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BACKGROUND: To investigate the impact of the tumor microenvironment (TME) on the responsiveness to chemotherapy in ovarian cancer (OV). METHODS: We integrated single cell RNA-seq datasets of OV containing chemo-response information, and characterize their clusters based on different TME sections. We focus on analyzing cell-cell communication to elaborate on the mechanisms by which different components of the TME directly influence the chemo-response of tumor cells. RESULTS: scRNA-seq datasets were annotated according to specific markers for different cell types. Differential analysis of malignant epithelial cells revealed that chemoresistance was associated with the TME. Notably, distinct TME components exhibited varying effects on chemoresistance. Enriched SPP1+ tumor-associated macrophages in chemo-resistant patients could promote chemoresistance through SPP1 binding to CD44 on tumor cells. Additionally, the overexpression of THBS2 in stromal cells could promote chemoresistance through binding with CD47 on tumor cells. In contrast, GZMA in the lymphocytes could downregulate the expression of PARD3 through direct interaction with PARD3, thereby attenuating chemoresistance in tumor cells. CONCLUSION: Our study indicates that the non-tumor cell components of the TME (e.g. SPP1+ TAMs, stromal cells and lymphocytes) can directly impact the chemo-response of OV and targeting the TME was potentially crucial in chemotherapy of OV.
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INTRODUCTION: The global incidence of thyroid cancer (TC) has increased in the last decades. While improvements in diagnosis may contribute, overdiagnosis is also a possibility. This review focuses on the epidemiology, risk factors, and immune microenvironment associated with differentiated TC (DTC). AREAS COVERED: A search was conducted in Scielo, Scopus, and EMBASE databases, involving 72 articles. TC is the most common endocrine neoplasm, with DTC form being predominant. Its incidence has globally risen, particularly among women aged over 45. Endogenous risk factors for DTC include genetic disorders, race, age, female gender, obesity, and type 2 diabetes mellitus. Environmental risks involve ionizing radiation, whether through therapeutic treatment or environmental contamination from nuclear accidents, iodine deficiency, endocrine disruptors, residence in volcanic areas, environmental pollution, and stress. The use of anti-obesity medications remains controversial. The tumor's immune microenvironment is the histological space where tumor cells interact with host cells, crucial for understanding aggressiveness. Immunotherapy emerges as a promising intervention. EXPERT OPINION: Recent advances in DTC management offer transformative potential, requiring collaborative efforts for implementation. Emerging areas like precision medicine, molecular profiling, and immunotherapy present exciting prospects for future exploration, shaping the next era of diagnostic and therapeutic strategies in thyroid cancer research.
The global incidence of thyroid cancer (TC) has significantly increased, attributed partly to improved diagnosis and potentially to overdiagnosis. This review focuses on the epidemiology, risk factors, and immune microenvironment associated with differentiated TC (DTC). DTC is the most common endocrine neoplasm, and predominantly affects women over 45 years old. Endogenous risk factors include genetic disorders, race, age, female gender, obesity, and type 2 diabetes mellitus (T2DM). Environmental risks encompass ionizing radiation, iodine deficiency, endocrine disruptors, volcanic residence, pollution, and stress. The use of glucagon-like peptide 1 agonists remains controversial. The tumor's immune microenvironment is crucial for understanding aggressiveness, with immunotherapy showing promise. Understanding both macro and microenvironmental factors is crucial for devising effective prevention and treatment strategies for DTC.
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Breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Immunotherapies are a promising approach in cancer treatment, particularly for aggressive forms of BC with high mortality rates. However, the current eligibility for immunotherapy remains limited to a limited fraction of patients with BC. Myeloid-derived suppressor cells (MDSCs), originating from myeloid cells, are known for their dual role in immunosuppression and tumor promotion, significantly affecting patient outcomes by fostering the formation of premetastatic niches. Consequently, targeting MDSCs has emerged as a promising avenue for further exploration in therapeutic interventions. Leveraging nanotechnology-based drug delivery systems, which excel in accumulating drugs within tumors via passive or active targeting mechanisms, are a promising strategy for the use of MDSCs in the treatment of BC. The present review discusses the immunosuppressive functions of MDSCs, their role in BC, and the diverse strategies for targeting them in cancer therapy. Additionally, the present review discusses future advancements in BC treatments focusing on MDSCs. Furthermore, it elucidates the mechanisms underlying MDSC activation, recruitment and differentiation in BC progression, highlighting the clinical characteristics that render MDSCs suitable candidates for the therapy and targeted nanotherapy of BC.
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Solid tumors represent the most common type of cancer in humans and are classified into sarcomas, lymphomas, and carcinomas based on the originating cells. Among these, carcinomas, which arise from epithelial and glandular cells lining the body's tissues, are the most prevalent. Around the world, a significant increase in the incidence of solid tumors is observed during recent years. In this context, efforts to discover more effective cancer treatments have led to a deeper understanding of the tumor microenvironment (TME) and its components. Currently, the interactions between cancer cells and elements of the TME are being intensely investigated. Remarkable progress in research is noted, largely owing to the development of advanced in vitro models, such as tumor-on-a-chip models that assist in understanding and ultimately discovering new effective treatments for a specific type of cancer. The purpose of this article is to provide a review of the TME and cancer cell components, along with the advances on tumor-on-a-chip models designed to mimic tumors, offering a perspective on the current state of the art. Recent studies using this kind of microdevices that reproduce the TME have allowed a better understanding of the cancer and its treatments. Nevertheless, current applications of this technology present some limitations that must be overcome to achieve a broad application by researchers looking for a deeper knowledge of cancer and new strategies to improve current therapies.
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PURPOSE: This study aims to develop radiomics models and a nomogram based on machine learning techniques, preoperative dual-energy computed tomography (DECT) images, clinical and pathological characteristics, to explore the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC). METHODS: We retrospectively recruited of 87 patients diagnosed with ccRCC through pathological confirmation from Center I (training set, n = 69; validation set, n = 18), and collected their DECT images and clinical information. Feature selection was conducted using variance threshold, SelectKBest, and the least absolute shrinkage and selection operator (LASSO). Radiomics models were then established using 14 classifiers to predict TME cells. Subsequently, we selected the most predictive radiomics features to calculate the radiomics score (Radscore). A combined model was constructed through multivariate logistic regression analysis combining the Radscore and relevant clinical characteristics, and presented in the form of a nomogram. Additionally, 17 patients were recruited from Center II as an external validation cohort for the nomogram. The performance of the models was assessed using methods such as the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: The validation set AUC values for the radiomics models assessing CD8+, CD163+, and αSMA+ cells were 0.875, 0.889, and 0.864, respectively. Additionally, the external validation cohort AUC value for the nomogram reaches 0.849 and shows good calibration. CONCLUSION: Radiomics models could allow for non-invasive assessment of TME cells from DECT images in ccRCC patients, promising to enhance our understanding and management of the tumor.
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BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation. METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders. RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response. CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.
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Linfócitos T CD8-Positivos , Fator 1-alfa Nuclear de Hepatócito , Imunoterapia , Melanoma , Humanos , Melanoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia/métodos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Feminino , Masculino , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , IdosoRESUMO
Exosomes, measuring between 30 and 150 nm in diameter, are small vesicles enclosed by a lipid bilayer membrane. They are released by various cells in the body and carry a diverse payload of molecules, including proteins, lipids, mRNA, and different RNA species such as long non-coding RNA, circular RNA, and microRNA (miRNA). With lengths of approximately 19-22 nucleotides, miRNAs constitute the predominant cargo in exosomes and serve as crucial regulators of protein biosynthesis. In cancer detection, exosomal miRNAs show promise as non-invasive biomarkers due to their stability and presence in various bodily fluids, aiding in early detection and precise diagnosis with specific miRNA signatures linked to different cancer types. Moreover, exosomal miRNAs influence treatment outcomes by affecting cellular processes like cell growth, cell death, and drug resistance, thereby impacting response to therapy. Additionally, they serve as indicators of disease progression and treatment response, providing insights that can guide treatment decisions and improve patient care. Through longitudinal studies, changes in exosomal miRNA profiles have been observed to correlate with disease progression, metastasis, and response to therapy, highlighting their potential for real-time monitoring of tumor dynamics and treatment efficacy. Understanding the intricate roles of exosomal miRNAs in cancer biology offers opportunities for developing innovative diagnostic tools and therapeutic strategies tailored to individual patients, ultimately advancing precision medicine approaches and improving outcomes for cancer patients. This review aims to provide an understanding of the role of exosomal miRNAs in cancer detection, treatment, and monitoring, shedding light on their potential for revolutionising oncology practices and patient care.
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Cold tumors lack antitumor immunity and are resistant to therapy, representing a major challenge in cancer medicine. Because of the immunosuppressive spirit of the tumor microenvironment (TME), this form of tumor has a low response to immunotherapy, radiotherapy, and also chemotherapy. Cold tumors have low infiltration of immune cells and a high expression of co-inhibitory molecules, such as immune checkpoints and immunosuppressive molecules. Therefore, targeting TME and remodeling immunity in cold tumors can improve the chance of tumor repression after therapy. However, tumor stroma prevents the infiltration of inflammatory cells and hinders the penetration of diverse molecules and drugs. Nanoparticles are an intriguing tool for the delivery of immune modulatory agents and shifting cold to hot tumors. In this review article, we discuss the mechanisms underlying the ability of nanoparticles loaded with different drugs and products to modulate TME and enhance immune cell infiltration. We also focus on newest progresses in the design and development of nanoparticle-based strategies for changing cold to hot tumors. These include the use of nanoparticles for targeted delivery of immunomodulatory agents, such as cytokines, small molecules, and checkpoint inhibitors, and for co-delivery of chemotherapy drugs and immunomodulatory agents. Furthermore, we discuss the potential of nanoparticles for enhancing the efficacy of cancer vaccines and cell therapy for overcoming resistance to treatment.
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Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
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AMP Cíclico , Desoxiadenosinas , Simulação de Dinâmica Molecular , Neoplasias , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacologia , Desoxiadenosinas/química , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , AMP Cíclico/metabolismo , Trifosfato de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Simulação por Computador , Adenilil Ciclases/metabolismoRESUMO
Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a prospective phase II clinical trial involving allogeneic vaccination with dendritic cells (DCs). To date, six out of the thirty-seven reported cases remain alive without tumor recurrence. In this study, we focused on the characterization of infiltrating immune cells observed at the time of surgical resection. An analytical model employing a neural network-based predictive algorithm was used to ascertain the potential prognostic implications of immunological variables on patients' overall survival. Counterintuitively, immune phenotyping of tumor-associated macrophages (TAMs) has revealed the extracellular marker PD-L1 to be a positive predictor of overall survival. In contrast, the elevated expression of CD86 within this cellular subset emerged as a negative prognostic indicator. Fundamentally, the neural network algorithm outlined here allows a prediction of the responsiveness of patients undergoing dendritic cell vaccination in terms of overall survival based on clinical parameters and the profile of infiltrated TAMs observed at the time of tumor excision.
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Neoplasias Encefálicas , Células Dendríticas , Glioblastoma , Imunoterapia , Humanos , Células Dendríticas/imunologia , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/mortalidade , Glioblastoma/patologia , Imunoterapia/métodos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Antígeno B7-H1/metabolismo , Prognóstico , Adulto , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Idoso , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismoRESUMO
Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.
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The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.
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Fibroblastos Associados a Câncer , Neoplasias , Microambiente Tumoral , Humanos , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Citocinas/metabolismo , Progressão da DoençaRESUMO
BACKGROUND: Cancer stem cells (CSCs) represent a potential mechanism contributing to tumorigenesis, metastasis, recurrence, and drug resistance. The objective of this study is to investigate the status quo and advancements in CSC research utilizing bibliometric analysis. METHODS: Publications related to CSCs from 2010 to 2022 were collected from the Web of Science Core Collection database. Various analytical tools including CiteSpace, VOSviewer, Scimago Graphica, and GraphPad Prism were used to visualize aspects such as co-authorship, co-occurrence, and co-citation within CSC research to provide an objective depiction of the contemporary status and developmental trajectory of the CSC field. RESULTS: A total of 22,116 publications were included from 1942 journals written by 95,992 authors. Notably, China emerged as the country with the highest number of publications, whereas the United States exerted the most significant influence within the field. MD Anderson Cancer Center emerged as the institution making the most comprehensive contributions. Wicha M.S. emerged as the most prolific and influential researcher. Among journals, Cancers emerged as a focal point for CSC research, consistently publishing a wealth of high-quality papers. Furthermore, it was observed that most journals tended to approach CSC research from molecular, biological, and immunological perspectives. The research into CSCs encompassed a broad array of topics, including isolation and enrichment techniques, biomarkers, biological characteristics, cancer therapy strategies, and underlying biological regulatory mechanisms. Notably, exploration of the tumor microenvironment and extracellular vesicles emerged as burgeoning research frontiers for CSCs. CONCLUSION: The research on CSCs has garnered growing interest. A trend toward multidisciplinary homogeneity is emerging within the realm of CSCs. Further investigation could potentially center on the patients of extracellular vesicles and the tumor microenvironment in relation to CSCs.
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Bibliometria , Células-Tronco Neoplásicas , Células-Tronco Neoplásicas/patologia , Humanos , Pesquisa Biomédica , Neoplasias/patologia , Neoplasias/terapiaRESUMO
BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.
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Proteínas de Membrana , Neoplasias , Microambiente Tumoral , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Variações do Número de Cópias de DNA , Metilação de DNA , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/imunologiaRESUMO
CONTEXT: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. OBJECTIVE: Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). METHODS: We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.
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Células-Tronco Mesenquimais , Neoplasias Hipofisárias , Microambiente Tumoral , Humanos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Microambiente Tumoral/imunologia , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Adenoma/patologia , Adenoma/imunologia , Adenoma/metabolismo , Hipersecreção Hipofisária de ACTH/patologia , Hipersecreção Hipofisária de ACTH/imunologia , Hipófise/imunologia , Hipófise/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismoRESUMO
Bladder cancer (BC) is the 10th most common cancer worldwide, with about 0.5 million reported new cases and about 0.2 million deaths per year. In this scoping review, we summarize the current evidence regarding the clinical implications of single-cell sequencing for bladder cancer based on PRISMA guidelines. We searched PubMed, CENTRAL, Embase, and supplemented with manual searches through the Scopus, and Web of Science for published studies until February 2023. We included original studies that used at least one single-cell technology to study bladder cancer. Forty-one publications were included in the review. Twenty-nine studies showed that this technology can identify cell subtypes in the tumor microenvironment that may predict prognosis or response to immune checkpoint inhibition therapy. Two studies were able to diagnose BC by identifying neoplastic cells through single-cell sequencing urine samples. The remaining studies were mainly a preclinical exploration of tumor microenvironment at single cell level. Single-cell sequencing technology can discriminate heterogeneity in bladder tumor cells and determine the key molecular properties that can lead to the discovery of novel perspectives on cancer management. This nascent tool can advance the early diagnosis, prognosis judgment, and targeted therapy of bladder cancer.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Prognóstico , Microambiente Tumoral/genéticaRESUMO
Epidemiological studies show a strong correlation between diabetes and the increased risk of developing different cancers, including melanoma. In the present study, we investigated the impact of a streptozotocin (STZ)-induced hyperglycemic environment on B16F10-Nex2 murine melanoma development. Hyperglycemic male C57Bl/6 mice showed increased subcutaneous tumor development, partially inhibited by metformin. Tumors showed increased infiltrating macrophages, and augmented IL-10 and nitric oxide (NO) concentrations. In vivo neutralization of IL-10, NO synthase inhibition, and depletion of macrophages reduced tumor development. STZ-treated TLR4 KO animals showed delayed tumor development; the transfer of hyperglycemic C57Bl/6 macrophages to TLR4 KO reversed this effect. Increased concentrations of IL-10 present in tumor homogenates of hyperglycemic mice induced a higher number of pre-angiogenic structures in vitro, and B16F10-Nex2 cells incubated with different glucose concentrations in vitro produced increased levels of IL-10. In summary, our findings show that a hyperglycemic environment stimulates murine melanoma B16F10-Nex2 primary tumor growth, and this effect is dependent on tumor cell stimulation, increased numbers of macrophages, and augmented IL-10 and NO concentrations. These findings show the involvement of tumor cells and other components of the tumor microenvironment in the development of subcutaneous melanoma under hyperglycemic conditions, defining novel targets for melanoma control in diabetic patients.
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Hiperglicemia , Interleucina-10 , Macrófagos , Melanoma Experimental , Camundongos Endogâmicos C57BL , Óxido Nítrico , Animais , Interleucina-10/metabolismo , Óxido Nítrico/metabolismo , Masculino , Hiperglicemia/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Linhagem Celular TumoralRESUMO
Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell-cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.
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Adenocarcinoma de Pulmão , Neoplasias Encefálicas , Neoplasias Pulmonares , Síndromes Neurotóxicas , Humanos , Células Endoteliais , Adenocarcinoma de Pulmão/genética , Neoplasias Encefálicas/genética , Neoplasias Pulmonares/genética , Perfilação da Expressão Gênica , Microambiente Tumoral/genéticaRESUMO
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Introduction: Worldwide, breast cancer is the most important cancer in incidence and prevalence in women. Different risk factors interact to increase the probability of developing it. Biological agents such as helminth parasites, particularly their excretory/secretory antigens, may play a significant role in tumor development. Helminths and their antigens have been recognized as inducers or promoters of cancer due to their ability to regulate the host's immune response. Previously in our laboratory, we demonstrated that chronic infection by Toxocara canis increases the size of mammary tumors, affecting the systemic response to the parasite. However, the parasite does not invade the tumor, and we decided to study if the excretion/secretion of antigens from Toxocara canis (EST) can affect the progression of mammary tumors or the pathophysiology of cancer which is metastasis. Thus, this study aimed to determine whether excretion/secretion T. canis antigens, injected directly into the tumor, affect tumor growth and metastasis. Methods: We evaluated these parameters through the monitoring of the intra-tumoral immune response. Results: Mice injected intratumorally with EST did not show changes in the size and weight of the tumors; although the tumors showed an increased microvasculature, they did develop increased micro and macro-metastasis in the lung. The analysis of the immune tumor microenvironment revealed that EST antigens did not modulate the proportion of immune cells in the tumor, spleen, or peripheral lymph nodes. Macroscopic and microscopic analyses of the lungs showed increased metastasis in the EST-treated animals compared to controls, accompanied by an increase in VEGF systemic levels. Discussion: Thus, these findings showed that intra-tumoral injection of T. canis EST antigens promote lung metastasis through modulation of the tumor immune microenvironment.