Bone Abstracts

Tumour growth and metastatic dissemination are significantly reduced in mice bearing an inactivation of the macrophage-colony stimulating factor (M-CSF) gene, due to angiogenesis impairment. In fact, M-CSF directly induces angiogenesis by increasing vascular endothelial growth factor (VEGF) production. Interleukin 34 (IL34), the M-CSF’s ‘twin’ cytokine, was characterized as a new cytokine promoting the growth, survival and differentiation of the myeloid lineage. Consistent with these findings, this work studied the involvement of IL34 in in vitro and in vivo angiogenesis.

IL34 activities on endothelial cells were first analyzed in vitro using endothelial progenitors or differentiated endothelial cells and by studying cell proliferation and the differentiation into vascular cord on Matrigel. Furthermore, the adherence of hematopoietic stem cells to endothelial cells under physiological conditions of blood flow and the intracellular signaling pathways by western blot were investigated. The effects of IL34 on angiogenesis were also studied in vivo, using two murine models: subcutaneous implants of Matrigel plugs containing fibroblast growth factor (FGF2)±IL34 (authorization n °C75.06.02) and paratibial inoculation of human osteosarcoma cells overexpressing IL34 in nude mice (authorization no 1280.01).

In association with the FGF2, IL34 enhanced the vascular tube formation in vitro as demonstrated by their significant higher size and number. Western blot analyses revealed that IL34 effects were partially mediated by the MAPK pathway. In addition, IL34 increased adherence of both CD34⁺ hematopoietic stem cells and CD14⁺ monocytes on activated endothelium. The in vitro pro-angiogenic effect of IL34 was confirmed in vivo. Results showed that IL34 induced a neovascularisation of Matrigel plugs in mice and IL34 promoted tumour angiogenesis in osteosarcoma.

This work demonstrates that similar to M-CSF, IL34 promotes angiogenesis, inducing vascularisation both in vitro and in vivo. By promoting new vessel formation and extravasation of cells from the immune system, IL34 could play a key role in tumour developmet.