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Glioma Invasiveness Signaling

Gliomas are the most common intracranial malignant tumors in humans. High grade gliomas in particular pose a unique challenge due to their propensity for proliferation and tissue invasion. The invasion of neoplastic cells into healthy brain tissue is a pathologic hallmark of gliomas and contributes to the failure of current therapeutic modalities (surgery, radiation and chemotherapy). Glioma cells have the ability to invade as single cells through the unique environment of the normal CNS. The brain parenchyma has a unique composition, mainly hyaluronan, and is devoid of rigid protein barriers composed of collagen, fibronectin and laminin...

Glioma Invasiveness Signaling

Pathway Summary

Gliomas are the most common intracranial malignant tumors in humans. High grade gliomas in particular pose a unique challenge due to their propensity for proliferation and tissue invasion. The invasion of neoplastic cells into healthy brain tissue is a pathologic hallmark of gliomas and contributes to the failure of current therapeutic modalities (surgery, radiation and chemotherapy). Glioma cells have the ability to invade as single cells through the unique environment of the normal CNS. The brain parenchyma has a unique composition, mainly hyaluronan, and is devoid of rigid protein barriers composed of collagen, fibronectin and laminin. Integrins and the hyaluronan receptors, CD44 and RHAMM (hyaluronan mediated motility receptor) are specific adhesion receptors active in glioma-ECM adhesion. Each integrin recognizes specific ligands which are either molecules of the EC, such as vitronectin, or other cell surface counter-receptors of the family of GPI-anchored membrane proteins that lack transmembrane and cytoplasmic domains, such as UPAR. These adhesion molecules, paired with their receptors play a major role in glioma cell-matrix interactions as neoplastic cells use these receptors to adhere to and migrate along the components of the brain ECM.Extracellular proteolytic enzymes are critical for the invasive properties of malignant neoplasms such as carcinomas and sarcomas which must break down rigid protein barriers in order to invade adjacent structures and metastasize. Glioma cells activate zymogens such as plasminogen and serine proteases such as UPA. In a mutually interdependent process, UPA converts plasminogen to the active serine-protease plasmin, while plasmin as a proteolytic enzyme enhances the ability of UPAR to localize the proteolytic activity of UPA (via UPA-UPAR Signaling) on the cell surface, which is extremely important for the invasive ability of tumor cells. Plasmin, a broad specificity protease degrades several ECM components such as fibronectin, laminin and collagen. UPA is another protease that triggers a proteolytic cascade that involves the activation of MMPs, which are responsible for ECM degradation. Plasmin also activates MMP1, MMP2, MMP3 and MMP9 by cleavage. These MMPs have a 'hemopexin' domain, which contains a binding site for TIMPs. Plasmin cleaves TIMPs to inhibit their function and promote tissue invasion. In human Glioblastoma Multiforme, MMP2 is expressed most intensely by glioma cells, whereas MMP9 is expressed by proliferating endothelial cells, suggesting that MMP2 is important in the invasive properties of neoplastic cells, while MMP9 may regulate angiogenic remodeling. Plasmin also activates PAR1 and latent growth factors to enhance cell invasion and proliferation, leading to glioma metastasis.More recently, a proteolytic cleavage of the extracellular portion of CD44 has been shown to occur in gliomas but not in normal brain. In several tumor cell lines, cleavage leads to the release of a soluble fragment and a membrane-bound cleavage product. Both fragments promote tumor cell migration, mostly detected in low-grade (WHO Grade-II) and high-grade (WHO Grades, III and IV) gliomas. This potential link between cellular anchoring to ECM by integrins and co-localization of protease receptors appear to have an important role in tumor invasiveness and progression.

Glioma Invasiveness Signaling Genes list

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