This poor prognosis can be attributed to an intrinsic tumor cell resistance for the genotoxic stress induced by irradiation or classical chemotherapy making use of DNA damaging agents, too as towards the diffuse invasion of single glioma cells in to the surrounding brain tissue, which can make efforts at curative surgical resection futile. Glioma cell invasiveness usually requires interaction with distinct elements with the extracellular matrix . The ECM of the brain parenchymal tissue predominantly has glycosaminoglycans. In addition to working with the host ECM, glioma cells apparently produce their own ECM, which include parts this kind of as laminin, collagen kinds I, III, and IV, tenascin, vitronectin, and a number of types of glycosaminoglycans.3,4 Cell surface receptors within the integrin superfamily perform a primary part in mediating cell ECM interactions. Integrins consist of two noncovalently connected type I transmembrane glycoprotein a and b subunits.
To date, 19 integrin a subunits and 8 integrin b subunits happen to be described, forming at least 25 diverse a b heterodimers. In addition to regulating cell cell and cell ECM adhesion, integrins bidirectionally transmit signals vital compound screening for cell survival, proliferation, differentiation, and motility. 5 For instance, ligand receptor interactions between ECM elements and integrins activate cytoplasmatic tyrosine kinases, such as focal adhesion kinase, and their downstream effectors. The contribution of specific integrins towards the malignant phenotype of a lot of kinds of tumor has become a serious spot of cancer study.six,seven Two av integrins recognizing vitronectin through an Arg Gly Asp binding webpage, avb3 and avb5, are expressed by glioma cells and by endothelial cells associated with new blood vessel formation in glioblastomas.
eight twelve These av integrins would be the main target of cilengitide , an RGD based cyclic peptide developed as an antiangiogenic drug. Depending on the idea that avb3 and avb5 are proangiogenic receptors, two av antagonists have entered clinical trials:13 SP600125 JNK inhibitor cilengitide and vitaxin, a humanized monoclonal antiavb3 antibody. In endothelial cells, blocking integrins avb3 and avb5 by RGD mimetics induces detachment from vitronectin coated surfaces and effects in a unique form of caspase dependent apoptosis called anoikis. 14,15 Conversely, integrin engagement by vitronectin will provide essential survival signals and protects glioma cells from apoptosis.16 There exists some proof for any role of resistance to anoikis in malignancy in the failure to undergo detachment induced cell death may well confer a selective benefit for tumor cells en route to invasion and metastasis.
Cilengitide is presently currently being evaluated being a novel therapeutic agent for recurrent and newly diagnosed glioblastoma.