Association of trypsin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma

Abstract

Background: Overexpression of the matrix serine proteinase (MSP) trypsin has been implicated in tumor growth, invasion, and metastasis. The objective of this study was to clarify the clinicopathologic and prognostic significance of trypsin expression in esophageal squamous cell carcinomas (SCC).

Methods: Production of trypsin in tissue extracts was analyzed by immunoblotting and gelatin zymography. The authors analyzed the association between immunohistochemically detected trypsin expression in esophageal SCC and clinicopathologic characteristics, and they investigated whether trypsin is a predictor of recurrence and/or survival.

Results: Overproduction and activation of trypsin was observed in 6 of 10 tumor extracts. The trypsin immunoreactivities at the invasive front were more intense than those at the superficial layer. Sections with immunostaining signals in greater than 30% of carcinoma cells at the invasive front, which were observed in 52 (52%) cases, were judged to be positive for trypsin. Trypsin positivity was significantly correlated with the depth of invasion (P < 0.0001), lymph node metastasis (P = 0.0048), advanced pTNM classification (P = 0.0006), recurrence (P = 0.0003), and recurrence within the first postoperative year (P = 0.0005). Patients with trypsin positive carcinoma had significantly shorter disease free and overall survival times than did those with trypsin negative carcinoma (P < 0.0001 and P < 0.0001, respectively). Trypsin retained its significant predictive value for disease free and overall survival in multivariate analysis that included conventional clinicopathologic factors (P = 0.0029 and P = 0.0006, respectively). Patients with concomitant overexpression of trypsin and matrilysin at the invasive front, in which they often were colocalized, had the worst prognosis.

Conclusions: The authors' results suggest that trypsin plays a key role in the progression of esophageal carcinoma. Detection of trypsin expression as well as matrilysin is useful for the prediction of recurrence and poor prognosis.