title: Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis.
abstract: 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.
authors.affiliation: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland. ksenya.shchors@epfl.ch
authors.forename: K
authors.initials: K
authors.lastname: Shchors
authors.forename: H
authors.initials: H
authors.lastname: Nozawa
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: F
authors.initials: F
authors.lastname: Rostker
authors.forename: L
authors.initials: L
authors.lastname: Swigart-Brown
authors.forename: G
authors.initials: G
authors.lastname: Evan
authors.forename: D
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; D039481:CD11b Antigen; D020690:GTPase-Activating Proteins; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C490620:Ralbp1 protein, mouse; D051020:bcl-X Protein; D002401:Cathepsin B; D020780:Matrix Metalloproteinase 9; D003545:Cysteine