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A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation., Introduction Metastasis is a hallmark of cancer that remains a primary cause of cancer-related deaths (1). Brain metastases are the most common type of CNS malignancies. They often manifest with [...]

The virions of plant viruses and their structurally modified particles (SP) represent valuable platforms for recombinant vaccine epitopes and antitumor agents. The possibility of modifying their surface with biological compounds makes them a tool for developing medical biotechnology applications. Here, we applied a new type of SP derived from virions and virus-like particles (VLP) of Alternanthera mosaic virus (AltMV) and well-studied SP from Tobacco mosaic virus (TMV). We have tested the ability of SP from AltMV (AltMV SPV) and TMV virions also as AltMV VLP to bind to and penetrate Ewing sarcoma cells. The adsorption properties of AltMV SPV and TMV SP are greater than those of the SP from AltMV VLP. Compared to normal cells, AltMV SPV adsorbed more effectively on patient-derived sarcoma cells, whereas TMV SP were more effective on the established sarcoma cells. The AltMV SPV and TMV SP were captured by all sarcoma cell lines. In the established Ewing sarcoma cell line, the effectiveness of AltMV SPV penetration was greater than that of TMV SP. The usage of structurally modified plant virus particles as a platform for drugs and delivery systems has significant potential in the development of anticancer agents. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is an extremely aggressive form of brain tumor with low survival rates. Current treatments such as chemotherapy, radiation, and surgery are problematic due to tumor growth, invasion, and tumor microenvironment. GBM cells are resistant to these standard treatments, and the heterogeneity of the tumor makes it difficult to find a universal approach. Progression of GBM and acquisition of resistance to therapy are due to the complex interplay between tumor cells and the TME. A significant portion of the TME consists of an inflammatory infiltrate, with microglia and macrophages being the predominant cells. Methods: Analysis of the literature data over a course of 5 years suggest that the tumor-associated macrophages (TAMs) are capable of releasing cytokines and growth factors that promote tumor proliferation, survival, and metastasis while inhibiting immune cell function at the same time. Results: Thus, immunosuppressive state, provided with this intensively studied kind of TME cells, is supposed to promote GBM development through TAMs modulation of tumor treatment-resistance and aggressiveness. Therefore, TAMs are an attractive therapeutic target in the treatment of glioblastoma. Conclusion: This review provides a comprehensive overview of the latest research on the nature of TAMs and the development of therapeutic strategies targeting TAMs, focusing on the variety of macrophage properties, being modulated, as well as molecular targets. [ABSTRACT FROM AUTHOR]

The rate of neurodegenerative disorders (NDDs) is rising rapidly as the world's population ages. Conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia are becoming more prevalent and are now the fourth leading cause of death, following heart disease, cancer, and stroke. Although modern diagnostic techniques for detecting NDDs are varied, scientists are continuously seeking new and improved methods to enable early and precise detection. In addition to that, the present treatment options are limited to symptomatic therapy, which is effective in reducing the progression of neurodegeneration but lacks the ability to target the root cause—progressive loss of neuronal functioning. As a result, medical researchers continue to explore new treatments for these conditions. Here, we present a comprehensive summary of the key features of NDDs and an overview of the underlying mechanisms of neuroimmune dysfunction. Additionally, we dive into the cutting-edge treatment options that gene therapy provides in the quest to treat these disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma (ES) is one of the most common kinds of cancer in youngsters, and ES relapse after therapy treatment remains a problem. Carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as interesting molecular targets for the development of anticancer medicines as a fundamental regulator of cellular homeostasis. In this investigation, we used the commercially available acetazolamide and previously found CA inhibitors to target the CAII isoform, which was overexpressed and positively linked with relapse in ES patients. We detected that CAII inhibitors can trigger ferroptosis in ES cells by downregulating FTH1 and increasing cathepsin B expression, inhibit cell growth, limit invasion, and trigger apoptosis or autophagy-related cell death. The findings imply that cytosolic CAII may be a promising target for ES therapy, and CAII inhibitors may be useful as single-agent or combination antitumor therapies in the treatment of ES. Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES. [ABSTRACT FROM AUTHOR]

Simple Summary: It is known that doxorubicin is one of the standards for chemotherapy treatment against Ewing sarcoma. Despite its widespread use, doxorubicin treatment initiates tumor escape mechanisms and disease relapse. Our study aims to identify the potential biomarkers of doxorubicin resistance in primary cultures of Ewing sarcoma cells using single-cell transcriptomic and proteomic analyses. To assess the specificity of identified gene biomarkers, we used publicly available datasets to represent mRNA profiles of patient samples and short-lived cultures of tumor cells, established earlier. Through our investigation, we confirmed that MGST1 and the new marker COL6A2 are both produced by doxorubicin-resistant cells and demonstrated clinical significance for the survival of patients with Ewing sarcoma. Background: Ewing sarcoma (ES) cells exhibit extreme plasticity that contributes to the cell's survival and recurrence. Although multiple studies reveal various signaling pathways mediated by the EWSR1/FLI1 fusion, the specific transcriptional control of tumor cell resistance to doxorubicin is unknown. Understanding the molecular hubs that contribute to this behavior provides a new perspective on valuable therapeutic options against tumor cells. Methods: Single-cell RNA sequencing and LC-MS/MS-based quantitative proteomics were used. Results: A goal of this study was to identify protein hubs that would help elucidate tumor resistance which prompted ES to relapse or metastasize. Several differentially expressed genes and proteins, including adhesion, cytoskeletal, and signaling molecules, were observed between embryonic fibroblasts and control and doxorubicin-treated tumor cell lines. While several cancer-associated genes/proteins exhibited similar expression across fibroblasts and non-treated cells, upregulation of some proteins belonging to metabolic, stress response, and growth pathway activation was uniquely observed in doxorubicin-treated sarcoma cells, respectively. The novel information on differentially expressed genes/proteins provides insights into the biology of ES cells, which could help elucidate mechanisms of their recurrence. Conclusions: Collectively, our results identify a novel role of cellular proteins in contributing to tumor cell resistance and escape from doxorubicin therapy and contributing to ES progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcomas represent the largest group of rare solid tumors that arise from mesenchymal stem cells and are a leading cause of cancer death in individuals younger than 20 years of age. There is an immediate need for the development of an algorithm for the early accurate diagnosis of sarcomas due to the high rate of diagnostic inaccuracy, which reaches up to 30%. X-ray computed tomography is a non-invasive imaging technique used to obtain detailed internal images of the human or animal body in clinical practice and preclinical studies. We summarized the main imaging features of soft tissue and bone sarcomas, and noted the development of new molecular markers to reach tumor type-specific imaging. Also, we demonstrated the possibility of the use X-ray computed microtomography for non-destructive 3D visualization of sarcoma progression in preclinical studies. Finding correlations between X-ray computed tomography modalities and the results of the histopathological specimen examination may significantly increase the accuracy of diagnostics, which leads to the initiation of appropriate management in a timely manner and, consequently, to improved outcomes. Sarcomas are a leading cause of cancer death in individuals younger than 20 years of age and represent the largest group of rare solid tumors. To date, more than 100 morphological subtypes of sarcomas have been described, among which epidemiology, clinical features, management, and prognosis differ significantly. Delays and errors in the diagnosis of sarcomas limit the number of effective therapeutic modalities and catastrophically worsen the prognosis. Therefore, the development of an algorithm for the early accurate diagnosis of sarcomas seems to be as important as the development of novel therapeutic advances. This literature review aims to summarize the results of recent investigations regarding the imaging of sarcoma progression based on the use of X-ray computed tomography (CT) in preclinical studies and in current clinical practice through the lens of cancer hallmarks. We attempted to summarize the main CT imaging features of soft-tissue and bone sarcomas. We noted the development of new molecular markers with high specificity to antibodies and chemokines, which are expressed in particular sarcoma subtypes to reach tumor type-specific imaging. We demonstrate the possibility of the use of X-ray computed microtomography (micro-CT) for non-destructive 3D visualization of solid tumors by increasing the visibility of soft tissues with X-ray scattering agents. Based on the results of recent studies, we hypothesize that micro-CT enables the visualization of neovascularization and stroma formation in sarcomas at high-resolution in vivo and ex vivo, including the novel techniques of whole-block and whole-tissue imaging. Finding correlations between CT, PET/CT, and micro-CT imaging features, the results of the histopathological specimen examination and clinical outcomes may significantly increase the accuracy of soft-tissue and bone tumor diagnostics, which leads to the initiation of appropriate histotype-specific management in a timely manner and, consequently, to improved outcomes. [ABSTRACT FROM AUTHOR]

Multiple efforts are currently underway to develop targeted therapeutic deliveries to the site of glioblastoma progression. The use of carriers represents advancement in the delivery of various therapeutic agents as a new approach in neuro-oncology. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are used because of their capability in migrating and delivering therapeutic payloads to tumors. Two of the main properties that carrier cells should possess are their ability to specifically migrate from the bloodstream and low immunogenicity. In this article, we also compared the morphological and molecular features of each type of stem cell that underlie their migration capacity to glioblastoma. Thus, the major focus of the current review is on proteins and lipid molecules that are released by GBM to attract stem cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma is an uncommon cancer that arises in mesenchymal tissues and represents the second most widespread malignant bone neoplasm after osteosarcoma in children. Therapy has increased the 5-year survival rate in the last 40 years, although the recurrence rate has remained high. There is an immediate and unmet need for the development of novel Ewing sarcoma therapies. We offer new prospective targets for the therapy of Ewing sarcoma. The EWSR1/FLI1 fusion protein, which is identified in 85–90% of Ewing sarcoma tumors, and its direct targets are given special focus in this study. Experimantal therapy that targets multiple signaling pathways activated during ES progression, alone or in combination with existing regimens, may become the new standard of care for Ewing sarcoma patients, improving patient survival. Ewing sarcoma (ES) is an uncommon cancer that arises in mesenchymal tissues and represents the second most widespread malignant bone neoplasm after osteosarcoma in children. Amplifications in genomic, proteomic, and metabolism are characteristics of sarcoma, and targeting altered cancer cell molecular processes has been proposed as the latest promising strategy to fight cancer. Recent technological advancements have elucidated some of the underlying oncogenic characteristics of Ewing sarcoma. Offering new insights into the physiological basis for this phenomenon, our current review examines the dynamics of ES signaling as it related to both ES and the microenvironment by integrating genomic and proteomic analyses. An extensive survey of the literature was performed to compile the findings. We have also highlighted recent and ongoing studies integrating metabolomics and genomics aimed at better understanding the complex interactions as to how ES adapts to changing biochemical changes within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Azvudine (FNC) is a novel cytidine analogue that has both antiviral and anticancer activities. This minireview focuses on its underlying molecular mechanisms of suppressing viral life cycle and cancer cell growth and discusses applications of this nucleoside drug for advanced therapy of tumors and malignant blood diseases. FNC inhibits positive-stand RNA viruses, like HCV, EV, SARS-COV-2, HBV, and retroviruses, including HIV, by suppressing their RNA-dependent polymerase enzymes. It may also inhibit such enzyme (reverse transcriptase) in the human retrotransposons, including human endogenous retroviruses (HERVs). As the activation of retrotransposons can be the major factor of ongoing cancer genome instability and consequently higher aggressiveness of tumors, FNC has a potential to increase the efficacy of multiple anticancer therapies. Furthermore, FNC also showed other aspects of anticancer activity by inhibiting adhesion, migration, invasion, and proliferation of malignant cells. It was also reported to be involved in cell cycle arrest and apoptosis, thereby inhibiting the progression of cancer through different pathways. To the date, the grounds of FNC effects on cancer cells are not fully understood and hence additional studies are needed for better understanding molecular mechanisms of its anticancer activities to support its medical use in oncology. [ABSTRACT FROM AUTHOR]

Autophagy is the process of recycling and utilization of degraded organelles and macromolecules in the cell compartments formed during the fusion of autophagosomes with lysosomes. During autophagy induction the healthy and tumor cells adapt themselves to harsh conditions such as cellular stress or insufficient supply of nutrients in the cell environment to maintain their homeostasis. Autophagy is currently seen as a form of programmed cell death along with apoptosis and necroptosis. In recent years multiple studies have considered the autophagy as a potential mechanism of anticancer therapy in malignant glioma. Although, subsequent steps in autophagy development are known and well-described, on molecular level the mechanism of autophagosome initiation and maturation using autophagy-related proteins is under investigation. This article reviews current state about the mechanism of autophagy, its molecular pathways and the most recent studies on roles of autophagy-related proteins and their isoforms in glioma progression and its treatment. [ABSTRACT FROM AUTHOR]

Brain metastases are the most common type of brain tumours, harbouring an immune microenvironment that can in principle be targeted via immunotherapy. Elucidating some of the immunological intricacies of brain metastases has opened a therapeutic window to explore the potential of immune checkpoint inhibitors in this globally lethal disease. Multiple lines of evidence suggest that tumour cells hijack the immune regulatory mechanisms in the brain for the benefit of their own survival and progression. Nonetheless, the role of the immune checkpoint in the complex interplays between cancers cells and T cells and in conferring resistance to therapy remains under investigation. Meanwhile, early phase trials with immune checkpoint inhibitors have reported clinical benefit in patients with brain metastases from melanoma and non-small cell lung cancer. In this review, we explore the workings of the immune system in the brain, the immunology of brain metastases, and the current status of immune checkpoint inhibitors in the treatment of brain metastases. [ABSTRACT FROM AUTHOR]

Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty‐five combination therapy trials were selected (n = 65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main‐stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%) and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER‐dimerization inhibitors (3 trials), microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER‐dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2‐positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti‐cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood–brain barrier permeable agents may potentiate the overall therapeutic outcomes. What's new? Advances in combination therapy have created new opportunities in cancer therapeutics, especially with regard to combatting drug resistance and tumor metastasis. Here, the authors surveyed data from clinical trials registered in clinicaltrials.gov to identify combination strategies effective specifically against breast cancer brain metastases (BCBM). Of multiple combination strategies identified, those employing thymidylate synthase inhibitors, HER2 inhibitors, and microtubule inhibitors were notably more common. The combination of trastuzumab, tucatinib, and capecitabine cut risk of disease progression or death from BCBM by more than half. The findings warrant investigation of mechanisms underlying effective therapeutic combinations to better understand their actions. [ABSTRACT FROM AUTHOR]

Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production. • KISS1 and E-cadherin expression levels exhibit an inverse correlation in the primary patient samples. • KISS1 inhibition induces E-cadherin. • MiR345 induces E-cadherin expression via KISS1 suppression on the mRNA level. • Downregulation of KISS1 induces cancer cell resistance to ionizing radiation and chemotherapy (temozolomide). [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most aggressive primary brain tumors with frequent recurrences following the standard methods of treatment—temozolomide (TMZ), ionizing radiation and surgical resection. The objective of our study was to investigate GBM resistance mediated via MMP14 (matrix metalloproteinase 14). We used multiple PDX GBM models and established glioma cell lines to characterize expression and subcellular localization of MMP14 after TMZ treatment. We performed a Kiloplex ELISA‐based array to evaluate changes in cellular proteins induced by MMP14 expression and translocation. Lastly, we conducted functional and mechanistic studies to elucidate the role of DLL4 (delta‐like canonical notch ligand 4) in regulation of glioma stemness, particularly in the context of its relationship to MMP14. We detected that TMZ treatment promotes nuclear translocation of MMP14 followed by extracellular release of DLL4. DLL4 in turn stimulates cleavage of Notch3, its nuclear translocation and induction of sphering capacity and stemness. What's new? Despite the efficacy of TMZ chemotherapy on primary brain tumors, glioblastoma recurrence and resistance to therapy are almost inevitable outcomes of the currently‐available therapeutic options. This study sheds light on the underlying resistance mechanisms by showing that MMP14 contributes to enhanced glioblastoma stemness following TMZ treatment via release of DLL4, a ligand of Notch3 signaling pathway. Furthermore, the data reveals that DLL4 release is dependent on the nuclear translocation of MMP14 and that MMP14 promotes glioblastoma stemness via induction of nestin. The results identify a novel autocrine feedback loop which helps neoplastic cells resist TMZ therapy and promotes glioblastoma recurrence. [ABSTRACT FROM AUTHOR]

Tumor suppressors are cellular proteins typically expressed in normal (non-cancer) cells that not only regulate such cellular functions as proliferation, migration and adhesion, but can also be secreted into extracellular space and serve as biomarkers for pathological conditions or tumor progression. KISS1, a precursor for several shorter peptides, known as metastin (Kisspeptin-54), Kisspeptin-14, Kisspeptin-13 and Kisspeptin-10, is one of those metastasis suppressor proteins, whose expression is commonly downregulated in the metastatic tumors of various origins. The commonly accepted role of KISS1 in metastatic tumor progression mechanism is the ability of this protein to suppress colonization of disseminated cancer cells in distant organs critical for the formation of the secondary tumor foci. Besides, recent evidence suggests involvement of KISS1 in the mechanisms of tumor angiogenesis, autophagy and apoptosis regulation, suggesting a possible role in both restricting and promoting cancer cell invasion. Here, we discuss the role of KISS1 in regulating metastases, the link between KISS1 expression and the autophagy-related biology of cancer cells and the perspectives of using KISS1 as a potential diagnostic marker for cancer progression as well as a new anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development.KISS1expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulateKISS1expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression ofKISS1downregulatesATG5andATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism ofKISS1-mediated BrCa metastatic transformation. We also found that expression ofKISS1in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis. [ABSTRACT FROM PUBLISHER]

Glioblastoma multiforme (GBM) is the most common and lethal adult brain tumor. Resistance to standard radiation and chemotherapy is thought to involve survival of GBM cancer stem cells (CSCs). To date, no single marker for identifying GBM CSCs has been able to capture the diversity of CSC populations, justifying the needs for additional CSC markers for better characterization. Employing targeted mass spectrometry, here we present five cell-surface markers HMOX1, SLC16A1, CADM1, SCAMP3, and CLCC1 which were found to be elevated in CSCs relative to healthy neural stem cells (NSCs). Transcriptomic analyses of REMBRANDT and TCGA compendiums also indicated elevated expression of these markers in GBM relative to controls and non-GBM diseases. Two markers SLC16A1 and HMOX1 were found to be expressed among pseudopalisading cells that reside in the hypoxic region of GBM, substantiating the histopathological hallmarks of GBM. In a prospective study ( N = 8) we confirmed the surface expression of HMOX1 on freshly isolated primary GBM cells (P0). Employing functional assays that are known to evaluate stemness, we demonstrate that elevated HMOX1 expression is associated with stemness in GBM and can be modulated through TGFβ. siRNA-mediated silencing of HMOX1 impaired GBM invasion-a phenomenon related to poor prognosis. In addition, surgical resection of GBM tumors caused declines (18% ± 5.1SEM) in the level of plasma HMOX1 as measured by ELISA, in 8/10 GBM patients. These findings indicate that HMOX1 is a robust predictor of GBM CSC stemness and pathogenesis. Further understanding of the role of HMOX1 in GBM may uncover novel therapeutic approaches. S tem C ells 2016;34:2276-2289 [ABSTRACT FROM AUTHOR]

Metastatic brain tumors provide a formidable obstacle in the survival of affected cancer patients, an obstacle that current treatment is essentially ineffective against. Our understanding of the metastatic cascade has demonstrated the role of incorrectly regulated protein expression and proved it to be a crucial component of this process. Recently, molecular studies have emphasized the role of microRNAs, small non-coding RNAs that alter protein expression, in the regulation of both normal and abnormal biological processes, including cancer and its metastasis to the brain. Furthermore, studies have demonstrated the ability to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on microRNA profiles. Interestingly, manipulation of microRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy, and individually directed therapy, using microRNA in the treatment of metastatic brain tumors may prove very useful. In this review, we focus on the multiple potential microRNA targets for the treatment of metastatic brain lesions as well as current and future directions for its use in gene therapy. [ABSTRACT FROM AUTHOR]

MicroRNAs have recently emerged as key regulators of cancers. This study was therefore conducted to investigate the role of miR-330 in biological behaviors of human glioblastoma U87 and U251 cell lines and its molecular mechanism. SH3GL2 gene was identified as the target of miR-330. MiR-330 overexpression was established by transfecting miR-330 precursor into U87 and U251 cells, and its effects on proliferation, migration, invasion, cell cycle and apoptosis were studied. Overexpression of miR-330 can enhance cellular proliferation, promote migration and invasion, activate cell cycle and also inhibit apoptosis in U87 and U251 cells. Collectively, these above-mentioned results suggest that miRNA-330 plays an oncogenic role in human glioblastoma by regulating SH3GL2 gene and might be a new therapeutic target of human glioblastoma. [ABSTRACT FROM AUTHOR]

Cell-derived microparticles participate in intercellular communication similar to the classical messenger systems of small and macro-molecules that bind to specialized membrane receptors. Microparticles have been implicated in the regulation of a variety of complex physiopathologic processes, such as thrombosis, the control of innate and adaptive immunity, and cancer. The neurokinin 1 receptor (NK1R) is a Gq-coupled receptor present on the membrane of a variety of tissues, including neurons in the central and peripheral nervous system, immune cells, endocrine and exocrine glands, and smooth muscle. The endogenous agonist of NK1R is the undecapeptide substance P (SP). We have previously described intracellular signaling mechanisms that regulate NK1R-mediated rapid cell shape changes in HEK293 cells and U373MG cells. In the present study, we show that the activation of NK1R in HEK293 cells, but not in U373MG cells, leads to formation of sheer-stress induced microparticles that stain positive with the membrane-selective fluorescent dye FM 2-10. SP-induced microparticle formation is independent of elevated intracellular calcium concentrations and activation of NK1R present on HEK293-derived microparticles triggers detectable calcium increase in SP-induced microparticles. The ROCK inhibitor Y27632 and the dynamin inhibitor dynasore inhibited membrane blebbing and microparticle formation in HEK293 cells, strongly suggesting that microparticle formation in this cell type is dependent on membrane blebbing. [ABSTRACT FROM AUTHOR]

Latexin is a negative regulator of hematopoietic stem cell number in mice. Its dysregulated expression in other tumors led us to hypothesize that latexin may have tumor suppressor properties in hematological malignancies. We found that latexin was down-regulated in a variety of leukemia and lymphoma cell lines as well as in CD34+ cells from the blood and marrow of patients with these malignancies. 5-aza-29-deoxycytodine treatment and bisulfite sequencing revealed hypermethylation of latexin promoter in tumor cells. Retrovirus-mediated latexin overexpression in A20 mouse lymphoma cells inhibited their in vitro growth by 16 fold and in vivo tumor volume by 2 fold. Latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis through the down-regulation of anti-apoptotic genes Bcl-2 and Pim-2. The molecular mechanism underlying latexin-mediated tumor inhibition was not through its canonical carboxypeptidase inhibitor activity. These results are consistent with a tumor suppressor role for latexin and suggest that latexin may have clinical efficacy in the treatment of malignancies. [ABSTRACT FROM AUTHOR]