Brain tumor stem cells: Molecular characteristics and their impact on therapy

Abstract

Glioblastoma (GBM) is the most prevalent primary brain tumor and ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding brain cancer genetics and modeling these tumors with new targeted therapies being tested but these advances have not translated into substantially improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, the first-line treatment for glioblastoma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to healthy brain tissue and development of radioresistance. Therapeutic resistance is attributed at least in part to a cell population within the tumor that possesses stem-like characteristics and tumor propagating capabilities, referred to as cancer stem cells. Within GBM, the intratumoral heterogeneity is derived from a combination of regional genetic variance and a cellular hierarchy often regulated by distinct cancer stem cell niches, most notably perivascular and hypoxic regions. With the recent emergence as a key player in tumor biology, cancer stem cells have symbiotic relationships with the tumor microenvironment, oncogenic signaling pathways, and epigenetic modifications. The origins of cancer stem cells and their contributions to brain tumor growth and therapeutic resistance are under active investigation with novel anti-cancer stem cell therapies offering potential new hope for this lethal disease.

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

“…As expected, we found that the gene expression variations induced by the combined treatment result from the synergic effects of each conjugate, however, for the specific gene set analyzed, the contribution of the GL21.T-miR137 is clearly predominant over that of the Gint4.T-anti10b conjugate. Indeed, as previously reported, the GSCs share a common characteristic miRNA expression profile [ 42] suggesting that a reduced number of miRNAs act in concert to modulate the expression of large sets of genes that ultimately converge to propagate the stem-cell like glioblastoma cell population. Furthermore, recent reports have highlighted the involvement of miRNA deregulation in maintaining the GSC hypoxic microenvironment [45,46].…”

“…Furthermore, several miRNAs are differentially expressed in glioblastoma stem cells and normal neural stem cells and shown to be implicated in maintenance and propagation of the GSCs by regulating malignancy, differentiation and fate determination [42].…”

Tumor stem cells from glioblastoma multiforme

“…Регуляторы взрослого нейрогенеза SOX2 и SOX21 играют ключевую роль в пролиферации неопластических клеток, одновременно их инактива-ция останавливает рост глиомы in vivo [16,29,30].…”

“…TGF-β1-ре цеп-торы локализованы в межклеточных контактах и уси-ливают синтез белков межклеточного матрикса [40]. Под действием секретируемого TGF-β1 ОСК образуют ниши с клетками эндотелия через SDF-1/CXCR4-зависимый путь [21,29], а также дифференцируются в клетки, напоминающие перициты и, обеспечиваю-щие периваскулярную нишу питанием [7].…”

Growth factors and kinases in glioblastoma growth

“…Histopathologically, gliomas are classified as astrocytomas, oligodendrogliomas, oligoastrocytomas, and ependymomas [2] . Astrocytomas are the most common and malignant type of glioma, and can be caused by astrocytes, glial progenitors, and cancer stem cells [3][4][5][6] . According to the World Health Organization, gliomas are classified into four grades (I-IV), with glioblastoma (grade IV) being the most common and malignant grade [7] .…”