title: An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment.
abstract: BACKGROUND
  Breast to bone metastases frequently induce a "vicious cycle" in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment.
  
  
  RESULTS
  To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (μCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays).
  
  
  CONCLUSIONS
  Collectively, these studies identify a novel "mini-vicious cycle" between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFβ would be beneficial for the treatment of bone metastases.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thiolloy
authors.forename: James R
authors.initials: JR
authors.lastname: Edwards
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Conor C
authors.initials: CC
authors.lastname: Lynch
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000235:genetics; D002522:Chlorocebus aethiops; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010006:Osteoblasts / Q000201:enzymology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: D016212:Transforming Growth Factor beta; D020778:Matrix Metalloproteinase 2