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1.
World J Surg Oncol ; 19(1): 273, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507558

RESUMO

BACKGROUND: Breast cancer is the most common malignancy in women. Cancer driver gene-mediated alterations in the tumor microenvironment are critical factors affecting the biological behavior of breast cancer. The purpose of this study was to identify the expression characteristics and prognostic value of cancer driver genes in breast cancer. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets are used as the training and test sets. Classified according to cancer and paracancerous tissues, we identified differentially expressed cancer driver genes. We further screened prognosis-associated genes, and candidate genes were submitted for the construction of a risk signature. Functional enrichment analysis and transcriptional regulatory networks were performed to search for possible mechanisms by which cancer driver genes affect breast cancer prognosis. RESULTS: We identified more than 200 differentially expressed driver genes and 27 prognosis-related genes. High-risk group patients had a lower survival rate compared to the low-risk group (P<0.05), and risk signature showed high specificity and sensitivity in predicting the patient prognosis (AUC 0.790). Multivariate regression analysis suggested that risk scores can independently predict patient prognosis. Further, we found differences in PD-1 expression, immune score, and stromal score among different risk groups. CONCLUSION: Our study confirms the critical prognosis role of cancer driver genes in breast cancer. The cancer driver gene risk signature may provide a novel biomarker for clinical treatment strategy and survival prediction of breast cancer.


Assuntos
Neoplasias da Mama , Microambiente Tumoral , Neoplasias da Mama/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Prognóstico , Taxa de Sobrevida , Microambiente Tumoral/genética
2.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383407

RESUMO

BACKGROUND: Severe neurotoxicity after chimeric antigen receptor T cell (CAR-T) therapy can be a crucial lifethreatening event in diffuse large B-cell lymphoma (DLBCL), and management of those toxicities is still a serious clinical challenge. The underlying mechanisms of CAR-T cell-mediated neurotoxicity remain poorly elucidated because very few studies examine the intact tumor microenvironment before CAR-T cell infusion. Herein, we pur-posed to identify differentially expressed genes (DEGs) related to CAR-T cell-mediated neurotoxicity in the DLBCL microenvironment before CAR-T cell infusion and reveal their potential mechanisms. METHODS: The mRNA expression profile data of GSE153438 were obtained from the GEO database. The GSE153438 dataset includes 26 samples with non-severe neurotoxicity (grade 0 - 2) and 10 samples with severe neurotoxicity (grade 3 or higher). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) patway enrichment assessment was carried out. We screened the hub gene by protein-protein interaction (PPI) network analysis and Cytoscape software. Gene set enrichment analysis (GSEA) was also analyzed with the GSEA software. Moreover, the predictive value of the hub gene for severe neurotoxicity was evaluated via receiver operating characteristic (ROC) curve analysis. RESULTS: We identified a total of 25 up-regulated DEGs and 26 downregulated DEGs associated with CAR-T cell-mediated neurotoxicity in the DLBCL microenvironment before CAR-T cell infusion. Results of GO analysis showed that DEGs were mainly enriched in T cell activation, leukocyte cell-cell adhesion, and positive regulation of cell adhesion. The KEGG analysis revealed that DEGs were significantly enriched in T cell receptor signaling pathway, cell adhesion molecules, and Epstein-Barr virus infection. GSEA revealed that the glycolysis pathway was significantly associated with severe neurotoxicity. The top centrality hub gene GZMB was identified from the PPI network. ROC curve analysis showed that GZMB had a potential predictive value for severe neurotoxicity. CONCLUSIONS: In DLBCL microenvironment before CAR-T cell infusion, we identified T cell activation and glycolysis pathways significantly associated with CAR-T cell-mediated severe neurotoxicity. GZMB might be used as a predictive and therapeutic molecular marker for neurotoxicity. The study suggested that the tumor microenviron-ment before CAR-T cell infusion plays an essential role in the early prediction of neurotoxicity.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Herpesvirus Humano 4 , Humanos , Linfoma Difuso de Grandes Células B/genética , Transcriptoma , Microambiente Tumoral/genética
3.
Oncoimmunology ; 10(1): 1940675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290905

RESUMO

The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.


Assuntos
5'-Nucleotidase , Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Interleucina-27 , Neoplasias Pulmonares , Linfócitos T , Carcinoma Pulmonar de Células não Pequenas/genética , Retroalimentação , Proteínas Ligadas por GPI , Humanos , Ligantes , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética
4.
Front Immunol ; 12: 557994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220791

RESUMO

The immunosuppressive mechanisms of the surrounding microenvironment and distinct immunogenomic features in glioblastoma (GBM) have not been elucidated to date. To fill this gap, useful data were extracted from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, GSE43378, GSE23806, and GSE12907. With the ssGSEA method and the ESTIMATE and CIBERSORT algorithms, four microenvironmental signatures were used to identify glioma microenvironment genes, and the samples were reasonably classified into three immune phenotypes. The molecular and clinical features of these phenotypes were characterized via key gene set expression, tumor mutation burden, fraction of immune cell infiltration, and functional enrichment. Exhausted CD8+ T cell (GET) signature construction with the predictive response to commonly used antitumor drugs and peritumoral edema assisted in further characterizing the immune phenotype features. A total of 2,466 glioma samples with gene expression profiles were enrolled. Tumor purity, ESTIMATE, and immune and stromal scores served as the 4 microenvironment signatures used to classify gliomas into immune-high, immune-middle and immune-low groups, which had distinct immune heterogeneity and clinicopathological characteristics. The immune-H phenotype had higher expression of four immune signatures; however, most checkpoint molecules exhibited poor survival. Enriched pathways among the subtypes were related to immunity. The GET score was similar among the three phenotypes, while immune-L was more sensitive to bortezomib, cisplatin, docetaxel, lapatinib, and rapamycin prescriptions and displayed mild peritumor edema. The three novel immune phenotypes with distinct immunogenetic features could have utility for understanding glioma microenvironment regulation and determining prognosis. These results contribute to classifying glioma subtypes, remodeling the immunosuppressive microenvironment and informing novel cancer immunotherapy in the era of precision immuno-oncology.


Assuntos
Neoplasias Encefálicas/genética , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/genética , Glioma/genética , Linfócitos do Interstício Tumoral/imunologia , Algoritmos , Antineoplásicos , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Edema , Regulação Neoplásica da Expressão Gênica , Genoma , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Imunogenética/métodos , Imunofenotipagem , Prognóstico , Análise de Sobrevida , Transcriptoma , Microambiente Tumoral/genética
5.
Oncoimmunology ; 10(1): 1936758, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34221700

RESUMO

Emerging evidence has revealed the crucial role of transcriptional RNA methyladenosine modification in immune response. However, the potential role of RNA N1-methyladenosine (m1A) modification of immune cells in the tumor microenvironment (TME) still remains unclear. In this study, we identified three distinct m1A modification patterns based on the integrated analyses of nine m1A regulators, which are significantly related to Relapse-free survival (RFS), Overall survival (OS), and TME infiltration cells in colon cancer patients. Furthermore, the m1AScore was generated by using principal components analysis (PCA) of expression of the 71 m1A-related genes to further demonstrate the characteristics of m1A patterns in colon cancer. In summary, a low m1AScore could be characterized by lower EMT, pan-F TBRS, and TNM stages, as well as less presence of lymphatic invasion, and, hence, good prognosis. At the same time, a low m1AScore could also be linked to CD8 + T effector proliferation, in addition to high microsatellite instability (MSI), neoantigen burden and PD-L1 expression, showing prolonged survival and better response after undergoing an anti-PD-L1 immunotherapy regimen in the public immunotherapy cohort. Our work reveals that m1A modification patterns play a key role in the formation of TME complexity and diversity in the context of immune cell infiltration. Accordingly, this m1AScore system provides an efficient method by which to identify and characterize TME immune cell infiltration, thereby allowing for more personalized and effective antitumor immunotherapy strategies.


Assuntos
Neoplasias do Colo , Microambiente Tumoral , Neoplasias do Colo/genética , Humanos , Linfócitos do Interstício Tumoral , Instabilidade de Microssatélites , Recidiva Local de Neoplasia , Microambiente Tumoral/genética
6.
Oncoimmunology ; 10(1): 1932365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235002

RESUMO

The interaction of CNS tumors with infiltrating lymphocytes plays an important role in their initiation and progression and might be related to therapeutic responses. Gene expression-based methods have been successfully used to characterize the tumor microenvironment. However, methylation data are now increasingly used for molecular diagnostics and there are currently only few methods to infer information about the microenvironment from this data type. Using an approach based on differential methylation and principal component analysis, we developed DIMEimmune (Differential Methylation Analysis for Immune Cell Estimation) to estimate CD4+ and CD8+ T cell abundance as well as tumor-infiltrating lymphocytes (TILs) scores from bulk methylation data. Well-established approaches based on gene expression data and immunohistochemistry-based lymphocyte counts were used as benchmarks. The comparison of DIMEimmune to the previously published MethylCIBERSORT and MeTIL algorithms showed an improved correlation with both gene expression-based and immunohistological results across different brain tumor types. Further, we applied our method to large datasets of glioma, medulloblastoma, atypical teratoid/rhabdoid tumors (ATRTs) and ependymoma. High-grade gliomas showed higher scores of tumor-infiltrating lymphocytes than lower-grade gliomas. There were overall only few tumor-infiltrating lymphocytes in medulloblastoma subgroups. ATRTs were highly infiltrated by lymphocytes, most prominently in the MYC subgroup. DIMEimmune-based estimates of TILs were a significant prognostic factor in the overall cohort of gliomas and medulloblastomas, but not within methylation-based diagnostic subgroups. To conclude, DIMEimmune allows for robust estimates of TIL abundance and might contribute to establishing them as a prognostic or predictive factor in future studies of CNS tumors.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Neoplasias Encefálicas/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA/genética , Glioma/genética , Humanos , Linfócitos do Interstício Tumoral , Microambiente Tumoral/genética
7.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298879

RESUMO

Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer.


Assuntos
Hipóxia/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Microambiente Tumoral/genética , Animais , Apoptose/genética , Humanos , MicroRNAs/genética
8.
Aging (Albany NY) ; 13(13): 17789-17817, 2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34247149

RESUMO

Chemokines play a significant role in cancer. CXC-motif chemokine ligands (CXCLs) are associated with the tumorigenesis and progression of head and neck squamous cell carcinoma (HNSC); however, their specific functions in the tumor microenvironment remain unclear. Here, we analyzed the molecular networks and transcriptional data of HNSC patients from the Oncomine, GEPIA, String, cBioPortal, Metascape, TISCH, and TIMER databases. To verify immune functions of CXCLs, their expression was analyzed in different immune cell types. To our knowledge, this is the first report on the correlation between CXCL9-12 and 14 expression and advanced tumor stage. CXCL2, 3, 8, 10, 13, and 16 were remarkably related to tumor immunity. Kaplan-Meier and TIMER survival analyses revealed that high expression of CXCL1, 2, 4, and 6-8 is correlated with low survival in HNSC patients, whereas high expression of CXCL9, 10, 13, 14, and 17 predicts high survival. Only CXCL13 and 14 were associated with overall survival in human papilloma virus (HPV)-negative patients. Single-cell datasets confirmed that CXCLs are associated with HNSC-related immune cells. Thus, CXCL1-6, 8-10, 12-14, and 17 could be prognostic targets for HNSC, and CXCL13 and 14 could be novel biomarkers of HPV-negative HNSC.


Assuntos
Quimiocinas CXC/genética , Biologia Computacional/métodos , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Microambiente Tumoral/genética , Biomarcadores Tumorais/análise , Quimiocinas CXC/análise , Sondas de DNA de HPV/análise , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Redes e Vias Metabólicas/genética , Prognóstico , Sensibilidade e Especificidade , Análise de Sobrevida
9.
Aging (Albany NY) ; 13(13): 17847-17863, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257161

RESUMO

The deregulation of fatty acid metabolism plays a crucial role in cancer. However, the prognostic value of genes involved in the metabolism in hepatocellular carcinoma (HCC) remains largely unknown. We first constructed a multi-fatty acid metabolic gene prognostic model of HCC based on The Cancer Genome Atlas (TCGA) and further validated it using the International Cancer Genome Consortium (ICGC) database. The model was integrated with the clinical parameters, and a nomogram was built and weighted. Moreover, immune cell infiltration of the tumor microenvironment was investigated. A prognostic model was constructed using 6 selected fatty acid metabolism-related genes, and HCC patients were divided into high- and low-risk groups. Receiver operating characteristic curve (ROC) analysis, principal component analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE) analysis showed the optimal performance of the model. The concordance index (C-index), ROC curve, calibration plot and decision curve analysis (DCA) all confirmed the satisfactory predictive capacity of the nomogram. The analysis of immune cell infiltration in HCC patients revealed a correlation with different risk levels. Our findings indicate that a prognostic model based on fatty acid metabolism-related genes has superior predictive capacities, which provides the possibility for further improving the individualized treatment of patients with HCC.


Assuntos
Carcinoma Hepatocelular/genética , Ácidos Graxos/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Nomogramas , Valor Preditivo dos Testes , Análise de Componente Principal , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Processos Estocásticos , Análise de Sobrevida , Microambiente Tumoral/genética
10.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298989

RESUMO

Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.


Assuntos
Heteroplasmia/genética , Mitocôndrias/genética , Neoplasias/sangue , Neoplasias/genética , Alelos , Biomarcadores/sangue , Enzimas de Restrição do DNA/uso terapêutico , Progressão da Doença , Epigênese Genética , Terapia Genética/métodos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/genética
11.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298992

RESUMO

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.


Assuntos
Infecções Bacterianas/complicações , Linfoma de Burkitt/microbiologia , Infecções por Helicobacter/microbiologia , Interações Hospedeiro-Patógeno , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma Difuso de Grandes Células B/microbiologia , Infecções Bacterianas/imunologia , Linfoma de Burkitt/complicações , Linfoma de Burkitt/patologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
12.
Theranostics ; 11(14): 6668-6681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093846

RESUMO

Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are "cold" tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in "hot" tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8+ and CD4+ T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Interleucina-23/farmacologia , Vírus Oncolíticos/genética , Microambiente Tumoral/imunologia , Vírus Vaccinia/genética , Adenocarcinoma/imunologia , Adenocarcinoma/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/virologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/metabolismo , Perforina/metabolismo , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Vírus Vaccinia/metabolismo
13.
Theranostics ; 11(14): 6786-6799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093853

RESUMO

Rationale: Bone marrow-derived mesenchymal stem cells (BM-MSCs) recruited into breast tumors regulate the behavior of tumor cells via various mechanisms and affect clinical outcomes. Although signaling molecules, such as transforming growth factor ß (TGF-ß), are known to transmit signals between BM-MSCs and breast tumor cells for recruiting BM-MSCs, it is unclear which specific intrinsic molecules involved in cell motility mediate the migration of BM-MSCs into breast tumor. It is also unclear as to how specific intrinsic molecules contribute to the migration. Methods: Conditioned medium (CM) from breast tumor cells (MCF-7 and MDA-MB-231) that simulates breast tumor secreting TGF-ß was used to examine the migration of BM-MSCs into breast tumors. A three-dimensional migration assay was performed to investigate the collective migration of BM-MSCs, maintaining cell-cell adhesion, toward breast tumor cells. Results: N-cadherin formed adherens junction-like structures on the intercellular borders of BM-MSCs, and TGF-ß increased the expression of N-cadherin on these borders. Knockdown of Smad4 impaired the TGF-ß-mediated increase in N-cadherin expression in BM-MSCs, but inhibitors of non-canonical TGF-ß pathways, such as extracellular signal-regulated kinases, Akt, and p38, did not affect it. siRNA-mediated knockdown of N-cadherin and Smad4 impaired the migration of BM-MSCs in response to TGF-ß. Conditioned medium from breast tumor cells also enhanced the expression of N-cadherin in BM-MSCs, but inactivation of TGF-ß type 1 receptor (TGFBR1) with SB505124 and TGFBR1 knockdown abolished the increase in N-cadherin expression. BM-MSCs collectively migrated toward CM from MDA-MB-231 in vitro while maintaining cell-cell adhesion through N-cadherin. Knockdown of N-cadherin abolished the migration of BM-MSCs toward the CM from breast tumor cells. Conclusion: In the present study, we identified N-cadherin, an intrinsic transmembrane molecule in adherens junction-like structures, on BM-MSCs as a mediator for the migration of these cells toward breast tumor. The expression of N-cadherin increases on the intercellular borders of BM-MSCs through the TGF-ß canonical signaling and they collectively migrate in response to breast tumor cells expressing TGF-ß via N-cadherin-dependent cell-cell adhesion. We, herein, introduce a novel promising strategy for controlling and re-engineering the breast tumor microenvironment.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Antígenos CD/genética , Benzodioxóis/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad4/genética , Proteína Smad4/metabolismo , Microambiente Tumoral/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Theranostics ; 11(14): 7029-7044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093869

RESUMO

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.


Assuntos
Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Aloenxertos , Animais , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Prognóstico , Receptor de Morte Celular Programada 1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/ultraestrutura
15.
Crit Rev Oncol Hematol ; 164: 103397, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34146679

RESUMO

Head and neck cancer is globally challenging due to the resistance to therapy and aggressive behavior leading to high rates of mortality. Recent findings show that the tumor microenvironment plays a role in the maintenance and progression of many solid tumors, including head and neck cancer. The mechanisms involved in the modulation and regulation of the tumor microenvironment remain poorly understood. Increasing evidence suggests that epigenetic events can modulate the crosstalk between neoplastic and non-neoplastic cells during tumor progression. In this review, we explore the current understanding of the involvement of epigenetic events in the modulation of the tumor microenvironment and its impact on head and neck cancer behavior. We also explore the latest therapeutic strategies that use epigenetic-modulating drugs to manage tumor growth and progression.


Assuntos
Neoplasias de Cabeça e Pescoço , Microambiente Tumoral , Epigênese Genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Microambiente Tumoral/genética
16.
Biotechnol J ; 16(9): e2100041, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34125481

RESUMO

The tumor microenvironment (TME) harbors heterogeneous contents and plays critical roles in tumorigenesis, metastasis, and drug resistance. Therefore, the deconvolution of the TME becomes increasingly essential to every aspect of cancer research and treatment. Novel spatially-resolved high-plex molecular profiling technologies have been emerging rapidly as powerful tools to obtain in-depth understanding from TME perspectives due to their capacity to allow high-plex protein and RNA profiling while keeping valuable spatial information. Based on our practical experience, we review a variety of available spatial proteogenomic technologies, including 10X Visium, GeoMx Digital Spatial Profiler (DSP), cyclic immunofluorescence-based CODEX and Multi-Omyx, mass spectrometry (MS)-based imaging mass spectrometry (IMS) and multiplex ion-beam imaging (MIBI). We also discuss FISSEQ, MERFISH, Slide-seq, and HDST, some of which may become commercially available in the near future. In particular, with our experience, we elaborate on DSP for spatial proteogenomic profiling and discuss its unique features designed for immuno-oncology and propose anticipation towards its future direction. The emerging spatially technologies are rapidly reshaping the magnitude of our understanding of the TME.


Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/genética , Proteínas , Proteômica , Transcriptoma , Microambiente Tumoral/genética
17.
Aging (Albany NY) ; 13(12): 16198-16218, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34114970

RESUMO

An accumulation of studies has indicated aging to be a significant hazard factor for the development of tumors. Cellular senescence is positively associated with aging progress and aging-related genes (AGs) can regulate cellular senescence and tumor malignancy. While the association between AGs and the prognosis of patients with glioma is still unclear. In our study, we initially selected four survival-associated AGs and performed consensus clustering for these AGs based on The Cancer Genome Atlas (TCGA) database. We then explored the potential biological effects of four selected AGs. A prognostic risk model was constructed according to four selected AGs (LEP, TERT, PON1, and SSTR3) in the TCGA dataset and Chinese Glioma Genome Atlas (CGGA) database. Then we indicated the risk score was an independent prognostic index, and was also positively correlated with immune scores, estimate score, immune cell infiltration level, programmed death ligand 1 (PD-L1) expression, and expression of proinflammatory factors in patients with glioma. Finally, we performed the RT-qPCR and immunohistochemistry assay to validate our bioinformatics results. Thus, this study indicated the risk model was concluded to possibly have potential function as an immune checkpoint inhibitor and to provide promising targets for developing individualized immunotherapies for patients with glioma.


Assuntos
Envelhecimento/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Microambiente Tumoral/genética , Antígeno B7-H1/metabolismo , Análise por Conglomerados , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos/metabolismo , Modelos Biológicos , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Análise de Sobrevida
18.
Aging (Albany NY) ; 13(12): 16445-16470, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34148032

RESUMO

Acute myeloid leukemia (AML) is a group of heterogeneous hematological malignancies. We identified key genes as ITGAM and lncRNA ITGB2-AS1 through different bioinformatics tools. Furthermore, qPCR was performed to verify the expression level of essential genes in clinical samples. Retrospective research on 179 AML cases was used to investigate the relationship between the expression of ITGAM and the characteristics of AML. The critical gene relationship with immune infiltration in AML was estimated. The clinical validation and prognostic investigation showed that ITGAM, PPBP, and ITGB2-AS1 are highly expressed in AML (P < 0.001) and significantly associated with the overall survival in AML. Moreover, the retrospective research on 179 clinical cases showed that positive expression of ITGAM is substantially related to AML classification (P < 0.001), higher count of white blood cells (P < 0.01), and poor chemotherapy outcome (P < 0.05). Furthermore, based on grouping ITGAM as the high and low expression in TCGA-LAML profile, we found that genes in the highly expressed ITGAM group are mainly involved in immune infiltration and inflammation-related signaling pathways. Finally, we discovered that the expression level of ITGAM and lncRNA ITGB2-AS1 are not just closely related to the immune score and stromal score (P < 0.001) but also significantly positively correlated with various Immune signatures in AML (P < 0.001), indicating the association of these genes with immunosuppression in AML. The prediction of candidate drugs indicated that certain immunosuppressive drugs have potential therapeutic effects for AML. The critical genes could be used as potential biomarkers to evaluate the survival and prognosis of AML.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Genes Essenciais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Transcriptoma/genética , Resultado do Tratamento , Microambiente Tumoral/genética
19.
Theranostics ; 11(15): 7175-7187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158843

RESUMO

Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability, and has been proven to be a biomarker for target therapy. However, until now, no research has explored the changes in the transcriptomics landscape of HRD tumors. Methods: The HRD score was established from SNP array data of breast cancer patients from the cancer genome atlas (TCGA) database. The transcriptome data of patients with different HRD scores were analyzed to identify biomarkers associated with HRD. The candidate biomarkers were validated in the gene expression omnibus (GEO) database and immunotherapy cohorts. Results: Based on data from the gene expression profile and clinical characteristics from 1310 breast cancer patients, including TCGA database and GEO database, we found that downstream targets of the cGAS-STING pathway, such as CXCL10, were upregulated in HRD tumors and could be used as a predictor of survival outcome in triple-negative breast cancer (TNBC) patients. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that the expression of CXCL10 was positively correlated with neoantigen load and infiltrating immune cells. Finally, in vivo experimental data and clinical trial data confirmed that the expression of CXCL10 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Conclusions: Together, our study not only revealed that CXCL10 is associated with HRD but also introduced a potential new perspective for identifying prognostic biomarkers of immunotherapy.


Assuntos
Neoplasias da Mama , Quimiocina CXCL10 , Bases de Dados de Ácidos Nucleicos , Instabilidade Genômica/imunologia , Recombinação Homóloga , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias/imunologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Feminino , Humanos , Imunoterapia , Proteínas de Neoplasias/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
20.
Oncoimmunology ; 10(1): 1915574, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34104539

RESUMO

Immunotherapy that block PD-1-PD-L1 pathway can induce durable tumor control and result in the long-term survival of patients with advanced bladder cancers. However, these responses only occur in a subset of patients. We study gene expression profiles in 1763 muscle-invasive bladder cancers (MIBCs) and 11,835 solid tumors from TCGA. We establish an immune-based classification on the basis of the composition of the tumor microenvironment and identify six distinct phenotypes. The class F was characterized by a strong tertiary lymphoid structures (TLSs) related gene expression signature. Pan-cancer gene expression analysis of tertiary lymphoid structure markers in 11,835 solid tumors from TCGA unveiled the heterogeneity of TLSs abundance both within and between human cancer types. The class F group demonstrated improved survival and a high response rate to PD1 blockade. This work confirms the immune subtypes in patients with MIBC, and unravels the potential of TLS signatures to guide clinical decision-making and treatments.


Assuntos
Estruturas Linfoides Terciárias , Neoplasias da Bexiga Urinária , Humanos , Imunoterapia , Músculos , Prognóstico , Microambiente Tumoral/genética , Neoplasias da Bexiga Urinária/genética
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