Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future

Abstract

Glioma is the most common malignant intracranial tumor and exhibits diffuse metastasis and a high recurrence rate. The invasive property of glioma results from cell detachment. Anoikis is a special form of apoptosis that is activated upon cell detachment. Resistance to anoikis has proven to be a protumor factor. Therefore, it is suggested that anoikis resistance commonly occurs in glioma and promotes diffuse invasion. Several factors, such as integrin, E-cadherin, EGFR, IGFR, Trk, TGF-β, the Hippo pathway, NF-κB, eEF-2 kinase, MOB2, hypoxia, acidosis, ROS, Hsp and protective autophagy, have been shown to induce anoikis resistance in glioma. In our present review, we aim to summarize the underlying mechanism of resistance and the therapeutic potential of these molecules.

Keywords: anoikis resistance; apoptosis; glioma; molecular pathways; therapeutic targets.

Figure 1

Adhesion molecules involved in anoikis resistance mechanism of glioma. Overexpression of Integrins and loss of E-cadherin in glioma disrupt the initiating signal of anoikis. Upon cell detachment, overexpressed integrins still activate FAK, which in turn activates signalings such as TGFβ, EGFR, IGFR, PI3k/AKT pathway. Then through p53 inhibition, NF-κB activation or other mediators, these pathways lead to anoikis. α2 integrin induced FAK activation also promotes the release of β-catenin from the E-cadherin/β-catenin complex. Along with the loss of E-cadherin and the help of Wnt, this increased the cytoplasmic level of β-catenin. β-catenin thereby promote anoikis resistance through EMT, TRAIL resistance and upregulation of invasion-related protein ALDH1A1 and peroxiredoxin 4. Aside from β-catenin, loss of E-cadherin also downregulates tumor suppressor PTEN and therefore maintains NF-κB activation.

Figure 2

Signaling involved in anoikis resistance mechanism of glioma. EGFR, IGFR, TrkB, TGF-β and the hippo pathway are signaling pathways involved in the anoikis resistance of glioma. NF-κB is a common mediator in these pathways, for it regulates the expression of several anoikis-related proteins. Similarly, the hippo pathway promotes anoikis resistance through its transcription factor TAZ. Apart from transcription factors, EGFR also represses Bim expression through Erk/MAPK pathway. Meanwhile TrkB upregulates Bcl-xl and downregulates FasL and Bim through PI3K/AKT pathway. The signaling of TrkB and TGF-β triggers EMT as well, which promotes cell detachment and anoikis resistance. And there are also EGFR signaling triggered by the hippo pathway, and β-catenin promoted by TGF-β, indicating the connection between adhesion molecules and signaling pathways goes both way.