Emerging targets for glioblastoma stem cell therapy

Glioblastoma multiforme（GBM）,designated as World Health Organization（WHO）grade IV astrocytoma,is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations,including GBM stem cells（GSCs）which are believed to contribute to tumor recurrence following initial response to therapies.Emerging evidence demonstrates that GBM tumors are initiated from GSCs.The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate sternness,proliferation and migration of GSCs,immunotherapy,and non-coding microRNAs may provide better means of treating GBM.Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs.Several signaling pathways including mTOR,AKT,maternal embryonic leucine zipper kinase（MELK）,NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133,CD44,Oct4,Sox2,Nanog,and ALDHlA1 maintain GSC properties.Moreover,the data published in the Cancer Genome Atlas（TCGA）specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis.Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy.Furthemore,recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs,but the differentiated GBM cells and the entire bulk of tumor cells.

Glioblastoma stem cells(GSCs)epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

Cancer stem cells(CSCs)or cancer initiating cells(CICs)maintain self-renewal and multilineage differentiation properties of various tumors,as well as the cellular heterogeneity consisting of several subpopulations within tumors.CSCs display the malignant phenotype,self-renewal ability,altered genomic stability,specific epigenetic signature,and most of the time can be phenotyped by cell surface markers(e.g.,CD133,CD24,and CD44).Numerous studies support the concept that non-stem cancer cells(non-CSCs)are sensitive to cancer therapy while CSCs are relatively resistant to treatment.In glioblastoma stem cells(GSCs),there is clonal heterogeneity at the genetic level with distinct tumorigenic potential,and defined GSC marker expression resulting from clonal evolution which is likely to influence disease progression and response to treatment.Another level of complexity in glioblastoma multiforme(GBM)tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs,and the potential for non-GSCs to revert(dedifferentiate)to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population.Moreover,exposure of the differentiated GBM cells to therapeutic doses of temozolomide(TMZ)or ionizing radiation(IR)increases the GSC pool both in vitro and in vivo.This review describes various subtypes of GBM,discusses the evolution of CSC models and epigenetic plasticity,as well as interconversion between GSCs and differentiated non-GSCs,and offers strategies to potentially eliminate GSCs.

Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality.Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stemcells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, andexpress enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell populationand lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, theirclose relationship with the tumor microenvironment creates greater complexity in developing novel treatmentstrategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCsin various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activationof various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrantDNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency ofmitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADDlikeIL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, andPI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that areunresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs.Several studies have identified promising strategies to target CSCs. These emerging strategies may help targetCSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

Epithelial-mesenchymal transition:a hallmark in pancreatic cancer stem cell migration,metastasis formation,and drug resistance

Metastasis,tumor progression,and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma(PDAC).Tumor dissemination is associated with the activation of an epithelial-tomesenchymal transition(EMT)process,a program by which epithelial cells lose their cell polarity and cell-tocell adhesion,and acquire migratory and invasive abilities to become mesenchymal stem cells(MSC).These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state.Therefore,EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells.Furthermore,a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells(PCSCs)or cancer-initiating cells in pancreatic tumors.PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth.These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice.Therefore,the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors.PCSCs express markers of cancer stem cells(CSCs)including CD24,CD133,CD44,and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium.A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize.Evidence highlights a linkage between CSC and EMT.In this review,The current understanding of the PCSCs,signaling pathways regulating these cells,PDAC heterogeneity,EMT mechanism,and links between EMT and metastasis in PCSCs are summarised.This information may provide potential therapeutic strategies to prevent EMT and trigger CSC growth inhibition and cell death.