共查询到20条相似文献,搜索用时 30 毫秒
1.
Sune Munthe Mia D. Sørensen Mads Thomassen Mark Burton Torben A. Kruse Justin D. Lathia Frantz Rom Poulsen Bjarne Winther Kristensen 《Journal of neuro-oncology》2016,127(1):53-61
Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem cells (CSCs), has been identified in gliomas and many other cancers. These tumor cells have a stem cell-like phenotype and are suggested to be responsible for tumor growth, chemo- and radio-resistance as well as recurrence. However, functional evidence for migrating glioma cells having a stem cell-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures, but not of the commercial cell line U87MG. An in vitro limiting dilution assay showed preserved but reduced spheroid formation capacity of migrating cells. Orthotopic xenografting in mice showed preserved but reduced tumorigenic capacity. Profiling of mRNAs revealed no significant deregulation of 16 predefined CSC-related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since CSCs are reported to be highly resistant to therapy, these results emphasize that the CSC phenotype should be taken into consideration in future treatment of GBMs. 相似文献
2.
Zhi-hua Zhou Yi-fang Ping Shi-cang Yu Liang Yi Xiao-hong YaoJian-hong Chen You-hong CuiXiu-wu Bian 《Cancer letters》2009
Enrichment of cancer stem cells for studies of carcinogenesis remains a difficult issue. We hypothesized that the unique features of cancer stem cells (CSCs) may allow formation of their colonies in vitro with distinct morphology. We therefore investigated the possibility to use morphological diversity of colonies to identify and enrich CSCs from cultured malignant human glioma cells. We found that a small proportion of the cells from a human glioma cell line U251 formed tight and round-shaped colonies in culture. Most cells in such colonies were capable of self-renewal, generating tumor spheres and differentiating into lineages with markers for neurons, astrocytes and oligodendrocytes. In addition, several neural stem cell-related genes were highly expressed by tumor cells in those tight colonies. Our results thus demonstrate a novel approach to the identification and enrichment of CSCs based on unique morphology of their colonies formed in vitro. 相似文献
3.
Matteo Setti Daniela Osti Cristina Richichi Barbara Ortensi Massimiliano Del Bene Lorenzo Fornasari Galina Beznoussenko Alexandre Mironov Germana Rappa Alessandro Cuomo Mario Faretta Tiziana Bonaldi Aurelio Lorico Giuliana Pelicci 《Oncotarget》2015,6(31):31413-31427
Little progresses have been made in the treatment of glioblastoma (GBM), the most aggressive and lethal among brain tumors. Recently we have demonstrated that Chloride Intracellular Channel-1 (CLIC1) is overexpressed in GBM compared to normal tissues, with highest expression in patients with poor prognosis. Moreover, CLIC1-silencing in cancer stem cells (CSCs) isolated from human GBM patients negatively influences proliferative capacity and self-renewal properties in vitro and impairs the in vivo tumorigenic potential. Here we show that CLIC1 exists also as a circulating protein, secreted via extracellular vesicles (EVs) released by either cell lines or GBM-derived CSCs. Extracellular vesicles (EVs), comprising exosomes and microvesicles based on their composition and biophysical properties, have been shown to sustain tumor growth in a variety of model systems, including GBM. Interestingly, treatment of GBM cells with CLIC1-containing EVs stimulates cell growth both in vitro and in vivo in a CLIC1-dose dependent manner. EVs derived from CLIC1-overexpressing GBM cells are strong inducers of proliferation in vitro and tumor engraftment in vivo. These stimulations are significantly attenuated by treatment of GBM cells with EVs derived from CLIC1-silenced cells. However, CLIC1 modulation appears to have no direct role in EV structure, biogenesis and secretion. These findings reveal that, apart from the function of CLIC1 cellular reservoir, CLIC1 contained in EVs is a novel regulator of GBM growth. 相似文献
4.
Zhu TS Costello MA Talsma CE Flack CG Crowley JG Hamm LL He X Hervey-Jumper SL Heth JA Muraszko KM DiMeco F Vescovi AL Fan X 《Cancer research》2011,71(18):6061-6072
One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment. 相似文献
5.
Isolation of cancer stem cells from adult glioblastoma multiforme 总被引:45,自引:0,他引:45
Yuan X Curtin J Xiong Y Liu G Waschsmann-Hogiu S Farkas DL Black KL Yu JS 《Oncogene》2004,23(58):9392-9400
Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a distinguishing feature from normal NSCs, these tumor stem cells can reform spheres even after the induction of differentiation. Furthermore, only these tumor stem cells were able to form tumors and generate both neurons and glial cells after in vivo implantation into nude mice. The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets. 相似文献
6.
Glioblastoma multiforme (GBM), a grade IV glioma, appears to harbor therapy-resistant cancer stem cells (CSCs) that are the major cause of recurrence. All-trans retinoic acid (ATRA), a derivative of retinoid, is capable of differentiating a variety of stem cells, as well as normal neural progenitor cells, and down-regulates expression of the stem cell marker nestin. This study investigated the effects of ATRA on differentiation, proliferation, self-renewal, and signaling pathways of CSCs in GBM. CSCs differentiated into glial and neuronal lineages at low concentrations of ATRA (10 μM). Proliferation and self renewal of neurospheres were reduced following ATRA, although ATRA induced apopotsis at higher (40 μM) concentrations. Analysis of mitogen-activated protein kinase signaling pathways, specifically extracellular signal-regulated kinases (ERK1/2), showed that ATRA-induced alterations in ERK1/2 were associated with regulation of differentiation, proliferation and apoptosis. These results emphasize that low doses of ATRA may have therapeutic potential by differentiating GBM CSCs and rendering them sensitive to targeted therapy. 相似文献
7.
Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer in vitro and in vivo and especially, to determine whether this molecule could target the gastric CSCs. Metformin effects were evaluated on the proliferation and tumourigenic properties of the gastric CSCs from patient-derived primary tumour xenografts (PDXs) and cancer cell lines (MKN45, AGS and MKN74) in vitro in conventional 2 dimensional (2D) and in 3 dimensional (3D) culture systems, in which only CSCs are able to form tumourspheres and in mouse xenograft models in vivo. Metformin induced a cell cycle arrest, which decreased cell proliferation in the 2D cultures. In a 3D culture system, metformin decreased the number of tumourspheres, revealing its capacity to target the CSCs. This effect was confirmed by the study of the expression of CSC markers (CD44 and Sox2) and differentiation markers (Kruppel-like factor 4 and MUC5AC), which were decreased or increased in response to metformin, respectively. Finally, in vivo treatment of PDXs with metformin led to a tumour growth delay and decreased the self-renewal ability of the CSCs. These results suggest that the use of metformin could represent an efficient strategy to inhibit tumour growth by targeting gastric CSCs. 相似文献
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Lin-Lin Bu Zhi-Li Zhao Jian-Feng Liu Si-Rui Ma Cong-Fa Huang Bing Liu Wen-Feng Zhang Zhi-Jun Sun 《Oncotarget》2015,6(39):41944-41958
Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. 相似文献
12.
Daniel Klevebring Gustaf Rosin Ran Ma Johan Lindberg Kamila Czene Juha Kere Irma Fredriksson Jonas Bergh Johan Hartman 《Breast cancer research : BCR》2014,16(4):R72
Introduction
The cancer stem cell model implies a hierarchical organization within breast tumors maintained by cancer stem-like cells (CSCs). Accordingly, CSCs are a subpopulation of cancer cells with capacity for self-renewal, differentiation and tumor initiation. These cells can be isolated through the phenotypic markers CD44+/CD24-, expression of ALDH1 and an ability to form nonadherent, multicellular spheres in vitro. However, controversies to describe the stem cell model exist; it is unclear whether the tumorigenicity of CSCs in vivo is solely a proxy for a certain genotype. Moreover, in vivo evidence is lacking to fully define the reversibility of CSC differentiation.Methods
In order to answer these questions, we undertook exome sequencing of CSCs from 12 breast cancer patients, along with paired primary tumor samples. As suggested by stem classical cell biology, we assumed that the number of mutations in the CSC subpopulation should be lower and distinct compared to the differentiated tumor cells with higher proliferation.Results
Our analysis revealed that the majority of somatic mutations are shared between CSCs and bulk primary tumor, with similar frequencies in the two.Conclusions
The data presented here exclude the possibility that CSCs are only a phenotypic consequence of certain somatic mutations, that is a distinct and non-reversible population of cells. In addition, our results imply that CSCs must be a population of cells that can dynamically switch from differentiated tumor cells, and vice versa. This finding increases our understanding of CSC function in tumor heterogeneity and the importance of identifying drugs to counter de-differentiation rather than targeting CSCs. 相似文献13.
Gürsel DB Beyene RT Hofstetter C Greenfield JP Souweidane MM Kaplitt M Arango-Lievano M Howard B Boockvar JA 《Journal of neuro-oncology》2011,104(2):509-522
It has been postulated that brain tumor stem cells (TSCs) may be the population of cells responsible for the maintenance and
recurrence of glioblastoma multiforme (GBM). The purpose of this study was to optimize a reproducible protocol for generating
TSCs for their subsequent transfection or transduction. Patient GBMs were enzymatically and mechanically dissociated and tumor
spheres were resuspended in appropriate media and analyzed to ensure they met stem cell criteria. These cells were then transfected
with a plasmid or transduced with a viral vector to introduce a previously absent gene and then allowed to form tumor spheres.
Tumor spheres were generated from patient GBMs without contamination. These cells met stringent criteria as stem cells, including
multipotentiality and self-renewal. High efficiency transfection and transduction of tumor spheres was possible, even at the
core of the sphere. This allowed for the introduction of new genes to the TSCs, as evidenced by fluorescent microscopy and
Western blot analysis. This study is a guide to optimize the generation of patient derived GBM tumor spheres without RBC and
dead cell contamination. GBM TSCs within tumor spheres can easily be transfected with plasmids or transduced with a virus.
This is important from a therapeutic perspective if gene replacement is to be successful in replacing genes lost in GBM progression
or to knock down or silence genes that are over-expressed in malignant brain tumors. 相似文献
14.
Glioblastoma multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors, with a median survival of 14-16 months despite optimal surgery, radiation and chemotherapy. A reason for this dismal prognosis is insufficient understanding of the ontogeny of GBMs, which are highly heterogeneous at a pathological level. This pathological diversity, between and within GBMs as well as varying grades of gliomas, has not been fully explained solely on the grounds of oncogenic stimulus. Interaction with the tumor microenvironment is likely a source of this pathological heterogeneity, as well as the inherent characteristics of the tumor cell of origin. Currently, controversy exists on whether the initial transformed cell is a differentiated astrocyte, progenitor or neural stem cell. Putative cancer stem cells (CSCs), which have features of normal stem cell plus the ability to recapitulate the tumor phenotype in vivo in small numbers, have been identified from a variety of solid human cancers, including GBMs. Evidence suggesting that regions harboring normal stem cells in the adult CNS, such as the subventricular zone and the dentate gyrus, are more prone to viral and chemical oncogenesis, is supportive of the hypothesis that brain tumors arise from stem cells. However, it is still to be determined whether the appearance of brain tumor stem cells (BTSC) is the cause or consequence of tumor initiation and progression. This review discusses emerging evidence highlighting the relevance of the state of differentiation and regional heterogeneity in the ontogeny of GBM. This is an area of high interest in cancer in general, with potential significant therapeutic and prognostic implications. 相似文献
15.
Keita Shibuya Masashi Okada Shuhei Suzuki Manabu Seino Shizuka Seino Hiroyuki Takeda Chifumi Kitanaka 《Oncotarget》2015,6(2):651-661
Increased glucose metabolism is now recognized as an emerging hallmark of cancer. Recent studies have shown that glucose metabolism is even more active in cancer stem cells (CSCs), a rare population of cancer cells with the capacity to self-renew and initiate tumors, and that CSCs are dependent on glycolysis for their survival/growth. However, the role of glucose metabolism in the control of their self-renewal and tumor-initiating capacity per se still remains obscure. Moreover, much remains unknown as to which of the numerous molecules involved in the glucose metabolism is suitable as a target to control CSCs. Here we demonstrate that the facilitative glucose transporter GLUT1 is essential for the maintenance of pancreatic, ovarian, and glioblastoma CSCs. Notably, we found that WZB117, a specific GLUT1 inhibitor, could inhibit the self-renewal and tumor-initiating capacity of the CSCs without compromising their proliferative potential in vitro. In vivo, systemic WZB117 administration inhibited tumor initiation after implantation of CSCs without causing significant adverse events in host animals. Our findings indicate GLUT1-dependent glucose metabolism has a pivotal role not only in the growth and survival of CSCs but also in the maintenance of their stemness and suggest GLUT1 as a promising target for CSC-directed cancer therapy. 相似文献
16.
Xuekai Zhu Shruthi Prasad Simone Gaedicke Michael Hettich Elke Firat Gabriele Niedermann 《Oncotarget》2015,6(1):171-184
The AC133 epitope of CD133 is a cancer stem cell (CSC) marker for many tumor entities, including the highly malignant glioblastoma multiforme (GBM). We have developed an AC133-specific chimeric antigen receptor (CAR) and show that AC133-CAR T cells kill AC133+ GBM stem cells (GBM-SCs) both in vitro and in an orthotopic tumor model in vivo. Direct contact with patient-derived GBM-SCs caused rapid upregulation of CD57 on the CAR T cells, a molecule known to mark terminally or near-terminally differentiated T cells. However, other changes associated with terminal T cell differentiation could not be readily detected. CD57 is also expressed on tumor cells of neural crest origin and has been preferentially found on highly aggressive, undifferentiated, multipotent CSC-like cells. We found that CD57 was upregulated on activated T cells only upon contact with CD57+ patient-derived GBM-SCs, but not with conventional CD57-negative glioma lines. However, CD57 was not downregulated on the GBM-SCs upon their differentiation, indicating that this molecule is not a bona fide CSC marker for GBM. Differentiated GBM cells still induced CD57 on CAR T cells and other activated T cells. Therefore, CD57 can apparently be upregulated on activated human T cells by mere contact with CD57+ target cells. 相似文献
17.
Masashi Okada Keita Shibuya Atsushi Sato Shizuka Seino Shuhei Suzuki Manabu Seino Chifumi Kitanaka 《Oncotarget》2014,5(13):5100-5112
Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras – JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras – JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer. 相似文献
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Ran-Ju Kim Jeong-Ran Park Kyung-Jin Roh A-Ram Choi Soo-Rim Kim Pyeung-Hyeun Kim Jong Han Yu Jong Won Lee Sei-Hyun Ahn Gyungyub Gong Jae-Woong Hwang Kyung-Sun Kang Gu Kong Yhun Yhong Sheen Jeong-Seok Nam 《Cancer letters》2013
High aldehyde dehydrogenase (ALDH) activity has been recognized as a marker of cancer stem cells (CSCs) in breast cancer. In this study, we examined whether inhibition of ALDH activity suppresses stem-like cell properties in a 4T1 syngeneic mouse model of breast cancer. We found that ALDH-positive 4T1 cells showed stem cell-like properties in vitro and in vivo. Blockade of ALDH activity reduced the growth of CSCs in breast cancer cell lines. Treatment of mice with the ALDH inhibitor diethylaminobenzaldehyde (DEAB) significantly suppressed 4T1 cell metastasis to the lung. Recent evidence suggests that ALDH affects the response of stem cells to hypoxia; therefore, we examined a possible link between ALDH and hypoxia signaling in breast cancer. Hypoxia-inducible factor-2α (HIF-2α) was highly dysregulated in ALDH-positive 4T1 cells. We observed that ALDH was highly correlated with the HIF-2α expression in breast cancer cell lines and tissues. DEAB treatment of breast cancer cells reduced the expression of HIF-2α in vitro. In addition, reduction of HIF-2α expression suppressed in vitro self-renewal ability and in vivo tumor initiation in ALDH-positive 4T1 cells. Therefore, our findings may provide the evidence necessary for exploring a new strategy in the treatment of breast cancer. 相似文献
20.
Jorge A Benitez Darren Finlay Anthony Castanza Alison D Parisian Jianhui Ma Ciro Longobardi Alex Campos Raghavendra Vadla Alejandro Izurieta Gianluca Scerra Tomoyuki Koga Tao Long Lukas Chavez Jill P Mesirov Kristiina Vuori Frank Furnari 《Neuro-oncology》2021,23(7):1072
BackgroundGlioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months; therefore, more effective treatment options for GBM are required. To identify new drugs targeting GBMs, we performed a high-throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype.MethodsHigh-throughput drug screening was performed on GSCs followed by a dose-response assay of the 5 identified original “hits.” A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by genetic and pharmacologic experiments. Proteasome Inhibition Response Signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using three-dimensional (3D) GBM-organoids and preclinical orthotopic models.ResultsWe found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D GBM-organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition.ConclusionsProteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency. 相似文献