Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy

Abstract

Integrins are a large family of transmembrane adhesion receptors, which play a key role in interactions of a cell with the surrounding stroma. Integrins are comprised of non-covalently linked α and β chains, which form heterodimeric receptor complexes. The signals from integrin receptors are combined with those originating from growth factor receptors and participate in orchestrating morphological changes of cells, organization of the cytoskeleton, stimulation of cell proliferation and rescuing cells from programmed cell death induced by extracellular matrix (ECM) detachment. Upon binding to specific ligands or ECM components, integrin dimers activate downstream signaling pathways, including focal adhesion kinase, phosphoinositide-3-kinase (PI3K) and AKT kinases, which regulate migration, invasion, proliferation and survival. Expression of specific integrins is upregulated in both tumor cells and stromal cells in a tumor microenvironment. Therefore, integrins became an attractive therapeutic target for many cancers, including the most common primary brain tumors—gliomas. In this review we provide an overview of the involvement of integrin signaling in glioma pathogenesis, formation of the tumor niche and brain tissue infiltration. We will summarize up-to-date therapeutic strategies for gliomas focused on interference with integrin ligand-receptor signaling.

EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

“…The EGFR-independent pathway may maintain stimulation of the PI3K-AKT signaling pathway. We and others previously reported an impact of integrin or JAK signaling in glioma intracellular signaling 55,56 , and other receptor tyrosine kinases 57-60 may be involved. Clark et al 57 demonstrated a compensatory activation of EGFRrelated family members (ERBB2 and ERBB3) that enabled glioma stem cell proliferation, suggesting that simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.…”

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

“…The hypoxia-induced SRC pathway entirely influences the process described above, finally resulting in fostered invasiveness. In fact, it primarily involves EGFR-vIII and integrin β3 interaction, the recruitment of αvβ3 integrin on GBM cell membranes and the creation of focal adhesion complexes by FAK activation [ 62 ]. Finally, the EGFRvIII / integrin β3 / FAK / SRC axis leads to the activation of the intracellular signaling pathway ERK1/2, MAPK, AKT, and STAT3, which determines the upregulation of MMP-2 and MMP-9, further promoting cell invasion [ 63 ].…”

Involvement of Integrin-Activating Peptides Derived from Tenascin-C in Cancer Aggression and New Anticancer Strategy Using the Fibronectin-Derived Integrin-Inactivating Peptide

“…In addition, it also augments TMZ-induced cytotoxicity in the rat glioma 9L cells subcutaneous mouse xenograft model. It has been reported that the expression levels of α5-integrin increase with glioma grade [ 108 , 109 , 110 , 111 ] and correlate with poor prognosis in high-grade glioma/GBM [ 108 ]. In particular, integrin α5β1 is expressed at significantly higher levels in mesenchymal GBM, which is the most aggressive subtype of GBM [ 110 ].…”

“…To date, many synthetic peptides based on FN bioactive sequences, which are mostly derived from the RGD sequence within the 10th FN type III domains or PHSRN sequence within the 9th FN type III domains, have been widely attempted in clinical studies as antitumor agents [ 109 ]. Cilengitide (EMD 121974), a cyclic RGD pentapeptide, is a selective integrin antagonist for αvβ3 and αvβ5, and acts in an antiangiogenic manner [ 109 ].…”