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1.
Clin Exp Metastasis ; 38(6): 495-510, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34748126

RESUMO

Colorectal carcinoma is the third most common cancer in developed countries and the second leading cause of cancer-related mortality. Interest in the influence of the intestinal microbiota on CRC emerged rapidly in the past few years, and the close presence of microbiota to the tumour mass creates a unique microenvironment in CRC. The gastrointestinal microbiota secrete factors that can contribute to CRC metastasis by influencing, for example, epithelial-to-mesenchymal transition. Although the role of EMT in metastasis is well-studied, mechanisms by which gastrointestinal microbiota contribute to the progression of CRC remain poorly understood. In this review, we will explore bacterial factors that contribute to the migration and invasion of colorectal carcinoma and the mechanisms involved. Bacteria involved in the induction of metastasis in primary CRC include Fusobacterium nucleatum, Enterococcus faecalis, enterotoxigenic Bacteroides fragilis, Escherichia coli and Salmonella enterica. Examples of prominent bacterial factors secreted by these bacteria include Fusobacterium adhesin A and Bacteroides fragilis Toxin. Most of these factors induce EMT-like properties in carcinoma cells and, as such, contribute to disease progression by affecting cell-cell adhesion, breakdown of the extracellular matrix and reorganisation of the cytoskeleton. It is of utmost importance to elucidate how bacterial factors promote CRC recurrence and metastasis to increase patient survival. So far, mainly animal models have been used to demonstrate this interplay between the host and microbiota. More human-based models are needed to study the mechanisms that promote migration and invasion and mimic the progression and recurrence of CRC.


Assuntos
Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Carcinoma/microbiologia , Movimento Celular , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal , Animais , Bactérias/patogenicidade , Carcinoma/metabolismo , Carcinoma/secundário , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Disbiose , Interações Hospedeiro-Patógeno , Humanos , Invasividade Neoplásica , Transdução de Sinais
2.
Sci Rep ; 11(1): 17750, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493772

RESUMO

Lineage tracing in mice indicates that LGR5 is an adult stem cell marker in multiple organs, such as the intestine, stomach, hair follicles, ovary, and mammary glands. Despite many studies exploring the presence of LGR5 cells in human tissues, little is known about its expression profile in either human mammary tissue or pathological lesions. In this study we aim to investigate LGR5 expression in normal, benign, and malignant lesions of the human breast using RNA in situ hybridization. LGR5 expression has not been observed in normal lactiferous ducts and terminal duct lobular units, whereas LGR5-positive cells have been specifically observed in the basal myoepithelium of ducts in the regenerative tissues, ductal carcinoma in situ, and in ducts surrounded by invasive cancer cells. These findings suggest LGR5 marks facultative stem cells that are involved in post injury regeneration instead of homeostatic stem cells. LGR5 positivity was found in 3% (9 of 278 cases) of invasive breast cancers (BC), and it showed positive associations with higher histologic grades (P = 0.001) and T stages (P < 0.001), while having negative correlations with estrogen receptor (P < 0.001) and progesterone receptor (P < 0.001) expression. Remarkably, all LGR5-positive BC, except one, belong to triple-negative BC (TNBC), representing 24% (9 of 38 cases) of all of them. LGR5 histoscores have no correlations with EGFR, CK5/6, Ki-67, or P53 expression. Additionally, no ß-catenin nuclear localization was observed in LGR5-positive BC, indicating that canonical Wnt pathway activation is less likely involved in LGR5 expression in BC. Our results demonstrate that LGR5 expression is induced in regenerative conditions in the myoepithelium of human mammary ducts and that its expression is only observed in TNBC subtype among all invasive BC. Further studies regarding the functional and prognostic impact of LGR5 in TNBC are warranted.


Assuntos
Mama/metabolismo , Células Epiteliais/metabolismo , Proteínas de Neoplasias/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Mama/citologia , Mama/fisiologia , Doenças Mamárias/genética , Doenças Mamárias/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Feminino , Fibroadenoma/genética , Fibroadenoma/metabolismo , Humanos , Hibridização In Situ , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Papiloma Intraductal/genética , Papiloma Intraductal/metabolismo , Tumor Filoide/genética , Tumor Filoide/metabolismo , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Receptores Acoplados a Proteínas G/genética , Regeneração/genética , Neoplasias de Mama Triplo Negativas/genética
3.
DNA Cell Biol ; 40(10): 1317-1324, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34591648

RESUMO

Breast invasive carcinoma (BRCA) is becoming the most common malignant disease worldwide, and there is intense interest in identifying diagnostic biomarkers that can be targeted for treatment of BRCA. Recent evidence has shown that calcyclin binding protein (CacyBP) can function as either a tumor promoter or suppressor during carcinogenesis. Data in The Cancer Genome Atlas (TCGA) database show that CacyBP is overexpressed in human BRCA tissues, and high levels of CacyBP are associated with shorter overall survival. Immunohistochemical staining has shown that CacyBP levels are high in cancer tissue samples and associated with a higher likelihood of disease progression. We, therefore, conducted a knockout assay to determine the role of CacyBP in the development of BRCA. Knockout of CacyBP significantly inhibited MCF7 cell proliferation and colony formation. Apoptosis was higher in CacyBP knockout cells compared with control cells. Microarray analysis showed that the CacyBP knockout caused dysregulation of numerous genes closely related to ß-catenin signaling, whereas quantitative reverse-transcription PCR and immunoblotting showed that it to be inactivated. In summary, we conclude that when overexpressed, CacyBP acts as a potential oncogene for BRCA by regulating ß-catenin signaling.


Assuntos
Apoptose , Neoplasias da Mama/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma/metabolismo , Proliferação de Células , beta Catenina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Feminino , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Transdução de Sinais
4.
Int J Mol Sci ; 22(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34576020

RESUMO

BACKGROUND: The possible involvement of p53 signaling, FGFR3 expression, and FGFR3 mutation rates in the prediction of the NMIBC anti-PD-L1 treatment response needs to be clarified. The main aim of our study was to explore predictive value of p53 expression, FGFR3 expression, and its gene mutation status for the therapeutic success of anti-PD-L1 treatment in the patient-derived murine model of recurrent high-PD-L1(+) GATA3(-)/CR5/6(-) high-grade and low-grade NMIBC. METHODS: twenty lines of patient-derived xenografts (PDXs) of relapsed high-PD-L1(+) double-negative NMIBC were developed, of which 10 lines represented high-grade tumors and the other ones-low-grade bladder cancer. Acceptors of each grade-related branch received specific anti-PD-L1 antibodies. Animals' survival, tumor-doubling time, and remote metastasis were followed during the post-interventional period. PD-L1, GATA3, CR5/6, and p53 protein expressions in engrafted tumors were assessed by immunohistochemistry. The FGFR3 expression and FGFR3 mutations in codons 248 and 249 were detected by real-time polymerase chain reaction. RESULTS: The expression of p53 protein is an independent factor affecting the animals' survival time [HR = 0.036, p = 0.031] of anti-PD-L1-treated mice with low-grade high-PD-L1(+) double-negative NMIBC PDX. The FGFR3 expression and FGFR3 mutation rate have no impact on the anti-PD-L1 treatment response in the interventional groups. CONCLUSIONS: p53 expression may be considered as a prognostic factor for the anti-PD-L1 treatment efficacy of low-grade high-PD-L1-positive GATA3(-)/CR5/6(-)-relapsed noninvasive bladder cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Animais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/mortalidade , Feminino , Humanos , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361031

RESUMO

Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to what extent it is justified that HLA-G expression is considered as a target for immune checkpoint inhibiting therapy by critically assessing the association between HLA-G expression by carcinomas and clinical outcome of patients. The used HLA-G-detecting mAb, HLA-G quantification methods and statistically significant HLA-G-associated clinicopathological parameters are discussed. Tumour HLA-G expression correlated with poor clinical outcome in breast, esophageal, gastric and hepatocellular carcinoma patients. Tumour HLA-G expression was not associated with clinical outcome in ovarian and oral carcinoma patients. Cervical, colorectal, lung, and pancreatic carcinoma patients presented discrepant and therefore inconclusive results regarding the association between tumour HLA-G expression and clinical outcome. These disparities might partly be the result of differences in the methodological approach to quantify HLA-G expression between studies. Therefore, implementation of universal methodological procedures is strongly advised. Overall, HLA-G expression did not univocally result in poor clinical outcome of carcinoma patients. This implies that tumour HLA-G expression is not necessarily part of an inhibited tumour-immune response and tumour progression. Consequently, it remains elusive whether HLA-G expression by carcinomas functions as an immune checkpoint molecule affecting a tumour-immune response. It may also reflect derailed control of gene expression in tumours, with no real functional consequences.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma/genética , Neoplasias do Sistema Digestório/genética , Antígenos HLA-G/genética , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Antígenos HLA-G/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia
6.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445547

RESUMO

Gangliosides serve as antitumor therapy targets and aberrations in their composition strongly correlate with tumor growth and invasiveness. Anaplastic ganglioglioma is a rare, poorly characterized, malignant neuronal-glial tumor type. We present the first comparative characterization of ganglioside composition in anaplastic ganglioglioma vs. peritumoral and healthy brain tissues by combining mass spectrometry and thin-layer chromatography. Anaplastic ganglioglioma ganglioside composition was highly distinguishable from both peritumoral and healthy tissue despite having five to six times lower total content. Ten out of twelve MS-identified ganglioside classes, defined by unique glycan residues, were represented by a large number and considerable abundance of individual species with different fatty acid residues (C16-C24) in ceramide portions. The major structurally identified class was tumor-associated GD3 (>50%) with 11 species; GD3 (d18:1/24:0) being the most abundant. The dominant sphingoid base residue in ganglioside ceramides was sphingosine (d18:1), followed by eicosasphingosine (d20:1). The peritumoral tissue ganglioside composition was estimated as normal. Specific ganglioside composition and large variability of ganglioside ceramide structures determined in anaplastic ganglioglioma demonstrate realistic ganglioside expression patterns and correspond to the profile of high-grade malignancy brain tumors.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Carcinoma/patologia , Cromatografia em Camada Delgada/métodos , Ganglioglioma/patologia , Gangliosídeos/metabolismo , Espectrometria de Massas/métodos , Idoso , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Carcinoma/metabolismo , Feminino , Ganglioglioma/metabolismo , Gangliosídeos/análise , Humanos , Pessoa de Meia-Idade
7.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444911

RESUMO

Plant-derived conjugated linolenic acids (CLnA) have been widely studied for their preventive and therapeutic properties against diverse diseases such as cancer. In particular, punicic acid (PunA), a conjugated linolenic acid isomer (C18:3 c9t11c13) present at up to 83% in pomegranate seed oil, has been shown to exert anti-cancer effects, although the mechanism behind its cytotoxicity remains unclear. Ferroptosis, a cell death triggered by an overwhelming accumulation of lipid peroxides, has recently arisen as a potential mechanism underlying CLnA cytotoxicity. In the present study, we show that PunA is highly cytotoxic to HCT-116 colorectal and FaDu hypopharyngeal carcinoma cells grown either in monolayers or as three-dimensional spheroids. Moreover, our data indicate that PunA triggers ferroptosis in carcinoma cells. It induces significant lipid peroxidation and its effects are prevented by the addition of ferroptosis inhibitors. A combination with docosahexaenoic acid (DHA), a known polyunsaturated fatty acid with anticancer properties, synergistically increases PunA cytotoxicity. Our findings highlight the potential of using PunA as a ferroptosis-sensitizing phytochemical for the prevention and treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Ácidos Linolênicos/farmacologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Células HCT116 , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos
8.
Exp Cell Res ; 406(1): 112735, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265287

RESUMO

Tripartite motif containing 16 (TRIM16) is a member of the tripartite motif protein family and functions as a potential tumor suppressor in several cancers. However, the specific function and clinical significance of TRIM16 in colorectal cancer (CRC) remains unclear. In this study, we observed that low TRIM16 expression was detected frequently in primary colorectal cancer (CRC) tissues and was closely associated with a better prognosis. Functional studies demonstrate that TRIM16 overexpression notably inhibits the metastasis abilities of CRC in vivo and in vitro. Mechanistically, our results demonstrated that TRIM16 directly bound and ubiquitinated Snail family transcriptional repressor 1 (Snail), an important transcriptional factor of the epithelial-mesenchymal transition (EMT) process suppressing the EMT in CRC. Additionally, our data revealed that the inhibition effect of TRIM16 on cancer metastasis was dependent on Snail degradation. Collectively, our study is the first to report that TRIM16 plays a crucial anti-tumor role in CRC tumorigenesis. We also provided novel evidence that TRIM16 might act as a prognostic and therapeutic target to assess and inhibit CRC progression.


Assuntos
Carcinoma/genética , Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Fatores de Transcrição da Família Snail/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/secundário , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Proteólise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Análise de Sobrevida , Proteínas com Motivo Tripartido/antagonistas & inibidores , Proteínas com Motivo Tripartido/metabolismo , Carga Tumoral , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
9.
J Comput Assist Tomogr ; 45(3): 431-441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34297512

RESUMO

INTRODUCTION: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor with characteristic BRD4-NUTM1 translocation and a poor prognosis. The primary objective of this study was to describe the clinical and radiologic features, treatment response, and survival of NUT carcinoma (NC). MATERIALS AND METHODS: This retrospective single-center study was based on the review of medical records of NC patients with a specific genetic rearrangement or positive anti-NUT nuclear staining. Overall survival (OS) was analyzed according to primary tumor location. RESULTS: This series of 22 patients had a mean age of 36.27 ± 2.68 years with 68% women and 32% men. The median age at diagnosis was 34 years (range, 17-55 years). The primary tumor was located in the chest (n = 12/22; 55%), head and neck (n = 9/22; 40%), and 1 patient had a renal tumor. About 68% (n = 15/22) patients presented with regional lymph nodal involvement and 77% (n = 17/22) had distant metastases. All the bone metastases were lytic (100%) with mixed lytic and sclerotic metastases in 5 patients. Only 18% (n = 4/22) of the patients showed response to treatment, with progression in the remaining 18 patients. The median OS was 7 months. The OS was significantly (P = 0.024) more in patients with primary head and neck NC (n = 9; OS, 16 months) versus those with pulmonary and other locations (n = 13; OS, 6 months). CONCLUSIONS: Nuclear protein of the testis carcinoma is an aggressive disease refractory to conventional therapy. Imaging with the complementary use of computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography is important for staging, guiding management, assessing the treatment response, and surveillance.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Carcinoma/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Carcinoma/metabolismo , Carcinoma/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Adulto Jovem
10.
Elife ; 102021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34219652

RESUMO

Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pHi) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na+,HCO3- cotransport and Na+/H+ exchange dominate cellular net acid extrusion in human breast carcinomas. Na+/H+ exchange elevates pHi preferentially in estrogen receptor-negative breast carcinomas, whereas Na+,HCO3- cotransport raises pHi more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na+/H+ exchanger NHE1/SLC9A1 and Na+,HCO3- cotransporter NBCn1/SLC4A7. Increased dependency on Na+,HCO3- cotransport associates with severe breast cancer: enlarged CO2/HCO3--dependent rises in pHi predict accelerated cell proliferation, whereas enhanced CO2/HCO3--dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na+,HCO3- cotransport for pHi regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Idoso , Animais , Bicarbonatos/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Pessoa de Meia-Idade , Organoides/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Trocador 1 de Sódio-Hidrogênio/genética , Trocador 1 de Sódio-Hidrogênio/metabolismo , Trocadores de Sódio-Hidrogênio , Transcriptoma
11.
Front Immunol ; 12: 634741, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220801

RESUMO

Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of metastatic urothelial carcinoma (mUC), a dominant type of bladder cancer (BC). Previous studies have shown an association between gene mutations in the DNA damage response (DDR) pathway and the immunotherapy response in mUC but have neglected the effect of the activation level of the DDR pathway on the ICI response in mUC. A published immunotherapy cohort with genome, transcriptome and survival data for 348 mUC patients was used. An external cohort (The Cancer Genome Atlas Bladder Cancer) and the GSE78220 cohort were used for validation. The activation level of the DDR pathway was quantified using single-sample gene set enrichment analysis (ssGSEA). Further analysis on the genome, immunogenicity, and the immune microenvironment was conducted using the DDR ssGSEA enrichment score-high (DSSH) group and the DDR ssGSEA enrichment score-low (DSSL) group. In the mUC cohorts, the DSSH group was associated with longer overall survival times (P=0.026; Hazard ratio=0.67; 95%CI: 0.46-0.95). The DSSH group was also associated with higher tumor mutation burden, neoantigen load, immune-activated cell patterns, and immune-related gene expression levels. The GSEA results indicated an immune activation state in DSSH group, which correlated with a down-regulation in the transforming growth factor ß receptor signaling pathway. Our study suggests that the activation level of the DDR pathway may be a novel predictive marker for immunotherapy efficacy in patients with mUC.


Assuntos
Carcinoma/tratamento farmacológico , Dano ao DNA , Reparo do DNA , Inibidores de Checkpoint Imunológico/uso terapêutico , Fator de Crescimento Transformador beta/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/metabolismo , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Transdução de Sinais , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Microambiente Tumoral , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/metabolismo , Urotélio/patologia
12.
Front Immunol ; 12: 690201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220848

RESUMO

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3+ T-cells and CD163+ tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS30) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1+pSTAT1Y701+) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10+IRF1+STAT1+ M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10+IRF1+STAT1+ macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies.


Assuntos
Carcinoma/metabolismo , Quimiocina CXCL10/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Ovarianas/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Complexo CD3/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/imunologia , Células Cultivadas , Quimiocina CXCL10/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Fenótipo , Prognóstico , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Macrófagos Associados a Tumor/imunologia
13.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207342

RESUMO

The transmembrane glycoprotein mucin 1 (MUC1) is a mucin family member that has different functions in normal and cancer cells. Owing to its structural and biochemical properties, MUC1 can act as a lubricant, moisturizer, and physical barrier in normal cells. However, in cancer cells, MUC1 often undergoes aberrant glycosylation and overexpression. It is involved in cancer invasion, metastasis, angiogenesis, and apoptosis by virtue of its participation in intracellular signaling processes and the regulation of related biomolecules. This review introduces the biological structure and different roles of MUC1 in normal and cancer cells and the regulatory mechanisms governing these roles. It also evaluates current research progress and the clinical applications of MUC1 in cancer therapy based on its characteristics.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Mucina-1/metabolismo , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Carcinoma/diagnóstico , Carcinoma/terapia , Células Epiteliais/metabolismo , Humanos , Mucina-1/química , Mucina-1/genética
14.
PLoS One ; 16(7): e0255007, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34314463

RESUMO

Ovarian high grade serous carcinoma (HGSC) is a lethal form of ovarian cancer (OVCA). In most cases it is detected at late stages as the symptoms are non-specific during early stages. Emerging information suggests that the oviductal fimbria is a site of origin of ovarian HGSC. Currently available tests cannot detect ovarian HGSC at early stage. The lack of a preclinical model with oviductal fimbria that develops spontaneous ovarian HGSC is a significant barrier to developing an early detection test for this disease. The goal of this study was to examine if the oviductal fimbria in hens is a site of origin of HGSC and whether it expresses several putative markers expressed in ovarian HGSC in patients. A total of 135 laying hens (4 years old) were selected from a flock using transvaginal ultrasound (TVUS) imaging, followed by euthanasia and gross examination for the presence of solid masses and ascites. Histological types of carcinomas were determined by hematoxylin and eosin staining. Expression of WT-1, mutant p53, CA-125, PAX2 and Ki67 in normal or malignant fimbriae or ovaries were examined using immunohistochemistry, immunoblotting and gene expression assays. This study detected tumors in oviductal fimbriae in hens and routine staining revealed ovarian HGSC-like microscopic features in these tumors. These tumors showed similarities to ovarian HGSC in patients in expressing several markers. Compared with normal fimbriae, intensities of expression of WT-1, mutant p53, CA-125, and Ki67 were significantly (P<0.05) higher in fimbrial tumors. In contrast, expression of PAX2 decreased gradually as the tumor progressed to late stages. The patterns of expression of these markers were similar to those in ovarian HGSC patients. Thus, tumors of the oviductal fimbria in hens may offer a preclinical model to study different aspects of spontaneous ovarian HGSC in women including its early detection.


Assuntos
Neoplasias Ovarianas/patologia , Oviductos/metabolismo , Animais , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/genética , Galinhas , Modelos Animais de Doenças , Feminino , Expressão Gênica , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Ovário/patologia , Oviductos/diagnóstico por imagem , Oviductos/patologia , Fator de Transcrição PAX2/genética , Fator de Transcrição PAX2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ultrassonografia , Proteínas WT1/genética , Proteínas WT1/metabolismo
15.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299016

RESUMO

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Carcinoma/imunologia , Carcinoma/metabolismo , Transição Epitelial-Mesenquimal/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
16.
Nutrients ; 13(5)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069974

RESUMO

The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K1, has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug-nutrient interaction mediated via PXR.


Assuntos
Citocromo P-450 CYP3A/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Receptor de Pregnano X/efeitos dos fármacos , Vitamina K/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/metabolismo , Fenômenos Fisiológicos da Nutrição/genética , Rifampina/administração & dosagem , Vitamina K 1/farmacologia , Vitamina K 2/análogos & derivados , Vitamina K 2/farmacologia
17.
BMC Mol Cell Biol ; 22(1): 33, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090331

RESUMO

BACKGROUND: In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration. RESULTS: At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level. CONCLUSION: Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Ibogaína/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinoma/induzido quimicamente , Carcinoma/metabolismo , Carcinoma/patologia , Simulação por Computador , Eletrocardiografia , Ácidos Graxos/biossíntese , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ibogaína/química , Ibogaína/farmacocinética , Ibogaína/uso terapêutico , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Metaboloma , Metilnitrosoureia , Neovascularização Patológica/tratamento farmacológico , Ratos Wistar , Tamoxifeno/uso terapêutico
18.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
19.
Am J Surg Pathol ; 45(9): 1274-1281, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115674

RESUMO

Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ≥1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ≥10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ≥1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ≥10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Imuno-Histoquímica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
20.
Mol Med Rep ; 24(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34132358

RESUMO

Bladder cancer (BC) is the second most common urological disease worldwide. Previous studies have reported that microRNA (miR)­16­5p is associated with the development of BC, but whether miR­16­5p regulates BC cell autophagy remains unknown. Thus, the aim of the present study was to investigate this issue. miR­16­5p expression in BC cells was assessed by reverse transcription­quantitative PCR. Cell viability and apoptosis were detected via Cell Counting Kit­8 and flow cytometry assays, respectively. For cell autophagy detection, autophagic flux was detected using a mCherry­green fluorescent protein­microtubule­associated proteins 1A/1B light chain 3B (LC3) puncta formation assay, followed by determination of autophagy­related protein markers. The targeting relationship between miR­16­5p and caspase recruitment domain family member 10 (BIMP1) was confirmed using a dual­luciferase reporter assay, followed by detection of the BIMP1/NF­κB signaling pathway. The results showed that miR­16­5p overexpression inhibited cell viability, whereas miR­16­5p knockdown promoted cell viability in BC. Furthermore, miR­16­5p overexpression induced autophagy, which was accompanied by increased autophagic flux and expression of the autophagy­related proteins LC3­II and beclin 1, as well as decreased p62 expression, whereas miR­16­5p silencing led to an inhibition of autophagy in BC cells. Moreover, autophagy inhibitor 3­methyladenine treatment inhibited cell autophagy and apoptosis in miR­16­5p­overexpressing cells. Mechanistic studies demonstrated that miR­16­5p could inhibit the BIMP1/NF­κB signaling pathway and this inhibition was achieved by directly targeting BIMP1. Furthermore, it was found that blockade of the BIMP1/NF­κB signaling pathway inversed the inhibitory effects of miR­16­5p knockdown on autophagy in BC cells. In vivo experiments further verified the tumor­suppressive effect on BC of the miR­16­5p/BIMP1/NF­κB axis. Therefore, the results of the present study indicated that miR­16­5p promotes autophagy of BC cells via the BIMP1/NF­κB signaling pathway, and an improved understanding of miR­16­5p function may provide therapeutic targets for clinical intervention in this disease.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/fisiologia , Transdução de Sinais , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Animais , Apoptose , Proteína Beclina-1/metabolismo , Biomarcadores Tumorais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/metabolismo , Proteínas de Ligação a RNA/metabolismo
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