Essential gene pathways for glioblastoma stem cells: clinical implications for prevention of tumor recurrence.

Glioblastoma (World Health Organization/WHO grade IV) is the most common and most aggressive adult glial tumor. Patients with glioblastoma, despite being treated with gross total resection and post-operative radiation/chemotherapy, will almost always develop tumor recurrence. Glioblastoma stem cells (GSC), a minor subpopulation within the tumor mass, have been recently characterized as tumor-initiating cells and hypothesized to be responsible for post-treatment recurrence because of their enhanced radio-/chemo-resistant phenotype and ability to reconstitute tumors in mouse brains. Genome-wide expression profile analysis uncovered molecular properties of GSC distinct from their differentiated, proliferative progeny that comprise the majority of the tumor mass. In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype. Thus, cell cycle-targeted radio-chemotherapy, which aims to kill fast-growing tumor cells, may not completely eliminate glioblastoma tumors. To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen. Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Cross-talk between microRNAs, long non-coding RNAs and p21Cip1 in glioma: diagnostic, prognostic and therapeutic roles

Glioblastoma multiforme is considered one of the most common malignant primary intracranial tumors. Despite treatment with a combination of surgery, chemotherapy and radiotherapy, patients with glioblastoma multiform have poor prognosis. It has been widely accepted that the occurrence, progression, and even recurrence of glioblastoma multiforme strictly depends on the presence of glioma cancer stem cells. The presence of glioma stem cells reduces the efficacy of standard therapies, thus increasing the imperative to identify new targets and therapeutic strategies in glioblastoma patients. In this regard, the p21Cip1 pathway has been found to play an important role in the maintenance of the glioma stem cells. It has been shown that this pathway regulates cancer stem cell pool by preventing hyperproliferation and exhaustion. MicroRNAs, endogenous small non-coding RNAs, and long non-coding RNAs, regulate post-transcription gene expression. These are not only altered in glioma, but also in other cancer types, and are involved in tumor development and progression. Notably, they have also been shown to modulate the expression of proteins in the p21Cip1 signaling pathway. This review highlights the extent and complexity of cross-talk between microRNAs, long non-coding RNAs and the p21Cip1 pathway, and demonstrates how such interplay orchestrates the regulation of protein expression and functions in glioma and glioma stem cells

Dexamethasone in glioblastoma multiforme therapy : mechanisms and controversies

Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.peer-reviewe

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

The role of the Bmi1-GSK3β pathway in glioblastoma

Malignant gliomas remain one of the deadliest of all cancers despite maximal therapy. They present unique challenges to therapy with a median survival of 12 months. Simultaneous activation of several growth promoting and anti-apoptotic pathways represents the basis for the failure of monotherapies against this disease. In order to efficiently block growth of glioblastoma (GBM) cells, we have applied several combinatorial approaches. We have found that combination of histone deactylase inhibitors along with the glycolytic inhibitor 2-deoxyglucose (2DG) efficiently induced apoptosis in GBM cells. Furthermore, combination of the microtubule inhibitor patupilone and AEE788 –an inhibitor of EGFR, which is frequently activated in gliomas, induced apoptosis in GBM cells at doses that as single drugs were not effective. In GBM and other cancers, subpopulations of tumor cells with stem cell properties that are believed to constitute a tumor cell reservoir, have been identified. GBM cells frequently express the progenitor cell markers Nestin and Sox2 and low levels of the differentiation markers CNPase, GFAP and !-tubulin III. Bmi1 and Glycogen synthase kinase 3 (GSK3) has been implicated in stem cell maintenance, but how Bmi1 regulates differentiation is still unknown. We have identified a link between Bmi1 and GSK3 and showed that blocking GSK3 may be instrumental to reduce the GBM cancer stem cell pool. We found that the GSK3 inhibitors SB216763 as well as Lithium chloride depleted the cancer stem cell population in GBM cells and induced tumor cell differentiation, irrespective of the CD133 status. Cell proliferation and colony formation were markedly reduced in a dosedependent manner. Future work giving a deeper insight into the regulatory mechanisms of the receptor tyrosine kinases and downstream effectors will help us to identify more specific targets. Understanding the mechanisms why some targeted therapies work and others fail will finally bring us to the level that efficient long-term treatment strategies can be envisaged

EZH2, HIF-1, and their inhibitors: An overview on pediatric cancers

During the past decades, several discoveries have established the role of epigenetic modifications and cellularmicroenvironment in tumor growth and progression. One of the main representatives concerning epigenetic modification is the polycomb group (PcG). It is composed of different highly conserved epigenetic effector proteins preserving, through several post-translational modifications of histones, the silenced state of the genes implicated in a wide range of central biological events such as development, stem cell formation, and tumor progression. Proteins of the PcG can be divided in polycomb repressive complexes (PRCs): PRC1 and PRC2. In particular, enhancer of zeste homolog 2 (EZH2), the catalytic core subunit of PRC2, acts as an epigenetic silencer ofmany tumor suppressor genes through the trimethylation of lysine 27 on histone H3, an essential binding site for DNA methyl transferases and histone deacetylases. A growing number of data suggests that overexpression of EZH2 associates with progression and poor outcome in a large number of cancer cases. Hypoxia inducible factor (HIF) is an important transcription factor involved in modulating cellular response to the microenvironment by promoting and regulating tumor development such as angiogenesis, inflammation, metabolic reprogramming, invasion, and metastatic fate. The HIF complex is represented by different subunits (α and β) acting together and promoting the expression of vascular endothelial growth factor (VEGF), hexokinase II (HKII), receptor for advanced glycation end products (RAGE), carbonic anhydrase (CA), etc., after binding to the hypoxia-response element (HRE) binding site on the DNA. In this review, we will try to connect these two players by detailing the following: (i) the activity and influence of these two important regulators of cancer progression in particular for what concerns pediatric tumors, (ii) the possible correlation between them, and (iii) the feasibility and efficiency to contrast them using several inhibitors

Therapeutic potentials of curcumin in the treatment of glioblstoma

Glioblastoma multiforme (GBM), a greatly aggressive malignancy of the brain, is correlated with a poor prognosis and low rate of survival. Up to now, chemotherapy and radiation therapy after surgical approaches have been the treatments increasing the survival rates. The low efficacy of mentioned therapies as well as their side-effects has forced researchers to explore an appropriate alternative or complementary treatment for glioblastoma. In experimental models, it has been shown that curcumin has therapeutic potentials to fight against GBM. Given that curcumin has pharmacological effects against cancer stem cells, as major causes of resistance to therapy in glioblastoma cells. Moreover, it has been showed that curcumin exerts its therapeutic effects on GBM cells via affecting on apoptosis, oxidant system, and inflammatory pathways. Curcumin would possess a synergistic impact with chemotherapeutic agents. Herein, we summarized the current findings on curcumin as therapeutic agent in the treatment of GBM. © 2020 Elsevier Masson SA

The role of hypoxia in glioblastoma invasion

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient's median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.info:eu-repo/semantics/publishedVersio

Elucidating the role of DNA damage and human cytomegalovirus in medulloblastoma and glioblastoma

The most common primary malignant brain tumor in children is Medulloblastoma, while Glioblastoma is the most common in adults. Treatment for both include some combination of surgery, radiation therapy, and chemotherapy. The evolution of most primary malignant brain tumors is unknown, although varying degree of genomic instability caused by defects in the DNA Damage Response (DDR) is suspected. Lately, even human cytomegalovirus (HCMV) has emerged as a suspected pathogen possibly implicated in malignant tumor evolution. Nevertheless, the causes of the chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies (i.e. radiation and chemotherapy) remain largely unknown. Thus, the main aim of this PhD thesis is to investigate the role of HCMV in the context of DDR in human Medulloblastoma and Glioblastoma. In the 1st study, we turned our attention towards Glioblastoma (GBM). We examined the ability of HCMV to induce a more aggressive cancer stem cell (CSC)-like phenotype in primary GBM cell lines. HCMV infection induced a stem cell phenotype in primary GBM cell lines as determined by changes in the cellular gene expression profile and by the conferred ability of cells to grow as neurospheres in vitro, and this phenotype was prevented by treatment with the anti-viral drug ganciclovir. As CSCs are known to be resistant to chemotherapy, our results imply that HCMV may enhance the malignancy grade of the tumor, and possibly contribute to therapy resistance. In the 2nd study, we found pronounced endogenous DNA damage signaling and constitutive activation of DNA damage checkpoint kinase cascades across our medulloblastoma cohort. The bulk of the specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection. Our results strongly indicate that in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair mechanisms. In the 3rd study, we examined cancer stem cell markers (CD133, CD15, VEGFR2) and HCMV protein expression in human medulloblastoma specimens and medulloblastoma cell lines, at the same time considering also the replication stress and DNA damage response, as cancer stem cells are often more resistant to standard-of-care radiation and chemotherapy treatments. Our immunohistochemistry analysis on clinical material identified widespread expression of the VEGFR2 receptor and CD15, yet more limited expression of CD133 compared to GBM. In addition, assessments of expression of HCMV early and late proteins have been carried out in parallel, along with cell culture experiments with HCMV infection and replication stress responses in medulloblastoma cell lines. Remarkably, we found that unlike the ‘non-stem cell’ medulloblastoma cell lines, the cell line that showed robust stemness phenotype featured a very distinct response to DNA replication stress and HCMV infection, both emerging hallmarks of brain cancers. In the 4th study, we show that HCMV infection induced replication stress (RS) and triggered host DNA damage response (DDR) in permissive and non-permissive human cells. Further, we show that undergoing standard-of-care genotoxic radiochemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV markers after tumor recurrence. We propose a model to explain oncomodulatory effects of HCMV, through RS induction, DDR subversion, cell death inhibition and host-cell’s genome destabilization. Our findings provide fresh insights into HCMV pathobiology and inspiration for future strategies to combine radio-chemotherapy with anti-viral drugs for cancer treatment