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1.
Isr Med Assoc J ; 22(1): 32-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927803

RESUMO

BACKGROUND: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency. OBJECTIVES: To identify a unique heterogeneity pattern that is associated with true MMR loss. METHODS: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing. RESULTS: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases. CONCLUSIONS: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , Proteínas MutS/genética , Adenoma/genética , Adenoma/patologia , Adulto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Corantes , Heterogeneidade Genética , Humanos , Masculino
2.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892565

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Fluoruracila/farmacologia , Xenoenxertos , Humanos , Receptores de Hialuronatos/genética , Camundongos
3.
Anticancer Res ; 40(1): 177-190, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892566

RESUMO

BACKGROUND/AIM: The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) regulates cancer cell proliferation and invasion via complex molecular mechanisms. We aimed to investigate whether COUP-TFII modulates proliferation and invasion of the colorectal adenocarcinoma cell line HT-29. MATERIALS AND METHODS: HT-29 cells were stably tranfected with COUP-TFII shRNA plasmid to knock-down COUP-TFII (COUP-TFII shRNA-HT-29 cells). Cell proliferation, colony formation assay, invasion assay, microarray assays and western blot analyses were performed. RESULTS: Cell proliferation and invasion were significantly enhanced in COUP-TFII shRNA-HT-29 cells. The protein levels of forkhead box C1 (FOXC1), p-Akt, p-glycogen synthase kinase-3ß (p-GSK-3ß), and ß-catenin, which are known to be involved in cell proliferation and invasion, were significantly increased in COUP-TFII shRNA-HT-29 cells. Akt inhibitor IV and dominant negative (DN)-Akt expression vector transfection reversed the increased proliferation and invasion, which was accompanied by decreased protein levels of p-Akt, p-GSK-3ß, ß-catenin and FOXC1. CONCLUSION: COUP-TFII knock-down promoted proliferation and invasion via activation of Akt/GSK-3ß/ß-catenin and up-regulation of FOXC1. Further studies on the molecular mechanism of interaction between ß-catenin and FOXC1 expression may reveal novel target molecules for metastatic colorectal cancer therapy.


Assuntos
Fator II de Transcrição COUP/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator II de Transcrição COUP/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , RNA Interferente Pequeno/genética
4.
Gut ; 69(1): 103-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31023832

RESUMO

OBJECTIVE: We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival. DESIGN: We sequentially sampled 92 patients undergoing CRC resection, and measured plasma 25OHD and CRP. For survival analyses, we assayed 25OHD and CRP in two temporally distinct CRC patient cohorts (n=2006, n=2100) and investigated the association between survival outcome, circulating vitamin D and systemic inflammatory response. RESULTS: Serial sampling revealed a postoperative fall (mean 17.3 nmol/L; p=3.6e-9) in plasma 25OHD (nadir days 1-2). CRP peaked 3-5 days postoperatively (143.1 mg/L; p=1.4e-12), yet the postoperative fall in 25OHD was independent of CRP. In cohort analyses, 25OHD was lower in the 12 months following operation (mean=48.8 nmol/L) than preoperatively (54.8 nmol/L; p=1.2e-5) recovering after 24 months (52.2 nmol/L; p=0.002). Survival analysis in American Joint Committee on Cancer stages I-III demonstrated associations between 25OHD tertile and CRC mortality (HR=0.69; 95% CI 0.46 to 0.91) and all-cause mortality (HR=0.68; 95% CI 0.50 to 0.85), and was independent of CRP. We observed interaction effects between plasma 25OHD and rs11568820 genotype (functional VDR polymorphism) with a strong protective effect of higher 25OHD only in patients with GG genotype (HR=0.51; 95% CI 0.21 to 0.81). We developed an online tool for predicted survival (https://apps.igmm.ed.ac.uk/mortalityCalculator/) that incorporates 25OHD with clinically useful predictive performance (area under the curve 0.77). CONCLUSIONS: CRC surgery induces a fall in circulating 25OHD. Plasma 25OHD level is a prognostic biomarker with low 25OHD associated with poorer survival, particularly in those with rs11568820 GG genotype. A randomised trial of vitamin D supplementation after CRC surgery has compelling rationale.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/cirurgia , Vitamina D/análogos & derivados , Idoso , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores de Calcitriol/genética , Análise de Sobrevida , Síndrome de Resposta Inflamatória Sistêmica/sangue , Vitamina D/sangue
5.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31296605

RESUMO

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/genética , Melanoma/secundário , Neoplasias/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fluxo de Trabalho
6.
Tumour Biol ; 41(11): 1010428319883721, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31718480

RESUMO

The involvement of microRNA in cancers plays a significant role in their pathogenesis. Specific expressions of these non-coding RNAs also serve as biomarkers for early colorectal cancer diagnosis, but their laboratory/molecular identification is challenging and expensive. The aim of this study was to identify potential microRNAs for colorectal cancer diagnosis using in silico approach. Sequence similarity search was employed to obtain the candidate microRNA from the datasets, and three target prediction software were employed to determine their target genes. To determine the involvement of these microRNAs in colorectal cancer, the microRNA gene list obtained was used alongside with colorectal cancer expressed genes from gbCRC and CoReCG databases for gene intersection analysis. The involvement of these genes in the cancer subtype was further strengthened with the DAVID database. KEGG and Gene Ontology were used for the pathway and functional analysis, while STRING was employed for the interactions of protein network and further visualized by Cytoscape. The cBioPortal database was used to prioritize the target genes; prognostic and expression analysis were finally performed on the candidate microRNAs and the prioritized targets. This study, therefore, identified five candidate microRNAs, two hub genes (CTNNB1 and epidermal growth factor receptor), and seven significant target genes associated with colorectal cancer. The molecular validation studies are ongoing to ascertain the biological fitness of these findings.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , MicroRNAs/genética , Transcriptoma/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Simulação por Computador , Bases de Dados Genéticas , Detecção Precoce de Câncer , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Mapeamento de Interação de Proteínas , beta Catenina/genética
7.
Anticancer Res ; 39(11): 5867-5877, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704811

RESUMO

BACKGROUND/AIM: The aim of this study was to examine clonal heterogeneity, to test the utility of liquid biopsy in monitoring disease progression and to evaluate the usefulness of ex vivo drug screening in a BRAF L597Q-mutated colorectal cancer (CRC) patient developing metastases during adjuvant therapy. MATERIALS AND METHODS: Next generation sequencing (NGS) and droplet digital PCR (ddPCR) were performed in samples from tumor tissues and liquid biopsies. Live cancer cells from a metastatic lesion were used in ex vivo drug sensitivity assays. RESULTS: We found evidence of continued dependence of MEK/MAPK pathway activation, but different activating mutations in primary tumor and metastases. Liquid biopsy based BRAF L597Q ddPCR testing was a sensitive personalized biomarker predicting the rise of clinically aggressive metastatic disease. Ex vivo drug sensitivity assays with BRAF L597Q mutated cells showed response to MEK/MAPK targeted therapies. CONCLUSION: The rare BRAF L597Q mutation may be associated with aggressive tumor behavior in CRC. Liquid biopsy can be used to capture clinically relevant tumor features.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 1/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Capecitabina/administração & dosagem , Evolução Clonal , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MAP Quinase Quinase 1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oxaliplatina/administração & dosagem , Prognóstico
8.
N Engl J Med ; 381(17): 1632-1643, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31566309

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Progressão da Doença , Eletrocorticografia , Feminino , Humanos , Análise de Intenção de Tratamento , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
9.
Anticancer Res ; 39(10): 5645-5652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570462

RESUMO

BACKGROUND/AIM: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. PATIENTS AND METHODS: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. RESULTS: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). CONCLUSION: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Panitumumabe/administração & dosagem
10.
Nature ; 574(7776): 127-131, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570881

RESUMO

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/tendências , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/genética , Nivolumabe/uso terapêutico , Medicina de Precisão , Intervalo Livre de Progressão , Projetos de Pesquisa , Adulto Jovem
11.
Toxicol Lett ; 317: 102-109, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31574306

RESUMO

BACKGROUND: Cigarette smoke is considered a risk factor for lung and colorectal cancer. A convincing link between epithelial-to-mesenchymal transition (EMT) with colorectal cancer progression and therapeutic resistance has emerged. Deregulated expression of E-Cadherin and Claudin-1 and increased miR-21 expression and invasiveness represent hallmarks of EMT. The effects of cigarette smoke exposure on EMT in colorectal adenocarcinoma cells are largely unknown. AIM: The aim of the study is to evaluate the effect of cigarette smoke extract (CSE) on miR-21, Claudin-1 and E-Cadherin, molecules associated to EMT in colorectal cancer cells. METHODS: A human colorectal adenocarcinoma cell line (Caco-2) was treated with CSE at different concentration (5% and 10%) and for different time points (3 h and 24 h). Metabolic activity (by MTS assay), cell necrosis/cell apoptosis (evaluating Propidium Iodide/Annexin V expression by flow cytometry), miR-21, Claudin-1 and E-Cadherin gene expression were evaluated by Real time PCR. Cell permeability, actin polymerization and cancer cell migration was assessed by Trans-Epitelial Electrical Resistance (TEER), Phalloidin expression and matrigel system, respectively. RESULTS: CSE at all the tested concentrations and at all time points reduced cell necrosis. CSE at 10% increased miR-21 and reduced the metabolic activity, cell necrosis, Claudin-1 and E-cadherin mRNA at 3 h. Cell permeability, actin polymerization and cancer cell migration were all increased upon CSE exposure. CONCLUSION: These results showed that CSE increasing miR-21, Claudin-1 and E-Cadherin and enhancing the aggressiveness of cancer cells, may concur to colorectal cancer progression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Movimento Celular , Fumar Cigarros/efeitos adversos , Claudina-1/metabolismo , Neoplasias Colorretais/metabolismo , MicroRNAs/metabolismo , Fumaça/efeitos adversos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antígenos CD/genética , Células CACO-2 , Caderinas/genética , Claudina-1/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica , Transdução de Sinais
12.
Adv Exp Med Biol ; 1164: 63-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576540

RESUMO

Gankyrin (also called PSMD10, p28, or p28GANK) is a crucial oncoprotein that is upregulated in various cancers and assumed to play pivotal roles in the initiation and progression of tumors. Although the in vitro function of gankyrin is relatively well characterized, its role in vivo remains to be elucidated. We have investigated the function of gankyrin in vivo by producing mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrinf/f) and gankyrin deletion both in liver parenchymal and in non-parenchymal cells (Mx1-Cre;gankyrinf/f). Gankyrin deficiency both in non-parenchymal cells and parenchymal cells, but not in parenchymal cells alone, reduced STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, leading to attenuated tumorigenic potential in the diethylnitrosamine hepatocarcinogenesis model. Essentially similar results were obtained by analyzing mice with intestinal epithelial cell-specific gankyrin ablation (Villin-Cre;Gankyrinf/f) and gankyrin deletion both in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f) in the colitis-associated cancer model. Clinically, gankyrin expression in the tumor microenvironment was negatively correlated with progression-free survival in patients undergoing treatment with Sorafenib for hepatocellular carcinomas. These findings indicate important roles played by gankyrin in non-parenchymal cells as well as parenchymal cells in the pathogenesis of liver cancers and colorectal cancers, and suggest that by acting both on cancer cells and on the tumor microenvironment, anti-gankyrin agents would be promising as therapeutic and preventive strategies against various cancers, and that an in vitro cell culture models that incorporate the effects of non-parenchymal cells and gankyrin would be useful for the study of human cell transformation.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Complexo de Endopeptidases do Proteassoma , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/terapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Deleção de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/terapia , Camundongos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
13.
Arq Bras Cir Dig ; 32(3): e1449, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31644669

RESUMO

INTRODUCTION: The matrix metalloproteinase-7 (MMP-7) gene -181A>G polymorphism has been reported to be associated with colorectal cancer (CRC) and gastric cancer (GC) susceptibility, yet the results of these previous results have been inconsistent or controversial. AIM: To elaborate a meta-analysis to assess the association of -181A>G polymorphism of MMP-7 with CRC and GC risk. METHODS: Published literature evaluating the association from PubMed, Web of Science, Google Scholar and other databases were retrieved up to April 25, 2018. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS: A total of 19 case-control studies, which included eleven studies on CRC (2,169 CRC cases and 2,346 controls) and eight studies on GC (1,545 GC cases and 2,366 controls) were identified. There was a significant association between MMP-7 -181A>G polymorphism and GC risk under the homozygote model (GG vs. AA: OR=1.672, 95% CI 1.161-2.409, p=0.006) and the recessive model (GG vs. GA+AA: OR=1.672, 95% CI 1.319-2.554, p=0.001), but not with CRC. By subgroup analysis based on ethnicity, an increased risk of CRC and GC was found only among Asians. CONCLUSIONS: This meta-analysis suggests that MMP-7 -181A>G polymorphisms is associated with GC risk, but not with CRC. However, our results clearly showed that the MMP-7 -181A>G polymorphism significantly increased the risk of CRC only in Asians.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Metaloproteinase 7 da Matriz/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/etnologia , Humanos , Razão de Chances , Fatores de Risco
14.
Nature ; 574(7779): 532-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645730

RESUMO

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismo
15.
Zhonghua Zhong Liu Za Zhi ; 41(10): 734-741, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648494

RESUMO

Microsatellite instability (MSI) which resulted from the deficiency of DNA mismatch repair (MMR), is an important clinical significance in the related solid tumors, such as colorectal cancer and endometrial cancer. There are several methods to detect MSI status, including immunohistochemistry for MMR protein, multiplex fluorescent polymerase chain reaction (PCR) for microsatellite site and MSI algorithm based on next generation sequencing (NGS). The consensus elaborates the definition and clinical significance of MSI as well as the advantages and disadvantages of the three detection methods. Through this expert consensus, we hope to promote the screening which based on MSI status in malignant tumors and improve the acknowledge of clinicians about various testing methods. Thereby, they could interpret the results more accurately and provide better clinical services to patients.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/genética , Consenso , Assistência à Saúde/normas , Instabilidade de Microssatélites , Guias de Prática Clínica como Assunto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , China , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Sequência de DNA Instável , Neoplasias do Endométrio , Feminino , Humanos , Imuno-Histoquímica , Repetições de Microssatélites , Microscopia de Fluorescência , Reação em Cadeia da Polimerase
16.
Presse Med ; 48(9): 904-914, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31561847

RESUMO

About 5% of colorectal cancer (CRC) cases occurred in the context of an underlying hereditary predisposition syndrome. Lynch syndrome is the main causes of hereditary CRC but is also associated with a higher risk of other cancers (such as endometrial cancer and ovarian cancer). It is the consequence of constitutional mutation in a MisMatch Repair (MMR) gene, involved in DNA repair: MLH1, MSH2, MSH6 or PMS2; or of the EPCAM gene (MSH2 promotor). If a mutation predisposing to Lynch Syndrome is identified in an individual, special monitoring should be initiated, adapted to estimated cancer risk. Clinical criteria (Amsterdam II and Bethesda) have been validated to identify the patients who should be referred for genetic counseling in order to initiate constitutional DNA testing. Furthermore, the French National Cancer Institute (INCa) systematically recommend tumoral testing looking for MMR system failure in case of CRC diagnosed under 60, endometrial cancer diagnosed under 50 or whatever the age in patients diagnosed with CRC or endometrial cancer harbouring personal or familal history of Lunch Syndrome cancers. In this review, we will discuss how to detect Lynch syndrome (identification of the index case and family screening) and how to monitor it in 2019.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Fatores Etários , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Intestino Grosso , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Vigilância da População/métodos , Guias de Prática Clínica como Assunto , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/genética
17.
Gene ; 721: 144097, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493507

RESUMO

BACKGROUND: Polo-like kinase 1 (PLK1) is a potential prognostic marker in colorectal cancer (CRC). Nevertheless, the clinicopathological and prognostic roles of PLK1 in CRC are still undefined. Therefore, we performed a meta-analysis to investigate the clinicopathological and prognostic relevance of PLK1 expression in CRC patients. METHODS: Studies published between 2003 and 2016 were selected for the meta-analysis based on an electronic literature search (PubMed, EMBASE and Chinese databases). Studies that investigated the clinicopathological and prognostic impacts of PLK1 expression in CRC patients were included for this analysis. RESULTS: Eleven studies that enrolled 1147 CRC patients were included in our meta-analysis. The effect of PLK1 level on overall survival (OS) was reported in five studies, which included 702 patients. Ten studies investigated the clinicopathological role of PLK1 expression in CRC patients. Consequently, PLK1 overexpression was associated with poorer OS in CRC patients. Furthermore, the results revealed that higher PLK1 levels were also observed in CRC tissues compared with that of normal colorectal tissues. In addition, this meta-analysis also revealed positive correlations between PLK1 upregulation and lymph node metastasis or invasion. PLK1 overexpression was significantly correlated with advanced TNM stages and higher Dukes stages. CONCLUSION: This meta-analysis strongly supports the hypothesis that PLK1 might serve as an important factor in evaluating the biological behavior and prognosis of CRC.


Assuntos
Biomarcadores Tumorais/biossíntese , Proteínas de Ciclo Celular/biossíntese , Neoplasias Colorretais , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Taxa de Sobrevida
18.
Tumour Biol ; 41(9): 1010428319863627, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500540

RESUMO

Stratification of colorectal cancer for better management and tangible clinical outcomes is lacking in clinical practice. To reach this goal, the identification of reliable biomarker(s) is a prerequisite to deliver personalized colorectal cancer theranostics. Osteopontin (SPP1) is a key extracellular matrix protein involved in several pathophysiological processes including cancer progression and metastasis. However, the exact molecular mechanisms regulating its expression, localization, and molecular functions in cancer are still poorly understood. This study was designed to investigate the SPP1 expression profiles in Saudi colorectal cancer patients, and to assess its prognostic value. Hundred thirty-four (134) archival paraffin blocks of colorectal cancer were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed, and automated immunohistochemistry was performed to evaluate SPP1 protein expression patterns in colorectal cancer. About 20% and 23% of our colorectal cancer samples showed high SPP1 cytoplasmic and nuclear expression patterns, respectively. Cytoplasmic SPP1 did not correlate with age, gender, tumor size, and location. However, significant correlations were observed with tumor grade (p = 0.008), tumor invasion (p = 0.01), and distant metastasis (p = 0.04). Kaplan-Meier survival analysis showed a significantly lower recurrence rate in patients with higher SPP1 cytoplasmic expression (p = 0.05). At multivariate analysis, high SPP1 cytoplasmic expression was an independent favorable prognostic marker (p = 0.02). However, nuclear SPP1 expression did not show any prognostic value (p = 0.712). Our results showed a particular SPP1 prognostic relevance that is not in line with most colorectal cancer previous studies that may be attributed to the molecular pathophysiology of our colorectal cancer cohort. Saudi Arabia has both specific genomic makeup and particular environment that could lead to distinctive molecular roots of cancer. SPP1 has several isoforms, tissue localizations and molecular functions, signaling pathways, and downstream molecular functions. Therefore, a more individualized approach for CRC studies and particularly SPP1 prognosis outcomes' assessment is highly recommended toward precision oncology.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/genética , Osteopontina/genética , Idoso , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Medicina de Precisão , Prognóstico , Arábia Saudita/epidemiologia
19.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
20.
Cancer Treat Rev ; 80: 101894, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518831

RESUMO

Despite advances in translating conventional research into multi-modal treatment for colorectal cancer (CRC), therapeutic resistance and relapse remain unresolved in advanced resectable and, particularly, non-resectable disease. Genome and transcriptome sequencing and editing technologies, coupled with interaction mapping and machine learning, are transforming biomedical research, representing the most rational hope to overcome unmet research and clinical challenges. Rapid progress in both bulk and single-cell next-generation sequencing (NGS) analyses in the identification of primary and metastatic intratumor genomic and transcriptional heterogeneity (ITH) and the detection of circulating cell-free DNA (cfDNA) alterations is providing critical insight into the origins and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse. Moreover, DNA and RNA editing pave new avenues towards the discovery of novel drug targets. Breakthrough combinations of sequencing and editing systems with technologies exploring dynamic interaction networks within pioneering studies could delineate how coding and non-coding mutations perturb regulatory networks and gene expression. This review discusses latest data on genomic and transcriptomic landscapes in time and space, as well as early-phase clinical trials on targeted drug combinations, highlighting the transition from research to clinical Colorectal Cancer Precision Medicine, through non-invasive screening, individualized drug response prediction and development of multiple novel drugs. Future studies exploring the potential to target key transcriptional drivers and regulators will contribute to the next-generation pharmaceutical controllability of multi-layered aberrant transcriptional biocircuits.


Assuntos
Neoplasias Colorretais/genética , Animais , DNA de Neoplasias/genética , Genômica/métodos , Humanos , Medicina de Precisão , RNA Neoplásico/genética , Transcrição Genética
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