasia from patients with Barrett's esophagus (n=15; Barrett's group); 2) biopsies with either low or high grade dysplasia (n=12; dysplasia group), and 3) biopsies containing cancer (n=42 cancer group). After laser-capture microdissection, expression levels of the two genes were measured by quantitative real-time PCR. Results: Expression levels of TSP-1 were 3.6-fold higher in the dysplasia and 4.6-fold higher in the cancer group compared to the Barrett's group (p=0.028, p<0.001). No significant differences among the study groups were detected for MMP-2. There was a significant correlation of expression levels of the two genes with each other in each epithelial type [Table]. Conclusions: TSP-1 but not MMP-2 is a potential biomarker able to distinguish histologic stages in the development of Barett's associated adenocarcinoma. The correlation of expression levels of each gene to the other suggests that MMP-2 may be regulated by TSP-1.

	Barrett's (n=15)	Dysplasia (n=12)	Cancer (n=42)
TSP-1 mRNA levels median, (range)	1.98 (0.58-5.2)	7.13 (0.59-23.9)	9.21 (0.45-173)
MMP-2 mRNA levels median, (range)	2.72 (0.66-5.9)	3.91 (0.9-11.5)	3.79 (0.06-76)
Spearman's coefficient (p-value)	0.557 (<0.03)	0.811 (0.001)	0.61 (<0.0001)

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