神経膠腫(Glioma)の総括

Brain tumors are characterized by high morbidity and mortality, and the five-year relative survival rate for malignant brain tumors is around 36%, and the 10-year survival rate is over 30%(1). However, survival rates can vary depending on several factors, including stage, histopathology, age, race, sex. Brain tumor has highly invasive trait. This “invasiveness” means that cancer cell cross the epithelial tissue to more deep tissue and spread into stroma. Therefore, generally, invasiveness makes surgical resection difficult. This invasiveness is associated with several factors, such as energy metabolism(5), ion channel(Ca, Na, Cl)(Ref.(4) Figure.2: Hydrodynamic model), glutamate, cell adhesion molecule(integrin, tenascin, laminin, versican), the remodeling of extracellular matrix(ECM) (hyaluronan)(ref.2, Figure 1), cytoskeleton and neurotransmitters, proteases . In energy metabolism, aggressive glioma with high mobility in neuronal tissue exhibit low carboxypeptidase E (CPE) whose level is negatively associated with prognosis(5). This CPE suppression has complex relation with glioma mobility such as remodeling of ECM, aberrant cytoskeleton dynamics, change of cell adhesion molecule, hypoxia. The association between CPE level and ECM formation remain elusive partly. However, CPE is enzyme for production of several neuropeptides and neuroendocrine peptide such as insulin, the enkephalins, vasopressin, oxytocin. Neuropeptides are released by dense core vesicles after depolarization of the cell. Depolarization triggers neural firing. Furthermore, diffusion length of neuropeptide is longer than neurotransmitter, which could make the molecules interact the other neuron. This interaction enhance synaptic activity through fast amino acids GABA(Ref.(6) Figure.6). Therefore, CPE may be able to strengthen synaptic connections, resulting that low level production of CPE disrupts brain circuit(6) and makes neuronal connection weak. In fact, CPE related gene mutations in Alzheimer’s diseases leads to comorbidity of depression and dementia in mice(7). Additionally, invasive glioma has mobile ability in perivascular region, brain parenchyma, white matter tract, subarachnoid space(Ref.(4) Box.2) that weaker connection to synapse may be conferred by suppressed production of CPE. Synapse formation and ECM production is bidirectionally affected(8). The cytoskeleton in synapse, cell adhesion molecules on synapse and ECM binding the surface receptor of synapse could have mixed relation, so CPE production could also affect these factors in a synapse-dependent manner. Therefore, CPE with synapse activities could affect remodeling of ECM. Glioma dynamics is explained by hydro- and ionic-dynamic model(4). The glioma could makes volume change up to theoretical limit (about 30%) by cytoplasmic water release mechanism(4) and realize ionic density gradient(4) to exploit electrostatic force for their mobility(9).
 The Ca2+ signaling pathway and other signaling cascades mediated by various ion channels contribute mainly to gene expression, motility, and invasion of GBM cells(2). In normal cellular state, cytosolic Ca ion is maintained at low level, so excess incorporation through several channels such as TRPM7, P2X7R, TRPV4, TRPC1, Orai1 of Ca ion is related to aberrant pathways such as STAT3/NOTCH(11), MEK/ERK(12), Akt/Rac1(13), CDC42/N-wasp(14) inducing invasion and migration of glioma(Ref.(2), Figure.1b). Cell migration related to cancer cell invasiveness requires a coordinated process including adhesion of the cell and attachment to and detachment from the ECM. Therefore, in principle, phenotype switch of cell adhesion molecule like integrin, cadherin, tenascin, laminin, versican is required to get mobility in the tissue form epithelial layer (surface) to stromal layer (deep). For example, integrin phenotype switch in the invasiveness is investigated in placental development through the mobility trophoblast cell in decidua(3). In general, a cell with high degree of freedom on mobility in tissue have weak cell-to-cell connection while strong cell-to-ECM connections, because cell-to-cell connections gives fixed trait, on the other hand, ECM could be “traffic line” for cell migration. Aberrant distribution of hyaluronan around glioma is associate with poor prognosis, so hyaluronan play an essential role in aggressive glioma. CD44 is binding partner of hyaluronan, and inhibition of CD44 suppresses glioma migration(15). In addition to cellular plasticity explained by hydro- and ionic- dynamics(4), the degradation ability (for ECM) of matrix metalloproteinase (MMP) such as MMP-2, MMP-9 play a vital role in the glioma mobility(10). Hyaluronan, which is one of ECMs, concentration is high in aggressive glioma while MMP-2, MMP-9, which are the enzymes able to degrade ECM is activated in glioma. What do these biological facts mean? Probably, this biology means that ECM components could be changed in aggressive glioma with high mobility from ? to hyaluronan. In normal brain, 20-40% of all volume is composed of ECM, such as collagen, proteoglycan, hyaluronan, glycoprotein, laminin, elastin et al. Among these ECMs, at least, MMP-9 overexpressed in glioma can make (collagen type I, II, III, IV, V, XI, XVI, fibronectin, laminin, osteopontin, thrombospondin-1, tenascin-C, galectin-3, decorin) degrade. Therefore, in microenvironment of glioma, the volume of collagen may be decreased, but that of hyaluronan may be increased.

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