Crosstalk between tumour cells and blood vessel pericytes is central to glioblastoma malignancy
Elisabetta M. Caspani*, Philip H. Crossley, Carolina Redondo-Garcia, Salvador Martinez.
Laboratory of Experimental Embryology, Institute of Neuroscience UMH-CSIC, Alicante, Spain.
Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Brain pericytes are contractile and function normally to regulate blood vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumour infiltration is not known. We found that GBM malignancy proceeds via specific and previously unknown interactions of tumour cells with brain pericytes of pre-existing blood vessels (co-option). Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions (flectopodia) to modify the normal contractile activity of pericytes, producing the co-option of the vessels and the expansion of the tumour margin. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favouring an innate immune response against the tumour. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumour-suppressor to tumour-promoter, indicating that GBM may harbour the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option, possibly in combination with anti-angiogenesis, which could lead to improved vascular targeting not only in glioblastoma but also for other cancers.