Cost of Migration: Invasion of Malignant Gliomas and Implications for Treatment

Abstract

Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

“…The median survival of patients with the most aggressive primary brain tumors, World Health Organization grade IV gliomas (glioblastoma multiforme) has reached only 14.6 months in a trial of concurrent chemotherapy and radiotherapy (Stupp et al, 2005). This high mortality is partially attributable to local invasion of tumor into normal brain, preventing complete surgical resection (Giese et al, 2003). Although relatively little is known about the molecular events underlying glioma invasion, one implicated protein is secreted protein, acidic and rich in cysteine (SPARC/osteonectin/BM-40).…”

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…This devastating disease is usually incurable and patients have a mean survival time of approximately 1 year after diagnosis. The highly invasive nature of glioblastoma makes surgical resection non-curative, and it has also been proposed that invading cells may be more resistant to radiation and chemotherapy (Giese et al, 2003). Glioblastoma cells invade as single cells; these cells travel along white matter tracts and also along blood vessel walls and through the subpial glial space, with some cells traveling long distances.…”

Reduced Glioma Infiltration in Src-deficient Mice

“…In glioblastoma the compromise of the BBB is associated with increased tumor growth and infiltration [9][10][11][12]. Glioma cells are distinct from other tumor cell types in that they rarely metastasize outside of the brain, however, they aggressively invade the surrounding normal brain parenchyma [13][14][15][16]. The migration of glioma cells away from the primary tumor mass prevents the complete surgical removal of tumor cells and represents a significant challenge in the treatment of brain tumors [17][18][19][20][21][22].…”