Glioma cell migration and invasion as potential target for novel treatment strategies

Abstract

Diffuse human gliomas constitute a group of most treatment-refractory tumors even if maximum treatment strategies including neurosurgical resection followed by combined radio-/chemotherapy are applied. In contrast to most other neoplasms, diffusely infiltrating gliomas invade the brain along pre-existing structures such as axonal tracts and perivascular spaces. Even in cases of early diagnosis single or small clusters of glioma cells are already encountered far away from the main tumor bulk. Complex interactions between glioma cells and the surrounding extracellular matrix and considerable changes in the cytoskeletal apparatus are prerequisites for the cellular movement of glioma cells through the brain thereby escaping from most current treatments. This review provides an overview about classical and current concepts of glioma cell migration/invasion and promising preclinical treatment approaches.

Glioma infiltration and extracellular matrix: key players and modulators

“…Eph is also a negative regulator of the Ras/MAPK pathway, which exerts anti‐mitogenic functions (Miao et al, ; Parri et al, ). Therefore, ephrins might be involved in the “Go or Grow” behavior of gliomas (Nakada et al, ; Naumann et al, ; Wang et al, ). In turn, the Slit/Robo pair functions in axon guidance and branching‐point regulation in the nervous system (Andrews, Barber, & Parnavelas, ; Devine & Key, ; Oliva et al, ).…”

“…However, the road from basic to translational research, and from preclinical models to clinical trials, is long. The methods for drug delivery across the blood‐brain barrier still necessitate considerable improvement (Balça‐Silva et al, ; Kahn et al, ; Naumann et al, ).…”

“…There is usually no clear boundary between the tumor and the surrounding brain parenchyma, which complicates complete surgical resection, and consequently, within months after surgery, recurrent neoplasms are triggered in the proximity of the resection zone (Pan, Ferguson, & Lam, ). Individual or small clusters of tumor cells (“guerrilla cells”) can migrate centimeters from the gross tumor into the surrounding healthy brain tissue (Claes, Idema, & Wesseling, ; Naumann et al ).…”

“…Tumor cells invade the brain parenchyma following preferential routes (Winkler et al ). Initially observed by Scherer (1938), so‐called “secondary structures”, they can follow white matter tracts (intrafascicular spread), grow around neurons (perineuronal satellitosis), spread along vessels (perivascular satellitosis), or extend below the pial margin (subpial spread) (Holland et al ; Louis ; Naumann et al ; Onishi, Ichikawa, Kurozumi, & Date, ). This behavior differs from the spreading of metastases from peripheral tumors in the brain, which are mainly perivascular (Steeg, Camphausen, & Smith, ), and suggests that glioma cells have a potential for invading different regions, or a tropism for particular sites, or both.…”

“…Another important characteristic influencing glioma cell migration is the ECM microenvironmental composition (including other cell types, see Charles, Holland, Gilbertson, Glass, and Kettenmann, for review) and its mechanical force, which is determined by ECM components (Vargová et al ). The more rigid the ECM, the more glioma cells migrate, whereas less ECM rigidity produces the opposite effect (Naumann et al ; Ulrich, de Juan Pardo, & Kumar, ).…”