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1.
BMJ Open ; 12(4): e054404, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487718

RESUMO

INTRODUCTION: Breast cancer is still the most common malignancy among women worldwide. The Prospective Breast Cancer Biobank (PBCB) collects blood and urine from patients with breast cancer every 6 or 12 months for 11 years from 2011 to 2030 at two university hospitals in Western Norway. The project aims to identify new biomarkers that enable detection of systemic recurrences at the molecular level. As blood represents the biological interface between the primary tumour, the microenvironment and distant metastases, liquid biopsies represent the ideal medium to monitor the patient's cancer biology for identification of patients at high risk of relapse and for early detection systemic relapse.Including patient-reported outcome measures (PROMs) allows for a vast number of possibilities to compare PROM data with biological information, enabling the study of fatigue and Quality of Life in patients with breast cancer. METHODS AND ANALYSIS: A total of 1455 patients with early-stage breast cancer are enrolled in the PBCB study, which has a one-armed prospective observational design. Participants consent to contribute liquid biopsies (i.e., peripheral blood and urine samples) every 6 or 12 months for 11 years. The liquid biopsies are the basis for detection of circulating tumour cells, circulating tumour DNA (ctDNA), exosomal micro-RNA (miRNA), miRNA in Tumour Educated Platelet and metabolomic profiles. In addition, participants respond to 10 PROM questionnaires collected annually. Moreover, a control group comprising 200 women without cancer aged 25-70 years will provide the same data. ETHICS AND DISSEMINATION: The general research biobank PBCB was approved by the Ministry of Health and Care Services in 2007, by the Regional Ethics Committee (REK) in 2010 (#2010/1957). The PROM (#2011/2161) and the biomarker study PerMoBreCan (#2015/2010) were approved by REK in 2011 and 2015 respectively. Results will be published in international peer reviewed journals. Deidentified data will be accessible on request. TRIAL REGISTRATION NUMBER: NCT04488614.


Assuntos
Neoplasias da Mama , MicroRNAs , Adulto , Idoso , Bancos de Espécimes Biológicos , Biomarcadores , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Biópsia Líquida , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Observacionais como Assunto , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida , Microambiente Tumoral
2.
Glia ; 68(2): 316-327, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31509308

RESUMO

Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co-culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM-associated astrocyte signature and to investigate astrocyte-induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM-activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high "astrocyte signature score". Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient-derived culture, in a manner dependent on cell-cell contact and involving increased cell proliferation. Furthermore, co-injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.


Assuntos
Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Movimento Celular/fisiologia , Glioblastoma/metabolismo , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Técnicas de Cocultura , Modelos Animais de Doenças , Glioblastoma/patologia , Glioma/metabolismo , Humanos , Camundongos Endogâmicos NOD
3.
Pharmacol Res ; 124: 74-91, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28712971

RESUMO

Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.


Assuntos
Antineoplásicos/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Humanos
4.
BMC Cancer ; 17(1): 108, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28173797

RESUMO

BACKGROUND: Little is known about the role of glial host cells in brain tumours. However, supporting stromal cells have been shown to foster tumour growth in other cancers. METHODS: We isolated stromal cells from patient-derived glioblastoma (GBM) xenografts established in GFP-NOD/scid mice. With simultaneous removal of CD11b+ immune and CD31+ endothelial cells by fluorescence activated cell sorting (FACS), we obtained a population of tumour-associated glial cells, TAGs, expressing markers of terminally differentiaed glial cell types or glial progenitors. This cell population was subsequently characterised using gene expression analyses and immunocytochemistry. Furthermore, sphere formation was assessed in vitro and their glioma growth-promoting ability was examined in vivo. Finally, the expression of TAG related markers was validated in human GBMs. RESULTS: TAGs were highly enriched for the expression of glial cell proteins including GFAP and myelin basic protein (MBP), and immature markers such as Nestin and O4. A fraction of TAGs displayed sphere formation in stem cell medium. Moreover, TAGs promoted brain tumour growth in vivo when co-implanted with glioma cells, compared to implanting only glioma cells, or glioma cells and unconditioned glial cells from mice without tumours. Genome-wide microarray analysis of TAGs showed an expression profile distinct from glial cells from healthy mice brains. Notably, TAGs upregulated genes associated with immature cell types and self-renewal, including Pou3f2 and Sox2. In addition, TAGs from highly angiogenic tumours showed upregulation of angiogenic factors, including Vegf and Angiopoietin 2. Immunohistochemistry of three GBMs, two patient biopsies and one GBM xenograft, confirmed that the expression of these genes was mainly confined to TAGs in the tumour bed. Furthermore, their expression profiles displayed a significant overlap with gene clusters defining prognostic subclasses of human GBMs. CONCLUSIONS: Our data demonstrate that glial host cells in brain tumours are functionally distinct from glial cells of healthy mice brains. Furthermore, TAGs display a gene expression profile with enrichment for genes related to stem cells, immature cell types and developmental processes. Future studies are needed to delineate the biological mechanisms regulating the brain tumour-host interplay.


Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioblastoma/metabolismo , Transcriptoma , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Análise em Microsséries , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Biomed Res Int ; 2013: 139674, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24312904

RESUMO

OBJECT: Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. METHODS: GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. RESULTS: In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P = 0.04). CONCLUSION: GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Radiocirurgia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Comportamento Animal , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Ratos , Ratos Nus , Análise de Sobrevida
6.
Cancer Invest ; 31(4): 221-30, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23521006

RESUMO

Here we describe a NOD/Scid mouse strain expressing the dsRed transgene. The strain is maintained by inbreeding of homozygous dsRed NOD/Scid siblings, and expresses red fluorescence from various organs. The model allows engraftment of human tumor tissue, and engrafted tumors were separated into stromal and malignant cell compartments. Furthermore, we compared tumor-associated and normal fibroblast for expression of fibroblast-associated markers, and identified a marker panel that was upregulated in the tumor-associated fibroblasts. In conclusion, we propose that this model may be used in a variety of studies of tumor progression and to elucidate the role of the tumor microenvironment.


Assuntos
Modelos Animais de Doenças , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Transgenes , Animais , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Humanos , Proteínas Luminescentes/biossíntese , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Transplante de Neoplasias/métodos , Células Estromais/metabolismo , Transplante Heterólogo , Regulação para Cima
7.
BMC Cancer ; 12: 21, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22251838

RESUMO

BACKGROUND: The tumor microenvironment is pivotal in tumor progression. Thus, we aimed to develop a mammary tumor model to elucidate molecular characteristics in the stroma versus the tumor cell compartment by global gene expression. Secondly, since tumor hypoxia influences several aspects of tumor pathophysiology, we hypothesized that hyperoxia might have an inhibitory effect on tumor growth per se. Finally, we aimed to identify differences in gene expression and key molecular mechanisms, both in the native state and following treatment. METHODS: 4T1 dsRed breast cancer cells were injected into eGFP expressing NOD/SCID mice. Group 1 was exposed to 3 intermittent HBO treatments (Day 1, 4 and 7), Group 2 to 7 daily HBO treatments (both 2.5 bar, 100% O2, à 90 min), whereas the controls were exposed to a normal atmosphere. Tumor growth, histology, vascularisation, cell proliferation, cell death and metastasis were assessed. Fluorescence-activated cell sorting was used to separate tumor cells from stromal cells prior to gene expression analysis. RESULTS: The purity of sorted cells was verified by fluorescence microscopy. Gene expression profiling demonstrated that highly expressed genes in the untreated tumor stroma included constituents of the extracellular matrix and matrix metalloproteinases. Tumor growth was significantly inhibited by HBO, and the MAPK pathway was found to be significantly reduced. Immunohistochemistry indicated a significantly reduced microvessel density after intermittent HBO, whereas daily HBO did not show a similar effect. The anti-angiogenic response was reflected in the expression trends of angiogenic factors. CONCLUSIONS: The present in vivo mammary tumor model enabled us to separate tumor and stromal cells, and demonstrated that the two compartments are characterized by distinct gene expressions, both in the native state and following HBO treatments. Furthermore, hyperoxia induced a significant tumor growth-inhibitory effect, with significant down-regulation of the MAPK pathway. An anti-angiogenic effect after intermittent HBO was observed, and reflected in the gene expression profile.


Assuntos
Hipóxia Celular/fisiologia , Perfilação da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Matriz Extracelular/genética , Feminino , Proteínas de Fluorescência Verde/metabolismo , Oxigenoterapia Hiperbárica , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
8.
BMC Cancer ; 11: 524, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-22185371

RESUMO

BACKGROUND: Expression of neuronal elements has been identified in various glial tumors, and glioblastomas (GBMs) with neuronal differentiation patterns have reportedly been associated with longer survival. However, the neuronal class III ß-tubulin has been linked to increasing malignancy in astrocytomas. Thus, the significance of neuronal markers in gliomas is not established. METHODS: The expressions of class III ß-tubulin, neurofilament protein (NFP), microtubule-associated protein 2 (MAP2) and neuron-specific enolase (NSE) were investigated in five GBM cell lines and two GBM biopsies with immunocytochemistry and Western blot. Moreover, the expression levels were quantified by real-time qPCR under different culture conditions. Following NSE siRNA treatment we used Electric cell-substrate impedance sensing (ECIS) to monitor cell growth and migration and MTS assays to study viability after irradiation and temozolomide treatment. Finally, we quantitated NSE expression in a series of human glioma biopsies with immunohistochemistry using a morphometry software, and collected survival data for the corresponding patients. The biopsies were then grouped according to expression in two halves which were compared by survival analysis. RESULTS: Immunocytochemistry and Western blotting showed that all markers except NFP were expressed both in GBM cell lines and biopsies. Notably, qPCR demonstrated that NSE was upregulated in cellular stress conditions, such as serum-starvation and hypoxia, while we found no uniform pattern for the other markers. NSE knockdown reduced the migration of glioma cells, sensitized them to hypoxia, radio- and chemotherapy. Furthermore, we found that GBM patients in the group with the highest NSE expression lived significantly shorter than patients in the low-expression group. CONCLUSIONS: Neuronal markers are aberrantly expressed in human GBMs, and NSE is consistently upregulated in different cellular stress conditions. Knockdown of NSE reduces the migration of GBM cells and sensitizes them to hypoxia, radiotherapy and chemotherapy. In addition, GBM patients with high NSE expression had significantly shorter survival than patients with low NSE expression. Collectively, these data suggest a role for NSE in the adaption to cellular stress, such as during treatment.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas , Dacarbazina/análogos & derivados , Glioma , Proteínas de Neurofilamentos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Adulto , Idoso , Biópsia , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dacarbazina/farmacologia , Impedância Elétrica , Feminino , Técnicas de Inativação de Genes , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioma/metabolismo , Glioma/terapia , Humanos , Imuno-Histoquímica , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Temozolomida , Tubulina (Proteína)/metabolismo , Adulto Jovem
9.
Cancer Res ; 70(11): 4274-9, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20460538

RESUMO

Although CD133 has been proposed as a marker for brain tumor-initiating cells, studies show that a tumorigenic potential exists among CD133(-) glioma cells as well. However, it is not established whether the ability of CD133(-) cells to form tumors is a property confined to a small subpopulation, rather than a common trait associated with most glioma cell types. Thus, we used lentiviral vectors expressing green fluorescent protein under lineage-specific promoters to identify CD133(-) glioma cells expressing Nestin, glial fibrillary acidic protein (GFAP), and neuron-specific enolase (NSE). Flow cytometry analysis showed the presence of CD133(-) subpopulations expressing these markers in glioma cell lines and in primary cultures from human glioblastoma (GBM) biopsies. Moreover, analysis of cell cycle distribution showed that subgroups expressing Nestin, GFAP, and NSE uniformly contained actively cycling cells, when cultured in serum-containing medium and stem cell medium. These subpopulations were fluorescence-activated cell sorted from CD133(-) U373 glioma cells and implanted intracerebrally in severe combined immunodeficient mice. Moreover, we implanted Nestin-, GFAP-, and NSE-positive glioma cells sorted from a human GBM biopsy, following removal of CD133-positive cells. All the CD133(-) subpopulations produced tumors, with no significant differences in survival or tumor take rates. However, there was a trend toward lower take rates for CD133(-) glioma subpopulations expressing GFAP and NSE. These findings suggest that the ability to form tumors may be a general trait associated with different glioma cell phenotypes, rather than a property limited to an exclusive subpopulation of glioma stem cells.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Antígeno AC133 , Animais , Antígenos CD/biossíntese , Neoplasias Encefálicas/classificação , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Vetores Genéticos , Proteína Glial Fibrilar Ácida/biossíntese , Proteína Glial Fibrilar Ácida/genética , Glioblastoma/classificação , Glicoproteínas/biossíntese , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Humanos , Proteínas de Filamentos Intermediários/biossíntese , Proteínas de Filamentos Intermediários/genética , Lentivirus/genética , Camundongos , Camundongos SCID , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Nestina , Peptídeos , Fosfopiruvato Hidratase/biossíntese , Fosfopiruvato Hidratase/genética
10.
Chronobiol Int ; 26(2): 242-57, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19212839

RESUMO

Circadian clocks have been shown to operate developmentally in mouse and human hematopoietic stem and progenitor cells in vivo, but little is known about their possible oscillations in vitro. Here, we show that repeated circadian oscillations could be induced in both cultured bone marrow-derived mesenchymal- and adipose-derived stem cells (MSCs and ASCs, respectively) by serum shock. In particular, the novel finding of rhythmic clock gene expression induced by cAMP analogs showed similarities as well as differences to serum-induced oscillations. Rhythmic PER1 expression was found in serum-shocked MSCs, suggesting the phosphorylation status of PER1 is important for its activity in circadian rhythms. Furthermore, immunofluoresent staining showed that the localization of PER1 was dependent on the level of PER1 expression. These inducible self-sustained circadian clocks in primary cultures of human MSCs in vitro with rhythmic changes in expression levels, phosphorylation, and localization of clock protein, PER1, may be of importance for maintaining the induced oscillations in stem cells. Therefore, the established cell models described here appear to be valuable for studying the molecular mechanism driving and coordinating the circadian network between stem and stromal cells.


Assuntos
Ritmo Circadiano/fisiologia , AMP Cíclico/análogos & derivados , Células-Tronco Mesenquimais/fisiologia , Soro/metabolismo , Estresse Fisiológico , Tecido Adiposo/citologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Proteínas CLOCK , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Proteínas Circadianas Period , Transativadores/genética , Transativadores/metabolismo
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