Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.
Highlights
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis
GBMs associated with the subventricular zone (SVZ) are most likely to be multifocal at diagnosis, recur at great distances from the initial lesion/s, and exhibit a transformation from neural stem cells (NSC) to glioma stem cells (GSCs) [53]
GSCs interact with the vasculature, and with pericytes within the niche [58,59] and are able to transdifferentiate into endothelial cells (EC) in order to contribute to their own vasculature
Summary
Gliomas account for 30% of all tumors of the central nervous system (CNS) and 80%. of all malignant brain tumors in adults [1]. GBM can appear at any age but the peak incidence is between 75 to 84 years [7] The incidence of these tumors is approximately 50% higher in males compared to females [8] and it differs substantially between ethnic groups, e.g., it is higher in Caucasians as compared to black populations [7,9,10]. Secondary GBM (10%) develops through progression from a low-grade lesion and is associated with a better prognosis and survival rate due to the IDH mutation (median OS of 3.6 years) [1,6,19–21]. This biomarker, used in combination with the loss of heterozygosity in chromosomal arms. The use of molecular traits is assisting with the classification of gliomas, the high biological heterogeneity of which require the use of different experimental models for their study [29] and different strategies of clinical management
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