Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours

• Published in: Nature communications 2018-01, Vol.9 (1), p.355-19, Article 355
• Main Authors: Sidibe, Adama, Ropraz, Patricia, Jemelin, Stéphane, Emre, Yalin, Poittevin, Marine, Pocard, Marc, Bradfield, Paul F., Imhof, Beat A.
• Format: Article
• Language: English
• Subjects: 14/1; 14/63; 38/15; 38/77; 631/250/2503; 631/250/256/2515; 631/67/580; 64/60; 82/29; 96/21; 96/95; Adenocarcinoma - immunology; Angiogenesis; Animals; Breast Neoplasms - immunology; CD14 antigen; CD16 antigen; Cell Line, Tumor; Cell Movement - immunology; Chemokine CX3CL1 - immunology; Chemokines; Colorectal Neoplasms - immunology; Extravasation; GATA-3 protein; GATA3 Transcription Factor - immunology; Gelatinase B; Humanities and Social Sciences; Humans; Inflammation; Inflammation - immunology; Interferon-gamma - immunology; Matrix Metalloproteinase 9 - immunology; Mice, Inbred NOD; Mice, SCID; Monocytes; Monocytes - immunology; multidisciplinary; Neoplasm Transplantation; Neovascularization, Pathologic - immunology; Science; Science (multidisciplinary); Subpopulations; Tumor necrosis factor; Tumor Necrosis Factor-alpha - immunology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - immunology; Xenografts; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02610-0

Recruitment of circulating monocytes is critical for tumour angiogenesis. However, how human monocyte subpopulations extravasate to tumours is unclear. Here we show mechanisms of extravasation of human CD14 dim CD16 + patrolling and CD14 + CD16 + intermediate proangiogenic monocytes (HPMo), using human tumour xenograft models and live imaging of transmigration. IFNγ promotes an increase of the chemokine CX3CL1 on vessel lumen, imposing continuous crawling to HPMo and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNF by tumour cells enables HPMo extravasation by inducing GATA3-mediated repression of CX3CL1 expression. Recruited HPMo boosts angiogenesis by secreting MMP9 leading to release of matrix-bound VEGF-A, which amplifies the entry of more HPMo into tumours. Uncovering the extravasation cascade of HPMo sets the stage for future tumour therapies. Circulating myeloid cells can leave the vasculature to infiltrate tumours and are thought to contribute to tumour angiogenesis. Here the authors live image monocytes that migrate to xenograft tumours and map an extravasation cascade of human proangiogenic monocytes into the tumour.