title: Glioblastoma: a pathogenic crosstalk between tumor cells and pericytes.
abstract: Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate 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 tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co-option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co-option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion-hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor-suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and modification of pre-existing blood vessels), possibly in combination with anti-angiogenesis (blocking new vessel formation), which could lead to improved vascular targeting not only in Glioblastoma but also for other cancers.
authors.affiliation: Laboratory of Experimental Embryology, Institute of Neuroscience, University Miguel Hernández-Spanish National Research Council, Alicante, Spain.
authors.forename: Elisabetta M
authors.initials: EM
authors.lastname: Caspani
authors.affiliation: Laboratory of Experimental Embryology, Institute of Neuroscience, University Miguel Hernández-Spanish National Research Council, Alicante, Spain.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Crossley
authors.affiliation: Laboratory of Experimental Embryology, Institute of Neuroscience, University Miguel Hernández-Spanish National Research Council, Alicante, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Redondo-Garcia
authors.affiliation: Laboratory of Experimental Embryology, Institute of Neuroscience, University Miguel Hernández-Spanish National Research Council, Alicante, Spain; Centro de Investigación Biosanitaria en Red de Salud Mental and Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Martinez
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology*; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000473:pathology; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D020286:Pericytes / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D020764:cdc42 GTP-Binding Protein