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      Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.

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          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.

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          Author and article information

          Journal
          Int. J. Cancer
          International journal of cancer
          1097-0215
          0020-7136
          Jul 1 2015
          : 137
          : 1
          Affiliations
          [1 ] 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.
          Article
          10.1002/ijc.29376
          25471534
          a5df64f2-f9da-462e-97c6-ebefb718e940
          © 2014 UICC.
          History

          M-CSF,angiogenesis,cell adhesion,endothelial cells,interleukin-34,osteosarcoma,tumor-associated macrophages

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