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1.
Cancer Treat Rev ; 79: 101888, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491663

RESUMO

Metaplastic breast carcinomas (MPBC) are rare, aggressive and relatively chemorefractory tumors with a high unmet need. While most are "triple negative" and lack expression of estrogen, progesterone and HER2 receptors, MPBC are associated with worse outcomes compared to conventional triple negative invasive tumors. MPBCs are genetically heterogeneous and harbor somatic mutations, most frequently in TP53, PIK3CA and PTEN, with emerging studies suggesting a role for novel targeted therapies. These tumors have also been associated with overexpression of PD-L1 and tumor-infiltrating lymphocytes suggesting an endogenous immune response and therefore a rationale for treatment with immunotherapies. Here, we focus on therapeutic options for this difficult to treat breast cancer subtype and encourage physicians to consider targeted therapies/immunotherapies as part of ongoing clinical trials.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Animais , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Gerenciamento Clínico , Transição Epitelial-Mesenquimal , Feminino , Variação Genética , Humanos , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Resultado do Tratamento
2.
J Cancer Res Clin Oncol ; 145(10): 2433-2444, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485767

RESUMO

PURPOSE: The clinical importance of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) is well recognized. However, a reliable method for the detection of functioning CSC has not yet been established. We hypothesized that YAP1, a transcriptional coactivator, and SOX2, a master transcription factor of SCC, may cooperatively induce stemness through transcriptional reprogramming. METHODS: We immunohistochemically examined the expression of SOX2 and YAP1 in the CD44 variant 9 (CD44v9)-positive invasion front. A CSC-inducible module was identified through a combination of siRNAs and sphere formation assays. YAP1 and SOX2 interactions were analyzed in vitro. RESULTS: The triple overexpression of SOX2, YAP1, and CD44v9 was significantly associated with poor prognosis. TCGA data revealed that the CSC-inducible module, which was related to EMT and angiogenesis, was significantly correlated with poor prognosis. The KLF7 expression, representatively chosen from the module, also correlated with poor prognosis and was essential for sphere formation and CSC propagation. Sphere stress-activated YAP1 enhanced SOX2 activity. CONCLUSIONS: The stress-triggered activation of YAP1/SOX2 transcriptionally reprograms HNSCC for the acquisition of stemness. Triple SOX2, YAP1, and CD44v9 immunostaining assays may be useful for the selection of high-risk patients with functioning CSCs, and YAP1 targeting may lead to the development of a CSC-targeting therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Estresse Fisiológico , Ativação Transcricional , Biomarcadores , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estresse Fisiológico/genética
3.
Anticancer Res ; 39(9): 4637-4642, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519561

RESUMO

AIM: The aim of this study was to characterize the role of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1 (AMMECR1) in human lung cancer cell lines. MATERIALS AND METHODS: AMMECR1 gene expression was evaluated in four lung cell lines, with A549 then selected for further in-depth examination. To characterize the role of AMMECR1, silencing was achieved utilizing lentivirus-mediated RNA interference, and confirmed by quantitative real-time polymerase chain reaction and western blotting. The impact of AMMECR1 silencing on cellular proliferation was assessed using Celigo-based and MTT assays. Apoptosis was determined using the annexin V-allophycocyanin single staining method. Cell-cycle arrest was assessed by flow cytometry. Finally, colony formation was assessed using Giemsa staining. RESULTS: In A549 cells, AMMECR1 silencing was found to significantly suppress cell proliferation, reduce colony formation, promote apoptosis, and arrest cells in the S and G2/M phases. CONCLUSION: AMMECR1 plays a critical role in cell proliferation, cell-cycle progression, and apoptosis of human lung cancer cells, and may serve as a potential therapeutic target for non-small-cell lung cancer.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Neoplasias Pulmonares/genética , Proteínas/genética , Células A549 , Linhagem Celular Tumoral , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas/metabolismo , RNA Mensageiro/genética
4.
Anticancer Res ; 39(9): 4817-4828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519584

RESUMO

BACKGROUND/AIM: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. MATERIALS AND METHODS: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. RESULTS: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. CONCLUSION: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Survivina/genética , Tiofenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(9): 4837-4843, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519586

RESUMO

BACKGROUND/AIM: The antiparasitic drug, ivermectin (IVM), exerts anticancer activities in diverse cancer types. However, its anticancer activity against cholangiocarcinoma (CCA), especially the drug-resistant phenotype, has not yet been explored. MATERIALS AND METHODS: IVM was tested for its anticancer activity against gemcitabine-sensitive (KKU214) and gemcitabine-resistant (KKU214GemR) CCA cell lines in vitro using the sulforhodamine B and clonogenic assays as well as cell-cycle analysis. RESULTS: IVM treatment inhibited cell proliferation and colony formation of both KKU214 and KKU214GemR in a dose- and time-dependent manner. KKU214GemR cells were more sensitive than KKU214 to IVM treatment. IVM treatment caused S-phase cell-cycle arrest and also cell death as indicated by an increase of sub-G0/G1 population in KKU214GemR cells treated with IVM for 48 h. CONCLUSION: IVM exerts anti-CCA activities and gemcitabine-resistant KKU214GemR cells are more sensitive to IVM treatment. Thus, IVM might be useful as an alternative treatment for CCA, especially in patients who do not respond to gemcitabine.


Assuntos
Antiparasitários/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Ivermectina/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
6.
Gene ; 718: 144030, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31390540

RESUMO

Opioids are widely used in the treatment of cancer related pain. They mainly exert their effects on opioid receptors. The most common opioid in the treatment of pain is morphine. Previous studies show that they may have effects on cancer cell behavior. These may include apoptosis, angiogenesis, invasion, inflammation and immune reactions. Tramadol, also an opioid is widely used in the treatment of cancer pain and is not well studied in cancer behavior. We aimed to investigate the effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells. We used Colo320 (ATCC, CCL-220), Colo741 (ECACC, 93052621) and HCT116 (ATCC, CCL-247) colon cancer cell lines. CD133 was considered colon cancer stem cell marker and used to sort CD133+ and CD133- cells by magnetic cell sorting. MTT (mitochondria-targeted therapeutics) technique was used to detect tramadol's cytotoxic effect on cells in the study groups. Cells were treated with 1 mg/kg, 1.5 mg/kg and 2 mg/kg tramadol for 24 h at 37 °C and 5% CO2.Caspase-3, Ki-67, Bcl-2 and VGEF distributions were performed using indirect immunoperoxidase staining for immunohistochemical analysis. The study showed that tramadol has triggering effect on apoptosis in Colo320 colon cancer stem cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo , Citotoxinas/farmacologia , Células-Tronco Neoplásicas , Tramadol/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
7.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(4): 691-695, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441273

RESUMO

Tumor cells have unique energy metabolism phenomena, namely high glucose absorption, aerobic glycolysis and high lactic acid production, which are characterized by down-regulation of related proteins involved in oxidative metabolism in tumor cells, and up-regulation of glucose transporters and monocarboxylate transporters. Studies have shown that drugs that target tumor cell glucose metabolism have the ability to selectively kill tumor cells, bringing new hope for tumor treatment. Tumor stem cells are considered to be the root cause of tumor recurrence, metastasis and poor prognosis, and their energy metabolism characteristics have not yet been agreed. Studies have shown that reversing the energy metabolism of tumor stem cells can increase their chemosensitivity. This article reviews recent studies on tumor and tumor stem cell glucose metabolism and the opportunities and challenges of tumor treatment through targeting glucose metabolism, which might provide new ideas and opportunities for clinical tumor therapy.


Assuntos
Metabolismo Energético , Glicólise , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo
8.
Anticancer Res ; 39(8): 4171-4177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366502

RESUMO

BACKGROUND/AIM: Identification of prostatic stem cells in primary prostate tissue sections, organ cultures of prostate and cell lines requires a range of techniques that allows characterization of stem cells for their potential use in the treatment of patients. Isolated cells usually round-up and develop changes in shape, size and cellular characteristics. The aim of this study was to provide a range of methods for identifying prostatic stem cells and characterizing them with regard to ultrastructure, nuclear morphology, cytoplasmic organelles, and/or expression stem cell marker CD133. MATERIALS AND METHODS: Prostate biopsy and prostatectomy specimens were used for studying prostatic stem cells and their known marker CD133 in tissue sections by light and/or electron microscopy. Inverted capsule embedding was used to study archival metastatic prostate in pelvic nodes and Du145 cell line in a monolayer culture. RESULTS: Staining for CD133 positively identified stem cells that were found in benign prostatic hyperplasia, benign prostate, and prostate cancer cells. Paraffin embedded sections showed a single type of stem cells, whereas methylene blue-stained Epon sections showed both light and dark stem cells. Electron microscopy showed that both basal and stem cells were closely associated with the basement membrane (basal lamina). Stem cells had smooth plasma and nuclear membranes, a prominent nucleolus, small mitochondria, and few ribosomes. Du145 cells were separated by intercellular spaces in monolayer culture. CONCLUSION: The inverted capsule embedding method allowed the study of metastasized prostate cancer in pelvic lymph nodes. Our approach enabled the assessment of stem cells in tissue sections by light and electron microscopy.


Assuntos
Antígeno AC133/genética , Membrana Basal/ultraestrutura , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Membrana Basal/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Microscopia Eletrônica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/ultraestrutura , Próstata/metabolismo , Próstata/patologia , Próstata/ultraestrutura , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/ultraestrutura
9.
Life Sci ; 234: 116781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430455

RESUMO

Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio- and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
10.
Medicine (Baltimore) ; 98(32): e16709, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393377

RESUMO

CD133 is currently believed to be one of the best colorectal cancer stem cell markers. This study aimed to evaluate prognostic significance of CD133 expression in colorectal cancer patients.A total of 303 patients with stage I to III colorectal cancer who underwent curative surgical resection from 2003 to 2008 at a single institution were included. CD133 expression was evaluated using immunohistochemical staining, and clinicopathological data were retrospectively reviewed. The patients were dichotomized after scoring CD133 expression (0 to 2+: low CD133 expression vs 3+ to 4+: high CD133 expression) according to the extent of area of CD133 positive tumor cells (<50% vs ≥50%) and pattern of staining (membranous staining of the luminal surface and/or staining of cellular debris in the tumor glands and cytoplasm).The 5-year overall survival (OS) (61.9% vs 80.2%, P = .001) and disease-free survival (64.8% vs 75.8%, P = .026) were poorer in the high CD133 expression group than the low CD133 expression group. In the multivariate analysis for risk factors of OS in the whole population, higher nodal stage (N2 compared to N0: hazard ratio [HR] 3.141; 95% confidence interval [CI] 1.718-5.744, P < .001), perineural invasion (HR 2.262; 95% CI 1.347-3.798, P = .002) and high CD133 expression (HR 1.929; 95% CI 1.221-3.048, P = .005) were independent poor prognostic factors of OS. Subgroup analyses according to each TNM stage revealed that CD133 expression was associated with OS only within the stage II patients (HR 3.167 95% CI 1.221-8.216, P = .018). Furthermore, the stage II patients demonstrating the high CD133 expression showed survival benefit of adjuvant chemotherapy, regardless of high-risk feature positivity (HR 0.201 95% CI 0.054-0.750, P = .017).High CD133 expression is correlated with poor prognosis in colorectal cancer patients after radical resection. The CD133 expression may serve as a more potent and informative biomarker for prognosis than conventional high-risk features in the stage II colorectal cancer patients.


Assuntos
Antígeno AC133/metabolismo , Neoplasias Colorretais/genética , Idoso , Biomarcadores Tumorais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Estudos Retrospectivos
11.
BMC Bioinformatics ; 20(Suppl 5): 181, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31272372

RESUMO

BACKGROUND: Within the cancer domain, ontologies play an important role in the integration and annotation of data in order to support numerous biomedical tools and applications. This work seeks to leverage existing standards in immunophenotyping cell types found in hematologic malignancies to provide an ontological representation of them to aid in data annotation and analysis for patient data. RESULTS: We have developed the Cancer Cell Ontology according to OBO Foundry principles as an extension of the Cell Ontology. We define classes in Cancer Cell Ontology by using a genus-differentia approach using logical axioms capturing the expression of cellular surface markers in order to represent types of hematologic malignancies. By adopting conventions used in the Cell Ontology, we have created human and computer-readable definitions for 300 classes of blood cancers, based on the EGIL classification system for leukemias, and relying upon additional classification approaches for multiple myelomas and other hematologic malignancies. CONCLUSION: We have demonstrated a proof of concept for leveraging the built-in logical axioms of the ontology in order to classify patient surface marker data into appropriate diagnostic categories. We plan to integrate our ontology into existing tools for flow cytometry data analysis to facilitate the automated diagnosis of hematologic malignancies.


Assuntos
Ontologias Biológicas , Neoplasias Hematológicas/patologia , Linhagem Celular Tumoral , Neoplasias Hematológicas/classificação , Neoplasias Hematológicas/metabolismo , Humanos , Imunofenotipagem , Aprendizado de Máquina , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo
12.
Life Sci ; 232: 116630, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279783

RESUMO

AIMS: Lung adenocarcinoma consists of multiple therapeutic targets, however, patients will inevitably progress to later stage diagnosis with Tyrosine Kinase Inhibitor treatment resistance. We aim to investigate the roles of non-coding TUSC7 in ordering the cell division tendency, helping to sensitize the resistance in a miRNA incorporating way. MATERIALS AND METHODS: Online study of bioinformatics analysis, molecular experiments of luciferase test, immunofluorescence staining and qRT-PCR were applied to dig out the mechanistic regulations. KEY FINDINGS: TUSC-7 inhibited the renewal ability of adenocarcinoma stem cells, yielding to asymmetric cell splitting. Informatics analysis and the luciferase testing confirmed the 3'UTR binding site, and revealed the post-transcriptional regulation of NUMB referring to miR-146. TUSC-7 sponged miR-146 and abolished its degradation toward to NUMB, and this integrated cascade made several genes become tangled to full functionality. SIGNIFICANCE: TUSC-7 was proved to be one strong suppressive lnc-RNA in lung adenocarcinoma stem cells, functioning through inactivating NOTCH signaling, and the turbulence on division modes precisely pointed to the key mechanisms of stem cells' renewal. The decreasing of tumor suppressive miR-146 was necessary in TUSC-7 conducted renewal repression, despite it alone could also reduce the renewal efficiency, indicating that more complicated non-coding genes may be involved in its regulation.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/fisiologia , Regiões 3' não Traduzidas , Adenocarcinoma de Pulmão/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo
13.
Cancer Invest ; 37(6): 242-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31296070

RESUMO

Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34+ progenitor/stem leukemia cells from CML patients. QC targets RNA polymerase I, which produces ribosomal (r)RNA, involving in protein translation process. Also, QC treatment prolongs CML-like mice survival and inhibits K562 tumor growth in vivo. In conclusion, we demonstrate that QC depletes BCR-ABL protein and suppresses Ph-positive leukemia cells in vitro and in vivo.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Quinacrina/uso terapêutico , Animais , Antígenos CD34/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
14.
Artigo em Chinês | MEDLINE | ID: mdl-31315361

RESUMO

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.


Assuntos
Neoplasias Laríngeas/fisiopatologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133/biossíntese , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Receptores de Hialuronatos/biossíntese , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/metabolismo , Laringe/patologia , Laringe/fisiopatologia , Invasividade Neoplásica/fisiopatologia , Processos Neoplásicos
15.
Nature ; 571(7765): 355-360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270458

RESUMO

Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.


Assuntos
Genótipo , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Neoplasias/genética , Neoplasias/patologia , Transcriptoma/genética , Animais , Antígenos CD34/metabolismo , Calreticulina/genética , Linhagem Celular , Proliferação de Células , Células Clonais/classificação , Células Clonais/metabolismo , Células Clonais/patologia , Endorribonucleases/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Camundongos , Modelos Moleculares , Transtornos Mieloproliferativos/classificação , NF-kappa B/metabolismo , Neoplasias/classificação , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Resposta a Proteínas não Dobradas/genética
16.
Cell Mol Life Sci ; 76(20): 4043-4070, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31317205

RESUMO

Stem cells give rise to all cells and build the tissue structures in our body, and heterogeneity and plasticity are the hallmarks of stem cells. Epigenetic modification, which is associated with niche signals, determines stem cell differentiation and somatic cell reprogramming. Stem cells play a critical role in the development of tumors and are capable of generating 3D organoids. Understanding the properties of stem cells will improve our capacity to maintain tissue homeostasis. Dissecting epigenetic regulation could be helpful for achieving efficient cell reprograming and for developing new drugs for cancer treatment. Stem cell-derived organoids open up new avenues for modeling human diseases and for regenerative medicine. Nevertheless, in addition to the achievements in stem cell research, many challenges still need to be overcome for stem cells to have versatile application in clinics.


Assuntos
Epigênese Genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Organoides/metabolismo , Células-Tronco/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Transdiferenciação Celular , Reprogramação Celular , Transição Epitelial-Mesenquimal , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas/patologia , Organoides/patologia , Medicina Regenerativa/métodos , Nicho de Células-Tronco/genética , Transplante de Células-Tronco/métodos , Células-Tronco/classificação , Células-Tronco/citologia
17.
Nat Commun ; 10(1): 2910, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266951

RESUMO

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinases Ciclina-Dependentes/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/metabolismo , Recombinação Homóloga , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Camundongos , Camundongos SCID , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Células-Tronco Neoplásicas/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Life Sci ; 231: 116520, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158379

RESUMO

Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor microenvironment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers-instead, deploying mechanisms to retard tumor type-dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression.


Assuntos
Plasticidade Celular/fisiologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Divisão Celular Assimétrica/fisiologia , Carcinogênese/metabolismo , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Recidiva Local de Neoplasia/patologia , Transdução de Sinais , Microambiente Tumoral/fisiologia
19.
Life Sci ; 231: 116545, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176782

RESUMO

AIMS: The extracellular matrix (ECM) within the tumor nest plays a key role in cancer cell proliferation and invasion. It has been proven that the increased density of ECM, especially collagen network, correlates with the poor distribution of gold-nanoparticles (GNPs) to the tumor mass. Here, for the first time, we examined the combined effect of collagenase (COL) with metformin (MET)-conjugated GNPs on mammosphere generated from JIMT-1 breast cell line in vitro. MAIN METHODS: Mammospheres (on days 7 and 14) and monolayer culture were treated with MET, MET-GNPs, and a mixture of COL-GNPs and MET-GNPs for 5 days. To assess the impacts of the engineered nanoparticles (NPs) on the survival/apoptosis of cancer cells and cancer stem cells (CSCs), the amount/activity of collagen and the expression of pyruvate kinase M2, different methods were applied, including MTT, flow cytometry, immunofluorescence, ELISA and real-time PCR analyses. Our results confirmed the enhanced cytotoxic effects of MET-GNPs combined with COL-GNPs on mammospheres compared to the cells treated with MET alone or MET-GNPs. KEY FINDINGS: Upon treatment with the mixture of MET-GNPs and COL-GNPs, the population of the apoptotic cells was significantly increased. A marked reduction was found in the number of CD24-/CD44+ CSCs and the amount of collagen in the group received a mixture of MET-GNPs and COL-GNPs. SIGNIFICANCE: Based on our findings, the use of COL can improve the cellular interaction/penetration of MET-GNPs in mammospheres and its antitumor impacts on the CSCs.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Colagenases/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Metformina/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colagenases/farmacocinética , Colagenases/farmacologia , Matriz Extracelular/efeitos dos fármacos , Feminino , Humanos , Metformina/farmacocinética , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo
20.
Life Sci ; 232: 116562, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201845

RESUMO

AIMS: Lung cancer is one of the main causes of cancer-related deaths worldwide and radiotherapy is a major treatment of choice. However, radioresistance is a main reason for radiotherapy failure or tumor relapse. Here, we investigated possible mechanisms associated with cancer cell radioresistance. MATERIALS AND METHODS: We compared two newly derived cell lines, namely A549-IR3 and A549-IR6, which survived repeated (3 or 6 times) 4 Gy exposure of parental A549 lung cancer cell line. DNA repair ability, stemness and senescence were comparatively studied. KEY FINDINGS: A549-IR3 exhibited higher proliferation ability and radioresistance compared to parental and A549-IR6 cells. Enhanced radioresistance was not accompanied by chemoresistance to cisplatin or docetaxel. DNA repair kinetics (γΗ2ΑΧ expression) were similar in all cell lines. A549-IR3 cells exhibited a significant rise in stem cell markers (CD44, CD133, OCT4, SOX2 and NANOG) whereas A549-IR6 displayed an increased senescent population. SIGNIFICANCE: Cancer cells surviving after radiotherapy may follow two different escape pathways: selection for radioresistance resulting in regrowth, and in clinical terms relapse, or above an irradiation threshold, stem-cells die and cancer cells become senescent, leading the tumor to a state of dormancy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Células-Tronco Neoplásicas/efeitos da radiação , Células A549 , Envelhecimento/efeitos da radiação , Apoptose/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Humanos , Neoplasias Pulmonares/metabolismo , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação
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