Invasive behaviour of glioblastoma cell lines is associated with altered organisation of the cadherin-catenin adhesion system

Abstract

As little is known about the role of cadherin-mediated cell-cell adhesion in astrocytes and its alteration in migrating and invasive glioblastomas, we investigated its molecular composition and organisation in primary cultured astrocytes and the T98G and U373MG glioblastoma cell lines. Biochemical and morphological analysis indicated that all three cell types express all of the structural components of the adhesion system, including the LIN-7 PDZ protein,a novel component involved in the organisation of the junctional domain in epithelia and neurons. However, only the astrocytes and T98G cells generated and maintained mature adhesive junctional domains to which LIN-7 was recruited. Alterations in the junctional domain of U373MG cells were associated with higher motility in a poly-L-lysine migration assay. When the T98G cells were cultured on Matrigel matrix, they acquired invasive properties but, despite unchanged cadherin adhesion system protein levels, the invasive T98G cell-cell contacts failed to accumulate LIN-7 and failed to mature. These results identify the LIN-7 PDZ protein as a marker of cell adhesion maturity and cell invasion and indicate that instability and disorganisation of cadherin-mediated junctions rather than reduced expression of cadherin-catenin system components are required to promote migration and invasiveness in glioblastoma cell lines.

Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells

“…As the expression of β-catenin contributes the progression of EMT we explored its expression, observing that the protein levels detected were independent from substrate stiffness ( 18 ). The mechanism employed by GBM cells to weaken cell–cell adhesion and enable migration and invasion may be related to alterations in the organization or processing of intercellular junction proteins rather than the regulation of their expression ( 70 , 71 ). In fact, N-cadherin expression has been shown to influence position, number and size of focal adhesions ( 11 ), thus the turnover of focal adhesions on the different stiffness might be responsible for the different responses of cell speed that we observed in our results.…”

Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

“…The switch from E-cadherin to N-cadherin has been associated with cell motility and a transition to a more invasive phenotype [ 67 ]. In glioblastoma, it has been shown that instability and disorganization of cadherin-mediated junctions increase invasion [ 68 ].…”

“…Ephrins mediate cell-to-cell signaling and control tissue organization, and the Ephrin pathway is overactivated in invasive glioblastoma cells [ 34 ]. Overactivation of Ephrin pathway elements, especially EphA2 and EphA3, has been associated with invasiveness and poor patient outcomes [ 34 , 68 ]. It was recently shown that TGFβ is associated with microtube formation and invasion in glioma cells through SMAD and Tsp1 signaling, as microtube formation is one of the drivers of invasion [ 108 ].…”

Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers

“…In malignant gliomas, cadherin levels fluctuate, as evidenced by multiple investigations, and reports in this respect are contradictory [ 58 , 59 , 60 , 61 ]. Some findings demonstrate an inverse relationship between N-cadherin expression and glioma invasion [ 62 ], while others demonstrate no link [ 61 ], or indicate a positive correlation with the grade of the gliomas [ 59 , 61 ].…”