Diffuse glioma growth: a guerilla war

Abstract

In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent "supply lines" for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted ("search & destroy") tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies.

Fig. 1

Schematic representation of the growth pattern of a GBM (a), including the following secondary structures of Scherer: perivascular accumulation of tumor cells (example in area indicated by b; vessels in red, tumor cells in blue), perineuronal satellitosis (b; neurons in green), subpial growth of tumor cells (b), and intrafascicular growth in the corpus callosum (c). Mitotic tumor cells are depicted in black. Furthermore, in GBMs necrosis (dark grey area) surrounded by pseudopalisading tumor cells and adjacent florid/glomeruloid microvascular proliferation (d) are often present. Images b–d on the right represent the histology of these features: in basterisk indicates subpial growth, arrow indicates perineuronal satellitosis, arrowhead indicates perivascular accumulation of tumor cells; image c shows increased cellularity with diffuse infiltration of tumor cells in the relatively well preserved myelinated tracts of the corpus callosum; in image dasterisk indicates area of necrosis, arrow indicates peri-necrotic pseudopalisading tumor cells, arrowheads indicate glomeruloid microvascular proliferation [b, d: H&E staining, c: combined Luxol Fast Blue and H&E staining; original magnification ×200 (b, c) and ×100 (c)]

Fig. 2

Examples of MR images in two glioblastoma patients. In patient 1 (a), the T1-weighted image reveals bifrontal Gadolinium enhancement of a tumor that crosses the corpus callosum (arrowhead), resulting in a so called “butterfly glioma”. In the second patient (b–e), the T1-weighted images with (b, d) and without Gadolinium (c) suggest multiple, independent lesions. In the T2-weighted image (e), however, these bifrontal lesions appear to be interconnected via the corpus callosum (arrowhead), indicating that in this latter area disruption of the blood-brain barrier by infiltrating glioma cells is (still) limited. a, b: coronal plane; c–e: axial plane

Fig. 3

Schematic overview of factors and mechanisms important for diffuse infiltration of glioma cells in the neuropil. As discussed in the section on the molecular background of diffuse infiltrative glioma growth, the following aspects relevant for this growth pattern can be recognized: (a) an intracellular system that coordinates all incoming and outgoing signals via a complex set of pathways, (b) a locomotor apparatus in which the actin cytoskeleton plays a crucial role, (c) a scaffold (ECM, surface of cells/cell processes) on which the glioma cells can travel, (d) cell–ECM and/or cell–cell receptors that allow direct interaction with the ECM and cellular microenvironment, (e) tools to remove obstacles like ECM degrading proteases, (f) growth factors that guide the way, and (g) other stimulatory or permissive microenvironmental factors (e.g., chemokines derived from inflammatory cells). In this scheme, the protrusion on the right side of the cell represents the lamellipodium at the front