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

Int J Cancer. 2015 Jul 1;137(1):73-85. doi: 10.1002/ijc.29376. Epub 2014 Dec 13.

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.

Keywords: M-CSF; angiogenesis; cell adhesion; endothelial cells; interleukin-34; osteosarcoma; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / blood supply
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • In Vitro Techniques
  • Interleukin-1beta / metabolism
  • Interleukins / metabolism*
  • Interleukins / pharmacology
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Macrophages / metabolism*
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / metabolism*
  • Osteosarcoma / blood supply
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-1beta
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • interleukin-34, human
  • interleukin-34, mouse