Invasion Precedes Tumor Mass Formation in a Malignant Brain Tumor Model of Genetically Modified Neural Stem Cells

Abstract

Invasiveness, cellular atypia, and proliferation are hallmarks of malignant gliomas. To effectively target each of these characteristics, it is important to understand their sequence during tumorigenesis. However, because most gliomas are diagnosed at an advanced stage, the chronology of gliomagenesis milestones is not well understood. The aim of the present study was to determine the onset of these characteristics during tumor development. Brain tumor-initiating cells (BTICs) were established by overexpressing H-Ras(V12) in normal neural stem/progenitor cells isolated from the subventricular zone of adult mice harboring a homozygous deletion of the Ink4a/Arf locus. High-grade malignant brain tumors were then created by orthotopic implantation of 10(5) BTICs into the forebrain of 6-week-old wild-type mice. Micewere killed every week for 5 weeks, and tumors were assessed for cellular atypia, proliferation, hemorrhage, necrosis, and invasion. All mice developed highly invasive, hypervascular glioblastoma-like tumors. A 100% penetrance rate and a 4-week median survival were achieved. Tumor cell migration along fiber tracts started within days after implantation and was followed by perivascular infiltration of tumor cells with marked recruitment of reactive host cells. Next, cellular atypia became prominent. Finally, mass proliferation and necrosis were observed in the last stage of the disease. Video monitoring of BTICs in live brain slices confirmed the early onset of migration, as well as the main cell migration patterns. Our results showed that perivascular and intraparenchymal tumor cell migration precede tumor mass formation in the adult brain, suggesting the need for an early and sustained anti-invasion therapy.

Overcoming therapeutic resistance in glioblastoma: the way forward

“…A high capacity for dissemination is one of the defining features of gliomas (45,46), and this invasion process renders tumors more complex. Invading tumor cells escape at the periphery of the tumor mass and diffusely infiltrate the normal brain parenchyma (47).…”

Constitutive Activation of Myosin-Dependent Contractility Sensitizes Glioma Tumor-Initiating Cells to Mechanical Inputs and Reduces Tissue Invasion

“…In addition to repopulating tumors, TICs directly participate in the invasion process in vivo . For example, both primary GBM TICs (10) and H-Ras-transduced neural stem cells (11) invade brain tissue prior to forming the tumor mass. Moreover, hypoxia, which is often associated with the TIC niche (12) and the necrotic tumor core in which GBM TICs may reside, can enhance migration of GBM tumor cells through induction of the family of hypoxia-inducible factors (13,14).…”

On the control of cell migration and proliferation in glioblastoma

“…The current model also doesn't take into account the role of some important players of the microenvironment that may affect the migration and growth of glioblastoma which include stromal cells such as fibroblasts, immune cells, and endothelial cells as well as growth factors and cytokines secreted by these cells. In a recent study [19], it was shown that intraparenchymal and perivascular glioma cell migration precede creation of tumor mass in the adult brain, suggesting the need for anti-invasion therapy for highly invasive glioblastoma. Our approach of optimal control of the core miR-451-AMPK control system may shed light on the development of a tool to deal with strategies in anti-invasion therapy.…”