title: Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.
abstract: Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases.
authors.affiliation: INSERM, UMR 957, Equipe LIGUE Nationale Contre le Cancer 2012, Nantes, 44035, France; Université de Nantes, Nantes atlantique universités, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, Nantes, France.
authors.forename: Aude I
authors.initials: AI
authors.lastname: Ségaliny
authors.forename: Amel
authors.initials: A
authors.lastname: Mohamadi
authors.forename: Blandine
authors.initials: B
authors.lastname: Dizier
authors.forename: Anna
authors.initials: A
authors.lastname: Lokajczyk
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: Rachel
authors.initials: R
authors.lastname: Lanel
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Catherine
authors.initials: C
authors.lastname: Boisson-Vidal
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012516:Osteosarcoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C529076:IL34 protein, human; D053583:Interleukin-1beta; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; C552364:interleukin-34, mouse
keywords: M-CSF; angiogenesis; cell adhesion; endothelial cells; interleukin-34; osteosarcoma; tumor-associated macrophages