Background: Osteosarcoma is the most common form of primary malignant bone tumour with a high propensity for inducing lung metastases. The tumour microenvironment (cytokines, immune cells, vessels, etc) plays key a role in the tumour growth and in the metastatic process. Interleukin-34 (IL-34) is a cytokine recently discovered by its ability to bind to the M-CSF receptor, to induce the differentiation of monocytes into immunosuppressive M2 and to promote osteoclastogenesis. The aim of the present work was to study the involvement of IL-34 in the pathogenesis of osteosarcoma.
Methods: The expression (qRT-PCR, immunohistochemistry) of IL-34 was assessed in a cohort of human samples. 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. 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.
Results: Our results demonstrated that IL-34 was expressed by human osteosarcoma cells and was regulated by TNF-α, IL-1β. IL-34 overexpression was associated in vivo with the tumour progression (tumour growth, lung metastases), an increase of neo-angiogenesis and recruitment of M2-Tumour Associated Macrophages into the tumour mass. In vitro investigations showed that IL-34 stimulated endothelial cell proliferation, vascular cord formation and increased monocyte/CD34+ cell adhesion to activated HUVEC under physiological shear stress conditions.
Discussion: IL-34, like M-CSF, plays a part in the inflammatory process by the control of macrophage survival, migration and polarisation. IL-34 may maintain the cancer inflammatory process by facilitating the extravasation of mononuclear phagocytes and may orientate the polarisation of these cells toward an M2 phenotype. IL-34 is a new cytokine clearly involved in the pathogenesis of osteosarcoma and its targeting represents a promising therapeutic approach in oncology.
Disclosure: The authors declared no competing interests. This work was supported by the Ligue Nationale Contre le Cancer (Equipe LIGUE 2012) and by the CIMATH II program (Region des Pays de la Loire, France).