Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth

• DOI: 10.15252/emmm.201607445
• Publication Date: 2017-10-17T00:40:30Z
• Authors: Thomas Mathivet; Claire Bouleti; Matthias Van Woensel; Fabio Stanchi; Tina Verschuere; Li‐Kun Phng; Joost Dejaegher; Marly Balcer; Ken Matsumoto; Petya B Georgieva; Jochen Belmans; Raf Sciot; Christian Stockmann; Massimiliano Mazzone; Steven De Vleesch...; Holger Gerhardt
• Keywords: Male; Medicine (General); Mice, Transgenic; QH426-470; Mice; R5-920; glioma; Cell Line, Tumor; Genetics; Animals; Humans; Antineoplastic Agents, Alkylating; Research Articles; glioma; live imaging; myeloid cells; VEGF; vessel dysmorphia; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Blood Vessels; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Disease Models, Animal; Female; Glioma; Humans; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; Phenotype; Proto-Oncogene Proteins c-sis; Temozolomide; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic; Brain Neoplasms; Macrophage Colony-Stimulating Factor; Macrophages; Antibodies, Monoclonal; live imaging; Glioma; Proto-Oncogene Proteins c-sis; VEGF; 3. Good health; Dacarbazine; Mice, Inbred C57BL; Disease Models, Animal; Phenotype; vessel dysmorphia; Cardiovascular and Metabolic Diseases; myeloid cells; Blood Vessels; Female

Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro-inflammatory M1-like macrophages in the early stages, followed by in situ repolarization to M2-like macrophages, which produced VEGF-A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti-CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences.