Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer

Abstract

Purpose: To enable the design of improved inhibitors of matrix metalloproteinases (MMPs) for the treatment of pancreatic cancer, the expression profiles of a range of MMPs and tissue inhibitors of MMPs (TIMPs) were determined.Experimental Design: Nine MMPs (MMPs 1-3, 7-9, 11, 12, and 14) and three TIMPs (TIMPs 1-3) were examined in up to 75 pancreatic ductal adenocarcinomas and 10 normal pancreata by immunohistochemistry. Eighteen additional pancreatic ductal adenocarcinomas and an additional eight normal pancreata were also analyzed by real-time reverse transcription-PCR and additionally for MMP-15.Results: There was increased expression by immunohistochemistry for MMPs 7, 8, 9, and 11 and TIMP-3 in pancreatic cancer compared with normal pancreas (P < 0.0001, 0.04, 0.0009, 0.005, and 0.0001, respectively). Real-time reverse transcription-PCR showed a significant increase in mRNA levels for MMP-11 in tumor tissue compared with normal pancreatic tissue (P ‫؍‬ 0.0005) and also significantly reduced levels of MMP-15 (P ‫؍‬ 0.0026). Univariate analysis revealed that survival was reduced by lymph node involvement (P ‫؍‬ 0.0007) and increased expression of MMP-7 (P ‫؍‬ 0.005) and (for the first time) MMP-11 (P ‫؍‬ 0.02) but not reduced by tumor grade, tumor diameter, positive resection margins, adjuvant treatment, or expression of the remaining MMPs and TIMPs. On multivariate analysis, only MMP-7 predicted shortened survival (P < 0.05); however, increased MMP-11 expression was strongly associated with lymph node involvement (P ‫؍‬ 0.0073). Conclusions:We propose that the principle specificity for effective inhibitors of MMPs in pancreatic cancer should be for MMP-7 with secondary specificity against MMP-11. Moreover, these studies indicate that MMP-7 expression is a powerful independent prognostic indicator and potentially of considerable clinical value.

BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

“…The critical pathologic turning point in cancer is the initiation of local invasion leading to the dissemination of tumor cells. Invasion is an active translocation of neoplastic cells across tissue boundaries through host cellular and extracellular matrix barriers (Westermarck and Kahari, 1999;Jones et al, 2004). MMP2/9, a tumor invasion signaling protein, was significantly increased in BI-1 cells (Figure 4d).…”

“…Furthermore, acidic media (pH 5.4-6.5) increases MMP activity in cell culture (Rofstad et al, 2006). Overall, the expression of these enzymes correlates with tumor aggressiveness (Westermarck and Kahari, 1999;Jones et al, 2004). Despite several studies of BI-1 in cancer (Grzmil et al, 2003(Grzmil et al, , 2006Harima et al, 2004), its role is still unclear.…”

Identification of Pro-MMP-7 as a Serum Marker for Renal Cell Carcinoma by Use of Proteomic Analysis

“…Recent data suggest a role for MMPs in a number of renal pathophysiologies (35 ). Many studies have shown that the overexpression of MMP-7 in several cancers is associated with advanced clinicopathological stages and unfavorable prognosis (21,36 ). Increased expression of MMP-7 has been observed in high-grade RCC tumors (24 ).…”

The Extracellular Matrix in Digestive Cancer

“…MMP-2, -7 and -9 levels in blood, pancreatic juice and tissue have been used to distinguish malignant from benign pancreatic pathologies, as well as for prognostication [83][84][85][86]. In CRC, levels of MMP-1, -7, and -13 within the malignant epithelium and stroma have been associated with decreased survival [87].…”