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1.
APMIS ; 129 Suppl 142: 1-30, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34399444

RESUMO

Over the past decade, 3D culture models of human and animal cells have found their way into tissue differentiation, drug development, personalized medicine and tumour behaviour studies. Embryoid bodies (EBs) are in vitro 3D cultures established from murine pluripotential stem cells, whereas tumoroids are patient-derived in vitro 3D cultures. This thesis aims to describe a new implication of an embryoid body model and to characterize the patient-specific microenvironment of the parental tumour in relation to tumoroid growth rate. In this thesis, we described a high-throughput monitoring method, where EBs are used as a dynamic angiogenesis model. In this model, digital image analysis (DIA) is implemented on immunohistochemistry (IHC) stained sections of the cultures over time. Furthermore, we have investigated the correlation between the genetic profile and inflammatory microenvironment of parental tumours on the in vitro growth rate of tumoroids. The EBs were cultured in spinner flasks. The samples were collected at days 4, 6, 9, 14, 18 and 21, dehydrated and embedded in paraffin. The histological sections were IHC stained for the endothelial marker CD31 and digitally scanned. The virtual whole-image slides were digitally analysed by Visiopharm® software. Histological evaluation showed vascular-like structures over time. The quantitative DIA was plausible to monitor significant increase in the total area of the EBs and an increase in endothelial differentiation. The tumoroids were established from 32 colorectal adenocarcinomas. The in vitro growth rate of the tumoroids was followed by automated microscopy over an 11-day period. The parental tumours were analysed by next-generation sequencing for KRAS, TP53, PIK3CA, SMAD4, MAP2K1, BRAF, FGFR3 and FBXW7 status. The tumoroids established from KRAS-mutated parental tumours showed a significantly higher growth rate compared to their wild-type counterparts. The density of CD3+ T lymphocytes and CD68+ macrophages was calculated in the centre of the tumours and at the invasive margin of the tumours. The high density of CD3+ cells and the low density of CD68+ cells showed a significant correlation with a higher growth rate of the tumoroids. In conclusion, a novel approach for histological monitoring of endothelial differentiation is presented in the stem cell-derived EBs. Furthermore, the KRAS status and density of CD3+ T cells and macrophages in the parental tumour influence the growth rate of the tumoroids. Our results indicate that these parameters should be included when tumoroids are to be implemented in personalized medicine.


Assuntos
Adenocarcinoma/patologia , Técnicas de Cultura de Células/métodos , Neoplasias Colorretais/patologia , Animais , Diferenciação Celular/fisiologia , Corpos Embrioides/patologia , Células Endoteliais/patologia , Humanos , Macrófagos/patologia , Camundongos , Células-Tronco/patologia , Linfócitos T/patologia , Microambiente Tumoral/fisiologia
2.
Theranostics ; 11(16): 7813-7828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335966

RESUMO

Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic. Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days. Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT). The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia. Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation. Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability. Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Hemodinâmica/fisiologia , Tomografia Óptica/métodos , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Docetaxel/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipóxia/metabolismo , Camundongos , Camundongos SCID , Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Tomografia/métodos , Tomografia Computadorizada por Raios X/métodos , Microambiente Tumoral/fisiologia
3.
Cancer Sci ; 112(10): 4005-4012, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34420253

RESUMO

Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.


Assuntos
Comunicação Celular/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Superfície Celular/metabolismo , Células Estromais/fisiologia , Microambiente Tumoral/fisiologia , Apoptose/fisiologia , Caderinas/metabolismo , Movimento Celular/fisiologia , Proliferação de Células , Técnicas de Cocultura , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Superfície Celular/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445720

RESUMO

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.


Assuntos
Mesotelioma Maligno/patologia , Mesotelioma Maligno/terapia , Terapia Combinada , Sistemas de Liberação de Medicamentos/métodos , Humanos , Imunoterapia/métodos , Mesotelioma/patologia , Mesotelioma/terapia , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
5.
Medicine (Baltimore) ; 100(28): e26574, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260536

RESUMO

BACKGROUND: Ovarian cancer is one of the lethal gynecological diseases in women. However, using tumor microenvironment related genes to identify prognostic signature of ovarian cancer has not been discussed in detail. METHODS: The mRNA profiles of 386 ovarian cancer patients were retrieved from The Cancer Genome Atlas. Univariate Cox regression and LASSO Cox regression analyses were performed and 14 optimized prognostic genes related to tumor microenvironment were identified. RESULTS: The multivariate Cox hazards regression showed risk score was an independent prognostic signature for ovarian cancer. Nomogram model could reliably predict the patients' survival. Furthermore, M1 macrophages, M2 macrophages, and follicular helper T cells, differentially expressed between the high- and low-risk groups, were found to be associated with the risk score. CONCLUSION: CTL-associated antigen 4 (CTLA4) and indoleamine 2,3-Dioxygenase 1 (IDO1), which were previously shown to be important immune checkpoints, probably contribute to the immunosuppressive microenvironment aberration. This study may shed light on the prognosis of ovarian cancer.


Assuntos
Neoplasias Ovarianas/genética , Microambiente Tumoral/fisiologia , Fatores Etários , Idoso , Biomarcadores Tumorais , Antígeno CTLA-4/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Células T Auxiliares Foliculares/metabolismo , Macrófagos Associados a Tumor/metabolismo
6.
Front Immunol ; 12: 637053, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108959

RESUMO

Background: Programmed cell death 10 (PDCD10) plays a crucial role in regulating tumor phenotyping, especially in glioblastoma (GBM). Glioma-associated microglia/macrophages (GAMs) in tumor pathological microenvironment contribute to GBM progression. We previously found that the infiltration of GAMs was associated with PDCD10 expression in GBM patients. The present study aims to further explore the regulation of PDCD10 on GAMs in GBM. Methods: Overexpression of PDCD10 in human- and murine-GBM cells was established by lentiviral transduction. Cell behaviors and polarization of primary microglia, microglia- and macrophage-like cells were investigated through indirect co-culture with GBM cells in vitro respectively. The PDCD10-induced release of chemokines was identified by a chemokine protein array. The cross-talk between GBM and microglia as well as macrophages was further studied using selective antagonist SB225002. Finally, an orthotopic homograft mouse model was employed to verify the results of in vitro experiments. Results: Indirect co-culture with PDCD10-overexpressed GBM cells promoted proliferation and migration of microglia- and macrophage-like cells, and stimulated pro-tumorigenic polarization of primary microglia, microglia- and macrophage-like cells. Pdcd10-upregulated GBM cells triggered a nearly 6-fold increase of CXC motif chemokine ligand 2 (CXCL2) release, which in turn activated CXC chemokine receptor 2 (CXCR2) and downstream Erk1/2 and Akt signaling in primary microglia, microglia- and macrophage-like cells. The blockage of CXCR2 signaling with specific inhibitor (SB225002) abolished microglia- and macrophage-like cell migration induced by PDCD10-upregulated GBM cells. Moreover, Pdcd10-upregulated GL261 cells promoted GAMs recruitment and tumor growth in vivo. Conclusion: Our study demonstrates that overexpression of PDCD10 in GBM recruits and activates microglia/macrophages, which in turn promotes tumor progression. CXCL2-CXCR2 signaling mediated by PDCD10 is potentially involved in the crosstalk between GBM cells and GAMs.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL2/antagonistas & inibidores , Quimiocina CXCL2/metabolismo , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas/genética , Células RAW 264.7 , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia
7.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067896

RESUMO

Exosomes are nanoscale vesicles generated by cells for intercellular communication. Due to their composition, significant research has been conducted to transform these particles into specific delivery systems for various disease states. In this review, we discuss the common isolation and loading methods of exosomes, some of the major roles of exosomes in the tumor microenvironment, as well as discuss recent applications of exosomes as drug delivery vessels and the resulting clinical implications.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Exossomos/metabolismo , Neoplasias/terapia , Exossomos/patologia , Exossomos/fisiologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
8.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067931

RESUMO

Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perilipina-5/metabolismo , Biomarcadores/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Doenças Metabólicas/metabolismo , Perilipina-5/fisiologia , Microambiente Tumoral/fisiologia
9.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067929

RESUMO

Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.


Assuntos
Fibroblastos/fisiologia , Melanoma/metabolismo , Microambiente Tumoral/fisiologia , Fibroblastos Associados a Câncer/metabolismo , Comunicação Celular , Plasticidade Celular/fisiologia , Matriz Extracelular/metabolismo , Humanos , Melanoma/patologia , Melanoma/fisiopatologia , Transdução de Sinais , Neoplasias Cutâneas/patologia , Células Estromais/metabolismo
10.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069564

RESUMO

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal stem cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.


Assuntos
Linfoma Folicular/imunologia , Células T Auxiliares Foliculares/imunologia , Microambiente Tumoral/fisiologia , Linfócitos B/imunologia , Diferenciação Celular/fisiologia , Quimiocina CXCL12/metabolismo , Humanos , Interleucina-4/imunologia , Interleucina-4/metabolismo , Linfoma de Células B/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/fisiopatologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Receptores Imunológicos/metabolismo , Células Estromais/patologia , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia
11.
Am J Physiol Cell Physiol ; 321(2): C343-C354, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34191627

RESUMO

Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single-cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Interconversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must, therefore, contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Microambiente Tumoral , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Humanos , Prognóstico , Receptores de Estrogênio/genética , Análise de Célula Única/métodos , Microambiente Tumoral/fisiologia
12.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063506

RESUMO

The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Microambiente Tumoral/imunologia , Anticarcinógenos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Fusobacterium nucleatum/metabolismo , Microbioma Gastrointestinal , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Micronutrientes/farmacologia , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
13.
Commun Biol ; 4(1): 747, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135460

RESUMO

Tumour recurrence is a serious impediment to cancer treatment, but the mechanisms involved are poorly understood. The most frequently used anti-tumour therapies-chemotherapy and radiotherapy-target highly proliferative cancer cells. However non- or slow-proliferative dormant cancer cells can persist after treatment, eventually causing tumour relapse. Whereas the reversible growth arrest mechanism allows quiescent cells to re-enter the cell cycle, senescent cells are largely thought to be irreversibly arrested, and may instead contribute to tumour growth and relapse through paracrine signalling mechanisms. Thus, due to the differences in their growth arrest mechanism, metabolic features, plasticity and adaptation to their respective tumour microenvironment, dormant-senescent and -quiescent cancer cells could have different but complementary roles in fuelling tumour growth. In this review article, we discuss the implication of dormant cancer cells in tumour relapse and the need to understand how quiescent and senescent cells, respectively, may play a part in this process.


Assuntos
Plasticidade Celular/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Ciclo Celular/fisiologia , Humanos , Neoplasias/terapia , Transdução de Sinais , Microambiente Tumoral/fisiologia
14.
J Clin Neurosci ; 89: 144-150, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119258

RESUMO

Gliomas are a heterogeneous group of primary brain cancers with poor survival despite multimodality therapy that includes surgery, radiation and chemotherapy. Numerous clinical trials have investigated systemic therapies in glioma, but have largely been negative. Multiple factors have contributed to the lack of progress including tumour heterogeneity, the tumour micro-environment and presence of the blood-brain barrier, as well as extrinsic factors relating to trial design, such as the lack of a contemporaneous biopsy at the time of treatment. A number of strategies have been proposed to progress new agents into the clinic. Here, we review the progress of perioperative, including phase 0 and 'window of opportunity', studies and provide recommendations for trial design in the development of new agents for glioma. The incorporation of pre- and post-treatment biopsies in glioma early phase trials will provide valuable pharmacokinetic and pharmacodynamic data and also determine the target or biomarker effect, which will guide further development of new agents. Perioperative 'window of opportunity' studies must use drugs with a recommended-phase-2-dose, known safety profile and adequate blood-brain barrier penetration. Drugs shown to have on-target effects in perioperative trials can then be evaluated further in a larger cohort of patients in an adaptive trial to increase the efficiency of drug development.


Assuntos
Neoplasias Encefálicas/patologia , Ensaios Clínicos como Assunto/métodos , Glioma/patologia , Assistência Perioperatória/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biópsia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/cirurgia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Terapia Combinada/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glioma/tratamento farmacológico , Glioma/cirurgia , Humanos , Assistência Perioperatória/tendências , Microambiente Tumoral/fisiologia
15.
Immunity ; 54(7): 1561-1577.e7, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34102100

RESUMO

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.


Assuntos
Antígenos CD36/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Peroxidação de Lipídeos/fisiologia , Lipoproteínas LDL/metabolismo , Neoplasias/metabolismo , Receptores Depuradores/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Leucócitos Mononucleares/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microambiente Tumoral/fisiologia
16.
Nat Rev Gastroenterol Hepatol ; 18(7): 469-481, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34089011

RESUMO

Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/genética , Genoma , Humanos , Mutação , Neoplasias Pancreáticas/terapia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
17.
Exp Cell Res ; 405(2): 112710, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34174319

RESUMO

Immune cells not only constitute tumour microenvironment but they may even affect disease prognosis as a result of dual functional roles that they may play in tumour tissues. Two frequently used established immune cell lines (lymphocytic Jurkat and monocytic THP-1) were used to test whether microenvironmental factors, especially molecular components of extracellular matrix, can shape the phenotype of immune cells. Proliferation, morphological and phenotypical analyses were applied to compare behaviour of the immune cells, typically cultured as suspensions in culture medium, with their behaviour in collagen type I-based and Matrigel-based 3D cultures. Density of both immune cell types in routine suspension cultures affected their subsequent proliferation in extracellular matrices. THP-1 cells appeared to be more sensitive to their surrounding microenvironment as judged from extracellular matrix type-dependent changes in their cell doubling times and from slight increase in their diameters in both extracellular matrix-containing cell cultures. Moreover, even chemically uninduced monocytic THP-1 cells were present in a minor fraction as CD68 positive cell population in collagen type I matrix indicating their partial differentiation to macrophages. Observed modifications of immune cells by microenvironmental factors may have profound implications for their roles in healthy and pathological tissues.


Assuntos
Diferenciação Celular/fisiologia , Matriz Extracelular/metabolismo , Fenótipo , Microambiente Tumoral/fisiologia , Células Cultivadas , Colágeno/metabolismo , Colágeno/farmacologia , Colágeno Tipo I/metabolismo , Combinação de Medicamentos , Humanos , Laminina/metabolismo , Laminina/farmacologia , Proteoglicanas/metabolismo , Proteoglicanas/farmacologia
18.
Immunity ; 54(5): 903-915, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979587

RESUMO

Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.


Assuntos
Fibroblastos/metabolismo , Fibrose/metabolismo , Macrófagos/metabolismo , Neoplasias/metabolismo , Animais , Diferenciação Celular/fisiologia , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Microambiente Tumoral/fisiologia
19.
Front Immunol ; 12: 633205, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025641

RESUMO

The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.


Assuntos
Imunoterapia , Células Matadoras Naturais/metabolismo , Células Supressoras Mieloides/metabolismo , Microambiente Tumoral/imunologia , Microambiente Tumoral/fisiologia , Animais , Humanos , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Camundongos , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia
20.
Methods Mol Biol ; 2318: 281-295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34019297

RESUMO

Myc is deregulated in most-if not all-cancers, and it not only promotes tumor progression by inducing cell proliferation but is also responsible for tumor immune evasion. In a nutshell, MYC promotes the development of tumor-associated macrophages, impairs the cellular response to interferons, induces the expression of immunosuppressive molecules, and excludes tumor infiltrating lymphocytes (TILs) from the tumor site. Based on the insights into the role of MYC in promoting and regulating immune evasion by cancer cells, it is of special interest to study the different immune cell populations infiltrating the tumors. MYC inhibition has emerged as a potential new strategy for the treatment of cancer, directly inhibiting tumor progression while also counteracting the immunosuppressive tumor microenvironment, allowing an optimal anti-tumor immune response. Hence, this chapter describes a flow cytometry-based method to study the different immune cell subsets infiltrating the tumor by combining surface, cytoplasmic, and nuclear multicolor protein stainings.


Assuntos
Citometria de Fluxo/métodos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Microambiente Tumoral/imunologia , Proliferação de Células , DNA/genética , Genes myc/genética , Genes myc/fisiologia , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Microambiente Tumoral/fisiologia
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