title: Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP/Endo180.
abstract: In osteosarcoma, a primary mesenchymal bone cancer occurring predominantly in younger patients, invasive tumour growth leads to extensive bone destruction. This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, uPARAP/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, MT1-MMP. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted NCTC-2472 sarcoma cells in mice. When analysed in vitro, these cells were capable of degrading the protein component of surface-labelled bone slices in a process dependent on MMP activity and uPARAP/Endo180. Systemic treatment of the sarcoma-inoculated mice with a mouse monoclonal antibody that blocks murine uPARAP/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell-resident uPARAP/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast-mediated attack on bone in the early tumour stage. This points to uPARAP/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy.
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Engelholm
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Melander
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hald
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Persson
authors.affiliation: Proteases and Tissue Remodelling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Madsen
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Jürgensen
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Kristina
authors.initials: K
authors.lastname: Johansson
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Kirstine S
authors.initials: KS
authors.lastname: Nørregaard
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Signe Z
authors.initials: SZ
authors.lastname: Ingvarsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
authors.affiliation: Department of Oncology/Orthopaedics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Clement S
authors.initials: CS
authors.lastname: Trovik
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.|Department of Clinical Medicine, Gade Laboratory of Pathology, University of Bergen, Norway.
authors.forename: Ole D
authors.initials: OD
authors.lastname: Laerum
authors.affiliation: Proteases and Tissue Remodelling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Eide
authors.affiliation: Finsen Laboratory/Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Behrendt
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012516:Osteosarcoma / Q000473:pathology*; D011975:Receptors, Mitogen / Q000378:metabolism*
chemical_list: C408294:Endo180; D011975:Receptors, Mitogen
keywords: bone cancer; collagen; matrix degradation; matrix metalloprotease; osteosarcoma; uPARAP/Endo180