Abstract
Cell migration and invasion in glioblastoma (GBM), the most lethal form of primary brain tumors, are critically dependent on Ca2+ signaling. Increases of [Ca2+]i in GBM cells often result from Ca2+ release from the endoplasmic reticulum (ER), promoted by a variety of agents present in the tumor microenvironment and able to activate the phospholipase C/inositol 1,4,5-trisphosphate PLC/IP3 pathway. The Ca2+ signaling is further strengthened by the Ca2+ influx from the extracellular space through Ca2+ release-activated Ca2+ (CRAC) currents sustained by Orai/STIM channels, meant to replenish the partially depleted ER. Notably, the elevated cytosolic [Ca2+]i activates the intermediate conductance Ca2+-activated K (KCa3.1) channels highly expressed in the plasma membrane of GBM cells, and the resulting K+ efflux hyperpolarizes the cell membrane. This translates to an enhancement of Ca2+ entry through Orai/STIM channels as a result of the increased electromotive (driving) force on Ca2+ influx, ending with the establishment of a recurrent cycle reinforcing the Ca2+ signal. Ca2+ signaling in migrating GBM cells often emerges in the form of intracellular Ca2+ oscillations, instrumental to promote key processes in the migratory cycle. This has suggested that KCa3.1 channels may promote GBM cell migration by inducing or modulating the shape of Ca2+ oscillations. In accordance, we recently built a theoretical model of Ca2+ oscillations incorporating the KCa3.1 channel-dependent dynamics of the membrane potential, and found that the KCa3.1 channel activity could significantly affect the IP3 driven Ca2+ oscillations. Here we review our new theoretical model of Ca2+ oscillations in GBM, upgraded in the light of better knowledge of the KCa3.1 channel kinetics and Ca2+ sensitivity, the dynamics of the Orai/STIM channel modulation, the migration and invasion mechanisms of GBM cells, and their regulation by Ca2+ signals.
Highlights
The GlioblastomaThe large majority (more than 90%) of cancer deaths are due not to the primary tumor per se, but to relapses arising from new foci established in distant organs via metastasis [1]
Cell migration and invasion in glioblastoma (GBM), the most lethal form of primary brain tumors, are critically dependent on Ca2+ signaling
GBM cell migration is a highly regulated multistep process that initiates with GBM cells losing adhesion with surrounding elements, avoiding the cell death often associated with extracellular matrix (ECM) disconnection, and acquiring a highly migratory phenotype, which is a critical feature of the invasive process
Summary
The large majority (more than 90%) of cancer deaths are due not to the primary tumor per se, but to relapses arising from new foci established in distant organs via metastasis [1]. Glioblastoma (GBM), the most common and aggressive form of primary brain tumors, is no exception, though it does not metastasize in the classical way (that is, by colonizing other tissues via the bloodstream), but invades brain parenchyma by detaching from the original tumor mass and infiltrating into the healthy tissue by degrading the extracellular matrix or squeezing through the brain interstitial spaces. The major obstacle with GBM remains its high migratory and invasive potential into healthy brain parenchyma, which prevents complete surgical removal of tumor cells. Even with full clinical treatment (temozolomide-based chemotherapy and radiation therapy), tumors normally recur at some distance from the site of resection, establishing new tumor lesions that are by far the primary cause of mortality in GBM patients. At the time of surgery, large numbers of cells have already detached from the original tumor mass and invaded normal brain tissue. Migration is a property of many non-tumor cells, it is often restricted to specific developmental stages or environmental conditions; the migration of tumor cells could be viewed as the result of mutation-induced dysregulation of specific biochemical pathways that in healthy tissue keep cell migration dormant
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