Original Contribution
The American Journal of Gastroenterology (2005) 100, 1835–1843; doi:10.1111/j.1572-0241.2005.50018.x
Matrix Metalloproteinases Expression Correlates with Survival in Patients with Esophageal Squamous Cell Carcinoma
Zhen-Dong Gu MD1, Ji-You Li MD1, Ming Li MD, PhD1, Jin Gu MD1, Xiao-Tian Shi MD1, Yang Ke PhD1 and Ke-Neng Chen MD, PhD1
1Department of Thoracic Surgery, Pathology, General Surgery, and Genetics, Peking University School of Oncology, Beijing Cancer Hospital, Beijing; and Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, People's Republic of China
Correspondence: Ke-Neng Chen, MD, PhD, Department of Thoracic Surgery, Peking University School of Oncology, Beijing Cancer Hospital, Beijing 100036, People's Republic of China. Dr. Ke-Neng Chen is currently positioned as a Postdoctoral Fellow in the Department of Plastic Surgery at The University of the Texas, M.D. Anderson Cancer Center, Houston TX, 77030, USA
Received 4 January 2005; Revised 0000; Accepted 7 March 2005.
Abstract
OBJECTIVES:
The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases capable of degrading the extracellular matrix and play important roles in malignancies. We evaluated the expression of four MMPs in esophageal squamous cell carcinoma (ESCC), and assessed the association between MMP expression and clinicopathologic characteristics and disease-free survival time.
METHODS:
We evaluated MMP1, MMP7, MMP9, and MMP13 expression in tissues from 208 patients with ESCC using immunohistochemistry (IHC), and correlated MMP expression to clinicopathologic characteristics and disease-free survival time. To confirm MMP9 expression at different levels, we simultaneously performed RT-PCR, Western blotting, and IHC on tissues from a separate cohort of 23 patients with ESCC.
RESULTS:
IHC analysis showed that 63.0%, 41.8%, 49.0%, and 32.2% of 208 ESCC samples were positive for MMP1, MMP7, MMP9, and MMP13, respectively. MMPs were strongly expressed in the cytoplasm of cancer cells, especially in the invasive margin, and weakly expressed in stromal cells. No immunostaining was detected in non-cancerous esophageal mucosa. MMP9 expression was positively associated with poor tumor cell differentiation (p= 0.001), vessel permeation (p= 0.027), and lymph node metastasis (p= 0.027). MMP9 expression was a negative, independent predictor of disease-free survival time (Hazard ratio, 1.470; 95% CI, 1.105 
1.955; p= 0.008). The expression of MMP7 (median survival time: 23 months for MMP7 positive patients, >77 months for MMP7 negative patients; p= 0.001) and MMP13 (median survival time: 18 months for MMP13 positive patients, 39 months for MMP13 negative patients; p= 0.014) correlated negatively with disease-free survival in relatively early stage ESCC patients. Co-expression of MMP7, MMP9, and MMP13 in relatively early stage ESCC samples identified patients with a poor prognosis (13 months median survival time) compared to those lacking MMP7, MMP9, and MMP13 expression (58 months median survival time, p < 0.001).
CONCLUSIONS:
MMP9 expression is a negative, independent prognostic factor in ESCC and correlates with tumor cell differentiation, vessel permeation, and lymph node metastasis. MMP7, MMP9, and MMP13 may function in early stage ESCC, and their co-expression predicts poor outcome for relatively early stage ESCC patients.
