Signaling Determinants of Glioma Cell Invasion

Abstract

Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

“…Glioblastoma invades surrounding tissue as single cells that often follow preferred anatomical routes including white matter tracts and the outside walls of blood vessels. Multiple studies have suggested a role for the Rac subclass of Rho GTPases in glioblastoma invasion [1][2][3] (reviewed in [4]). One limitation of these studies is that they were performed in glioblastoma cell lines that are not invasive in vivo in animal models.…”

The shaping of invasive glioma phenotype by the ubiquitin–proteasome system

“…Cbl-mediated ubiquitylation and subsequent degradation of the α 5 and α 3 subunits may allow limiting of integrin-mediated signaling toward cell migration (Schaefer et al, 2012). There are several studies showing overexpression of integrin subunits in gliomas, correlating with increased invasion and migration both in vitro and in vivo (Kwiatkowska & Symons, 2013).…”

“…RhoA, Rac1 and Cdc 42 are the best characterized of the Rho GTPases and their expression, particularly Rac1, is consistently elevated in glioma tumors, correlating with high tumor grade and dismal prognosis (Kwiatkowska & Symons, 2013). Emerging evidence implicates the tumor suppressor HACE1, a HECTdomain containing E3 ubiquitin ligase, in the targeting of Rac1 to proteasome-mediated degradation (Torrino et al, 2011).…”

“…Glioma cell invasion is a multistage process, involving detachment of invading cells from the primary tumor mass, adhesion to extracellular matrix (ECM), degradation of ECM, and cell motility and contractility (Onishi et al, 2011). All steps of this complex process involve autocrine and paracrine signaling through key proteins, most of which undergo several post-translational modifications (Kwiatkowska & Symons, 2013).…”

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

“…Почти все сигнальные пути, принимающие участие в эмбриональном развитии, регуляции пролиферации и миграции, так или иначе, задействованы в глиомагенезе. Большое количество исследований посвящено проонкогенным свойствам таких путей, как PI3K (фосфоинозитид-3-киназа)/Akt (протеинкиназа, относящаяся к семейству протеинкиназ B), MAPK (митоген-активируемая протеинкиназа)/ERK (киназа, регулируемая внеклеточным сигналом), PLC (фосфолипаза C)/PKC (протеинкиназа C), WNT (комбинация Wingless (бескрылый) и Int), Notch1 (трансмембранный рецепторный белок человека), mTOR (mammalian target of rapamycin, серин-треониновая протеинкиназа) и некоторым другим [1]. Относительно недавно появились исследования, показывающие возможное вовлечение в онкогенез вообще и в глиомагенез в частности сигнального пути HH [2,3].…”