Prognostic significance of stromelysin-3 and tissue inhibitor of matrix metalloproteinase-2 in esophageal cancer.
OBJECTIVE
Stromelysins (matrix metalloproteinases: MMP-10 or ST-2 and MMP-11 or ST-3) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and 2) have been shown to be associated with human tumor progression, invasion and metastasis. The aim of the present study was to determine the prognostic significance of these proteins in esophageal squamous cell carcinoma (ESCC).


METHODS
Immunohistochemical analysis was carried out in 65 surgically resected ESCCs and 49 distant histologically normal esophageal tissues and 16 cases of dysplasias. Statistical analyses were performed to determine the associations between the protein expression and clinicopathological parameters and survival of esophageal cancer patients.


RESULTS
Expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 43/65 (66%), 51/65 (78%), 43/65 (66%) and 47/65 (72%) ESCC cases, respectively. Univariate analysis showed that TIMP-2 expression was associated with tumor site (OR = 2.63, p = 0.017). TIMP-1+/TIMP-2+ phenotype was inversely correlated with nodal invasiveness of the tumor (OR = 0.4, p = 0.04). Interestingly, p53 expression was associated with increased levels of ST-3 (OR = 0.11, p = 0.02) and TIMP-1 (OR = 3.2, p = 0.007) suggesting possible involvement of p53 in the regulation of these proteins. An increased expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 11/16 (69%), 7/17 (44%), 11/16 (69%) and 8/16 (50%) dysplasias also suggesting that these alterations are early events in esophageal tumorigenesis. All the ESCC patients were followed up postesophagectomy for a maximum period of 59 months (mean disease-free survival = 12 months). Kaplan-Meier survival analysis showed that patients with ST-3-positive and TIMP-2-negative carcinoma had a significantly shorter disease-free survival (median disease-free survival time of 4 months) as compared to patients in the other groups (median disease-free survival time of 20 months; p = 0.0016). To our knowledge this is the first report showing that ST-3+/TIMP-2- phenotype remained of significant predictive value for disease-free survival (p = 0.0007) in multivariate analysis including a conventional clinicopathological factor, tumor stage (p = 0.051).


CONCLUSIONS
Our results suggest that ST-3+/TIMP-2- phenotype is an adverse prognosticator in esophageal cancer patients.
Sharma
Rinu
R
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Chattopadhyay
Tushar Kant
TK
Mathur
Meera
M
Ralhan
Ranju
R
D000328:Adult; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000473:pathology*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D053506:Matrix Metalloproteinase 10; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000032:analysis*; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis
D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10