Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

• Published in: Oncogene Vol. 32; no. 4; pp. 502 - 513
• Main Authors: Shchors, K, Nozawa, H, Xu, J, Rostker, F, Swigart-Brown, L, Evan, G, Hanahan, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2013; Nature Publishing Group
• Subjects: 631/45/607/1164; 692/420/755; 692/699/67/1459/1963; 692/699/67/322; Animals; Apoptosis; bcl-X Protein - genetics; bcl-X Protein - metabolism; Cathepsin B - genetics; Cathepsin B - metabolism; CD11b Antigen - genetics; CD11b Antigen - metabolism; Cell Biology; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cysteine - genetics; Cysteine - metabolism; Cytokines; Disease Models, Animal; Gene expression; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Human Genetics; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Internal Medicine; Leukocytes - drug effects; Leukocytes - metabolism; Leukocytes - pathology; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Medicine; Medicine & Public Health; Metalloenzymes; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neuroendocrine Tumors - blood supply; Neuroendocrine Tumors - enzymology; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Oncology; original-article; Pancreatic cancer; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proteases; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Tumors; Switzerland; invasion; cathepsin; tumor; metalloproteinase; Myc; interleukin-1β
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.60

Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1β-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumor-associated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.