title: TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis.
abstract: Cellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralized type I collagen matrix. Once metastatic niches establish in bone, the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognized function of Endo180 was suppressed in osteoblasts following heterotypic direct cell-cell contact in co-culture with prostate tumour cells. Reciprocal Endo180 up-regulation in osteolytic prostate tumour cells (PC3 and DU145) followed their direct contact with osteoblasts and promoted de novo collagen internalization, which is a previously characterized function of the constitutively recycling Endo180 receptor. The osteoblastic suppression and tumour cell-associated enhancement of Endo180 expression were equally sustained in these direct co-cultures. These findings are the first to demonstrate that increased tumour cell participation in collagen degradation and decreased collagen formation by osteoblasts in the osteolytic microenvironment are linked to the divergent regulation of a collagen-binding receptor. Immunohistochemical analysis of core biopsies from bone metastasis revealed higher levels of Endo180 expression in tumour cell foci than cells in the surrounding stroma. Additional experiments in prostate cell-osteoblast co-cultures indicate that divergent regulation of Endo180 is the result of dysregulated TGFβ1 signalling. The findings of this study provide a rationale for targeting collagen remodelling by Endo180 in bone metastases and other collagen matrix pathologies.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Caley
authors.forename: Giolanta
authors.initials: G
authors.lastname: Kogianni
authors.forename: Adam
authors.initials: A
authors.lastname: Adamarek
authors.forename: Julian H
authors.initials: JH
authors.lastname: Gronau
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodriguez-Teja
authors.forename: Ana-Violeta
authors.initials: AV
authors.lastname: Fonseca
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.forename: Ann
authors.initials: A
authors.lastname: Sandison
authors.forename: Johng S
authors.initials: JS
authors.lastname: Rhim
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pchejetski
authors.forename: Carlo
authors.initials: C
authors.lastname: Palmieri
authors.forename: Justin P
authors.initials: JP
authors.lastname: Cobb
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Justin
authors.initials: J
authors.lastname: Sturge
mesh_terms: D019898:Autocrine Communication; D001706:Biopsy; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D024042:Collagen Type I / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D024042:Collagen Type I; C408294:Endo180; C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I