β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas

Abstract

Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of β-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active—but dysregulated—in astrocytomas. Inhibition of β-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.

Glucocorticoid Receptor β Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation

“…Mechanically, the interplay between GRβ and β-catenin was demonstrated to be a necessary component of astrocyte reactivity through sustained Wnt/β-catenin/TCF signaling in its dominant-negative effect on GRα mediated trans-repression by a GSK-3β-independent manner. Several reports have shown that aberrant activation of Wnt/β-catenin/TCF signaling is an important contributing factor in glioma development (Ref) [11][12][13]. Our previous finding that GRβ is predominately distributed in the nucleus and contributes to glioma pathogenesis raises the consideration that the cross-talk between GRβ and β-catenin/TCF signaling involves in the progression of glioma [9].…”

The Role of Astrocytes in Tumor Growth and Progression

“…The genes activated by β-catenin signaling are regulatory and often lead to proliferation and migration [11,163]. Interestingly, Yang et al (2012) found this contact initiated activation of astrocytes to parallel what occurs in the transformation of astrocytomas, further coupling the process of astrocyte activation and tumor progression [162].…”

“…Therefore, mechanical disruption occurs when processes such as migration and/or proliferation of surrounding cells is initiated. Such mechanical signals could come potentially emerge from tumor cells, subsequently triggering astrocyte activation via disruption of these cell surface complexes such as cadherins and β-catenin [161,162]. The genes activated by β-catenin signaling are regulatory and often lead to proliferation and migration [11,163].…”

Receptor protein tyrosine phosphatases and cancer

“…21 The previous observations hinged on the fact that PTN was able to induce dimerization of PTPRZ and that this change of oligomeric state inactivated the intracellular phosphatase activity. A model implicating the dimerization/inhibition of RPTPs has been favored since the crystal structure of a dimeric form of the D1 domain of PTPRA was determined and showed that a helixturn-helix motif (called a wedge) of one protomer was inserted into the active site of a second protomer and blocked its active site.…”

“…18 Critically, alterations in the assembly of cadherin-catenin adhesion complexes are linked to the disassociation of adherent epithelial cells and their subsequent migration, a process that can be part of the normal aspect of tissue development, but is also a hallmark of cancer growth and metastasis 18,19 (the effects of E-and N-cadherin in cancer progression and epithelial-mesenchymal transitions are discussed by LeBras, Taubenslag and Andl in this issue). These transitions can be brought about by enhanced tyrosine phosphorylation of β-catenin, 20,21 which explains why the association of type IIb RPTPs with components of cadherin-catenin adhesion complexes has been of particular interest. [22][23][24][25][26][27][28] For example, PTPRM associates with E-cadherin 23 and dephosphorylates p120 catenin.…”