Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control.

The matrix metalloproteinases (MMPs) are a family of enzymes involved in degradation of extracellular matrix components such as collagen, gelatin, and fibronectin. 1 At least 17 of these enzymes are known, and secreted or membrane-bound types have been described. Secreted MMPs appear as proenzymes that require cleavage of a specific peptide for their activation. MMPs exist in equilibrium with physiologic tissue inhibitors of metalloproteinases (TIMPs), and their interaction is largely responsible for modification of the extracellular environment. 2 The proteolytic activity of MMPs is critically involved in embryonic development, normal tissue remodeling, growth, and wound healing. Disruption of the equilibrium between MMPs and TIMPs has been linked to pathologic conditions ranging from rheumatoid arthritis to cancer. 3,4 Cancer invasion and metastasis are two processes that MMPs, either from malignant cells or induced fibroblasts, are thought to mediate. The major component of the basement membrane is type IV collagen, 5 and studies have shown that basement membrane disruption is associated with metastases and poor prognosis in breast and colon carcinoma. 6,7 Type IV collagen serves as a substrate for MMP2 and MMP9, and reports have correlated overexpression of these enzymes in neoplastic epithelium with invasion and metastasis. 1 Examination of other MMPs (MMP3, MMP11) in breast and head and neck cancer has yielded similar results. 8,9 Conversely, some investigators have demonstrated downregulation of TIMPs in neoplastic tissues, consistent with a shift in balance toward proteolysis in cancer. 10 Pancreatic cancer is characterized by extensive local invasion, intense desmoplastic reaction, and early metastases to regional lymph nodes or other sites (peritoneum, liver, lungs). 11 To justify these features, investigators have looked at the participation of MMPs in the pathology of these tumors. Immunohistochemical studies have demonstrated overexpression of active MMPs by neoplastic epithelium, particularly MMP2 and MMP9, 12,13 but also MMP7 and MMP11, 14 and reduction in TIMP1 expression in tumors with lymph node metastases. 15 Also, several pancreatic cancer cell lines have been shown to produce MMP2, MMP9, and MMP11 in vitro. 16–18 In recent years, several potent MMP inhibitors have been developed (BB-94, BB-2516). Animal models of mammary, colorectal, and ovarian carcinoma have documented the efficacy of these compounds in decreasing the death rate, tumor growth, and metastasis. 19–21 Using an orthotopic model of pancreatic cancer in mice, an MMP inhibitor, BB-94, has also been shown to improve survival and reduce primary tumor growth. 22 However, no animal studies have evaluated the effect of these compounds on pancreatic metastatic disease. In this study, we investigated the role of MMPs in an animal model of pancreatic cancer metastases. The model is based on recreation of liver metastases by injection of cancer cells into the spleen of nude mice. Our experiments tested whether MMP inhibition can have therapeutic effects on such disease.