Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.711
Filtrar
1.
Urol Clin North Am ; 47(4): 475-485, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008498

RESUMO

Cancer is a highly complex and heterogeneous disease and immunotherapy has shown promise as a therapeutic approach. The increased resolution afforded by single-cell analysis offers the hope of finding and characterizing previously underappreciated populations of cells that could prove useful in understanding cancer progression and treatment. Urologic and prostate cancers are inherently heterogeneous diseases, and the potential for single-cell analysis to help understand and develop immunotherapeutic approaches to treat these diseases is very exciting. In this review, we view cancer immunotherapy through a single-cell lens and discuss the state-of-the-art technologies that enable advances in this field.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Feminino , Previsões , Humanos , Masculino , Terapia de Alvo Molecular/tendências , Prognóstico , Neoplasias da Próstata/patologia , Medição de Risco , Análise de Sequência de DNA , Análise de Sequência de RNA , Análise de Célula Única , Resultado do Tratamento , Microambiente Tumoral/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Neoplasias Urológicas/terapia
2.
Urol Clin North Am ; 47(4): 487-510, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008499

RESUMO

The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.


Assuntos
Produtos Biológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Previsões , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Resultado do Tratamento , Microambiente Tumoral/genética
3.
Anticancer Res ; 40(10): 5463-5469, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988868

RESUMO

BACKGROUND/AIM: Periostin exists as an extracellular matrix protein in several carcinomas and is related to metastasis and poor prognosis. It is mainly secreted from cancer associated fibroblasts, and not from carcinoma cells. As a tumor microenvironment component, periostin usually mediates tumor cell stemness, metastasis, angiogenesis and lymphangiogenesis. This study aimed to examine the role of periostin in chondrosarcoma. MATERIALS AND METHODS: To evaluate the effect of periostin on the proliferation of chondrosarcoma cells, MTT assay was performed on SW1353 cells and periostin knockdown SW1353 cells. Migration activity was examined using Boyden chamber. RESULTS: Periostin, secreted from chondrosarcoma cells, was found to support proliferation, and maintain stemness and migration of chondrosarcoma cells. Periostin also induced proliferation and migration of lymphatic endothelial cells. CONCLUSION: Periostin plays an important role in chondrosarcoma development and disease progression.


Assuntos
Moléculas de Adesão Celular/genética , Proliferação de Células/genética , Condrossarcoma/genética , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Condrossarcoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Linfangiogênese/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
4.
PLoS One ; 15(8): e0238380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866185

RESUMO

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
5.
Nat Commun ; 11(1): 4516, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908137

RESUMO

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
6.
Nat Commun ; 11(1): 4551, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917870

RESUMO

Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs) by sponging specific microRNAs. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, but highly expressed in stromal cells within the tumor microenvironment. Additionally, our data suggest that this generally apply to classical oncogene-driven adenocarcinomas, but not to other cancers, including malignant melanoma. Moreover, we find that correlations between circRNA and mRNA expression, which are commonly interpreted as evidence of a ceRNA function, can be explained by different cancer-to-stromal cell ratios among the studied tumor specimens. Together, these results have wide implications for future circRNA studies and highlight the importance of spatially resolving expression patterns of circRNAs proposed to function as ceRNAs.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Microambiente Tumoral/genética , Idoso , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncogenes/genética , Estudos Prospectivos , RNA Circular/genética , RNA Longo não Codificante/genética , Análise Espacial
7.
PLoS Med ; 17(9): e1003292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970670

RESUMO

BACKGROUND: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable. METHODS AND FINDINGS: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016). LIMITATIONS: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival. CONCLUSION: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Repetições de Microssatélites/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Casos e Controles , Quimioterapia Adjuvante , Neoplasias Colorretais/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Instabilidade de Microssatélites , Repetições de Microssatélites/imunologia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espanha , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Nat Commun ; 11(1): 4111, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807776

RESUMO

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células 3T3 , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Neoplasias Renais/genética , Espectrometria de Massas , Camundongos , Proteômica/métodos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
9.
Nat Commun ; 11(1): 3945, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770028

RESUMO

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Complexo de Golgi/patologia , Síndrome de Li-Fraumeni/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Biópsia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Feminino , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Microtúbulos/metabolismo , Microtúbulos/patologia , Mutação , Cultura Primária de Células , Vesículas Secretórias/metabolismo , Vesículas Secretórias/patologia , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
PLoS One ; 15(8): e0236516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776970

RESUMO

Breast cancer is the most common cause of cancer-related deaths in women worldwide. Identification of reliable prognostic indicators and therapeutic targets is critical for improving patient outcome. Cancer in companion animals often strongly resembles human cancers and a comparative approach to identify prognostic markers can improve clinical care across species. Feline mammary tumors (FMT) serve as models for extremely aggressive triple negative breast cancer (TNBC) in humans, with high rates of local and distant recurrence after resection. Despite the aggressive clinical behavior of most FMT, current prognostic indicators are insufficient for accurately predicting outcome, similar to human patients. Given significant heterogeneity of mammary tumors, there has been a recent focus on identification of universal tumor-permissive stromal features that can predict biologic behavior and provide therapeutic targets to improve outcome. As in human and canine patients, collagen signatures appear to play a key role in directing mammary tumor behavior in feline patients. We find that patients bearing FMTs with denser collagen, as well as longer, thicker and straighter fibers and less identifiable tumor-stromal boundaries had poorer outcomes, independent of the clinical variables grade and surgical margins. Most importantly, including the collagen parameters increased the predictive power of the clinical model. Thus, our data suggest that similarities with respect to the stromal microenvironment between species may allow this model to predict outcome and develop novel therapeutic targets within the tumor stroma that would benefit both veterinary and human patients with aggressive mammary tumors.


Assuntos
Colágeno/metabolismo , Neoplasias Mamárias Animais/cirurgia , Prognóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Animais , Gatos , Colágeno/genética , Modelos Animais de Doenças , Feminino , Humanos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética
12.
Gene ; 761: 145028, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32763490

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and inflicts high mortality worldwide. The effect of tumor microenvironment components on HCC oncogenesis remains unknown. In particular, the nonleukocyte portion of the stromal fraction (SF) is poorly understood. METHODS: We comprehensively evaluated the proportional cell counts and gene expression data from The Cancer Genome Atlas (TCGA) to examine the contributions of cell components to the tumor microenvironment. Single-cell sequencing data from the Gene Expression Omnibus (GEO) were also analyzed to verify the association between the nonleukocyte SF and genes. We classified HCC using a hierarchical clustering method based on diversity of nonleukocyte SF-related gene expression among different components, and we used an appropriate GEO dataset to verify the clusters with a support vector machine (SVM) model. The prognosis of subtypes and their relationship with tumor microenvironmental cell proportions, clinicopathogenesis factors, and other indicators were evaluated. RESULTS: Based on linear regression, 711 genes related to nonleukocyte SF were selected from the TCGA dataset. We classified HCC into three subtypes using genes related to the nonleukocyte SF. Additionally, the GEO single-cell sequencing data confirmed the relationship between genes and the nonleukocyte SF. The tumor microenvironment of Type 2 contained the most significant mutually reinforcing interaction between the nonleukocyte SF and tumor cells. Meanwhile, Type 2 patients had the poorest prognosis and the most severe tumor-node-metastasis (TNM) stages, histological grades, etc. The analysis based on the GEO dataset verified the classification results with an SVM model. Type 2 was associated with worse clinicopathological characteristics, including tumor grading and staging, than the other types. In addition, the pathway analysis revealed that signals related to the SF and cell proliferation were significantly enhanced in Type 2 compared to the other group, which consisted of Types 1 and 3. CONCLUSION: The nonleukocyte SF in the tumor microenvironment contributed greatly to HCC oncogenesis. We can use these HCC classification criteria to stratify patients into subtypes for personalized treatment.


Assuntos
Carcinoma Hepatocelular/genética , Células Estromais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Neoplasias Hepáticas/genética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral/genética
13.
Gene ; 761: 145049, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32791092

RESUMO

Breast cancer (BRCA) is a highly heterogeneous disease due to the complicated microenvironment in the tumor, making the treatment benefits varied. Therefore, this study aims to identify a gene signature in the tumor microenvironment (TME) associated with the prognosis of BRCA patients. We downloaded the immune, stromal, and proliferation (ISP)-associated genes from the literature on BRCA. mRNA expression and clinical information obtained from The Cancer Genome Atlas (TCGA) were performed to identify the initial biomarker. Furthermore, we validated the robustness of the gene signature in the independent validation data set GSE20685. A four-gene signature in TME, including CD74, MMP9, RPA3, and SHCBP1, was constructed to predict the overall survival of BRCA. The survival time of the high-risk group was significantly worse than that of the low-risk group. Univariate and multivariate Cox regression analysis showed that our four-gene ISP signature was an independent prognostic factor in TCGA and GSE20685 data sets. The AUC suggested that our four-gene ISP signature was comparable to TNM classification at predicting the overall survival of BRCA patients. Interestingly, BRCA patients with high-risk scores were more likely to be associated with stromal and proliferation of cancer. In contrast, those with high-risk scores were more likely to be associated with tumor immunity-related pathway. We found an innovative biomarker in TME to predict the prognosis of BRCA. This signal might reflect the imbalance of TME and provide potential biomarkers for the individualized and precise treatment of BRCA.


Assuntos
Neoplasias da Mama/genética , Microambiente Tumoral/genética , Adulto , Antígenos CD/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Haplótipos/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genética , Fatores de Risco , Proteínas Adaptadoras da Sinalização Shc/genética , Sialiltransferases/genética
14.
Nat Commun ; 11(1): 3515, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665557

RESUMO

An unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. Here, we develop a transformational spatial analytics computational and systems biology platform (SpAn) that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. We apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naïve colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of 55 fluorescently tagged antibodies. We show that SpAn predicts the 5-year risk of CRC recurrence with a mean AUROC of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. Additionally, SpAn infers the emergent network biology of tumor microenvironment spatial domains revealing a spatially-mediated role of CRC consensus molecular subtype features with the potential to inform precision medicine.


Assuntos
Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/genética , Biomarcadores/metabolismo , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Medicina de Precisão , Biologia de Sistemas , Microambiente Tumoral/genética
15.
Nat Commun ; 11(1): 3015, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541784

RESUMO

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6ß1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/ß-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/ß-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Sinalização Intercelular CCN/genética , Glioma/genética , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Sinalização Intercelular CCN/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Glioma/metabolismo , Glioma/terapia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Proc Natl Acad Sci U S A ; 117(27): 15673-15683, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571933

RESUMO

Stemness encompasses the capability of a cell for self-renewal and differentiation. The stem cell maintains a balance between proliferation, quiescence, and regeneration via interactions with the microenvironment. Previously, we showed that ectopic expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2) led to immortalization of primary fibroblasts, accompanied by induction of an embryonic stem cell (ESC) phenotype. Moreover, we demonstrated interaction between S18-2 and the retinoblastoma-associated protein (RB) and hypothesized that the simultaneous expression of RB and S18-2 is essential for maintaining cell stemness. Here, we experimentally investigated the role of S18-2 in cell stemness and differentiation. Concurrent expression of RB and S18-2 resulted in immortalization of Rb1 -/- primary mouse embryonic fibroblasts and in aggressive tumor growth in severe combined immunodeficiency mice. These cells, which express both RB and S18-2 at high levels, exhibited the potential to differentiate into various lineages in vitro, including osteogenic, chondrogenic, and adipogenic lineages. Mechanistically, S18-2 formed a multimeric protein complex with prohibitin and the ring finger protein 2 (RNF2). This molecular complex increased the monoubiquitination of histone H2ALys119, a characteristic trait of ESCs, by enhanced E3-ligase activity of RNF2. Furthermore, we found enrichment of KLF4 at the S18-2 promoter region and that the S18-2 expression is positively correlated with KLF4 levels. Importantly, knockdown of S18-2 in zebrafish larvae led to embryonic lethality. Collectively, our findings suggest an important role for S18-2 in cell stemness and differentiation and potentially also in cancerogenesis.


Assuntos
Mitocôndrias/genética , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Proteínas Ribossômicas/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Autorrenovação Celular/genética , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/genética , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Mitocôndrias/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Ribossômicas/química , Microambiente Tumoral/genética , Ubiquitina-Proteína Ligases/genética
17.
Nat Genet ; 52(6): 582-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483290

RESUMO

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização Wnt
18.
Cancer Sci ; 111(9): 3142-3154, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32536012

RESUMO

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antimetabólitos Antineoplásicos/metabolismo , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Fluoruracila/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Estresse Oxidativo/efeitos dos fármacos , Timidilato Sintase/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
19.
Life Sci ; 256: 117974, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553924

RESUMO

The brain tumor is the abnormal growth of heterogeneous cells around the central nervous system and spinal cord. Most clinically prominent brain tumors affecting both adult and pediatric are glioblastoma, medulloblastoma, and ependymoma and they are classified according to their origin of tissue. Chemotherapy, radiotherapy, and surgery are important treatments available to date. However, these treatments fail due to multiple reasons, including chemoresistance and radiation resistance of cancer cells. Thus, there is a need of new therapeutic designs to target cell signaling and molecular events which are responsible for this resistance. Recently epigenetic changes received increased attention because it helps in understanding chromatin-mediated disease mechanism. The epigenetic modification alters chromatin structure that affects the docking site of many drugs which cause chemo-resistance of cancer therapy. This review centers the mechanism of how epigenetic changes affect the transcription repression and activation of various genes including Polycomb gene, V-Myc avian myelocytomatosis viral oncogene (MYCN). This review also put forth the pathway of radiation-induced reactive oxygen species generation and its role in epigenetic changes in the cellular level and its impact on tissue physiology. Additionally, there is a strong relationship between the behavior of an individual and environment-induced epigenetic regulation of gene expression. The review also discusses Transcriptome heterogeneity and role of tumor microenvironment in glioblastoma. Overall, this review emphasis important and novel epigenetic targets that could be of therapeutic benefit, which helps in overcoming the unsolved chromatin alteration in brain cancer.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Epigênese Genética/genética , Animais , Neoplasias Encefálicas/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/efeitos da radiação , Humanos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Transcriptoma/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiação
20.
Cancer Sci ; 111(7): 2385-2399, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385953

RESUMO

The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer-associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF-ß, which induces endothelial-to-mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor-infiltrating inflammatory cells secrete various cytokines, including TNF-α. However, the role of TNF-α in TGF-ß-induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF-α on TGF-ß-induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF-ß and TNF-α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF-ß and TNF-α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF-ß type I receptor, TGF-ß2, activin A, and integrin αv, suggesting that TNF-α enhanced TGF-ß-induced EndMT by augmenting TGF-ß family signals. Furthermore, oral squamous cell carcinoma-derived cells underwent epithelial-to-mesenchymal transition (EMT) in response to humoral factors produced by TGF-ß and TNF-α-cultured ECs. This EndMT-driven EMT was blocked by inhibiting the action of TGF-ßs. Collectively, our findings suggest that TNF-α enhances TGF-ß-dependent EndMT, which contributes to tumor progression.


Assuntos
Transição Epitelial-Mesenquimal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Células Cultivadas , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA