Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling

Primary brain tumors are among the most refractory of malignancies. Their most aggressive form, glioblastoma multiform (GBM, WHO grade IV), is also the most common and lethal subtype.1 Although multimodal therapies have been developed, the overall median survival of GBM patients hardly reaches 15 months from the time of diagnosis.2 This poor survival rate is the consequence of tumor recurrence that systematically occurs despite classical therapeutic strategies. Trying to understand the origin of GBM relapses seems mandatory, in this context, for a better understanding of the tumor's biology and improving the patients' quality of life. The infiltrative patterns of GBM make tumor cells hard to target. Furthermore, recent studies using orthotopic xenografts have demonstrated that GBM cells are able to escape the tumor mass and specifically invade the subventricular zones (SVZs) of the adult brain.3,4 In that environment, GBM cells were first shown to be highly tumorigenic and were later characterized as glioblastoma stem cells (GSCs). The SVZ is known to be the major source of neural stem cells and progenitors in adults and functions as a supportive niche promoting self-renewal and inhibits differentiation.5,6 This “seed-and-soil” relationship has also been adapted to cancer stem cell research because GSCs also rely on a specific environment or niche to maintain their stem cell properties and their ability to drive tumor growth.7,8 In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-oriented invasion of the SVZ. CXCR4 is known to be expressed by highly malignant gliomas,9,10 be involved in tumor cell proliferation,11 and be associated with a poor survival.12 Recent studies have shown that CXCL12 and CXCR4 enhance tumorigenesis through increased proliferation of tumor cells13 and that CXCL12 boosts the release of vascular endothelial growth factor (VEGF) from GSC, leading to tumor growth-induced angiogenesis.14 When taken altogether, those facts led to investigating the eventual role of the CXCR4 signaling in the specific invasion of the SVZ by human GSC. Counteracting with the invasion abilities of GSC would make those cells more easily targeted by classical therapeutic strategies and would definitely improve the survival rate for GBM patients.