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1.
Sci Rep ; 10(1): 2439, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051509

RESUMO

IQGAP1 is a scaffold protein involved in a range of cellular activities, including migration, invasion, adhesion and proliferation. It is also oncogenic in a variety of cancers, promoting primary tumor growth and invasiveness. However, the role of IQGAP1 in tumor progression and metastasis remains unclear. In this study, we use both knockdown and knockout of IQGAP1 to investigate its role in the metastatic cascade of both melanoma and breast cancer cells in vivo. We find that reduction of IQGAP1 expression decreases the formation of both spontaneous and experimental metastases, without limiting primary or metastatic tumor growth. Furthermore, IQGAP1 knockout significantly inhibits extravasation of tumor cells from circulation, possibly involving invadopodial function. By expressing mutant forms of IQGAP1 in a knockout context, we also determine that IQGAP1's pro-metastatic functions are dependent on multiple domains and functions. These data demonstrate that IQGAP1 is crucial for metastasis in vivo through regulation of extravasation and suggest that it may represent a valid therapeutic target for inhibiting metastasis.

2.
Histopathology ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031712

RESUMO

INTRODUCTION: In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX show superior survival. Herein, we quantitatively assess pathologic tumor response to chemoradiation in pancreatectomy specimen and reassess guidelines for tumor regression grading. METHODS: We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumor regression grade (TRG), and overall survival (OS) was recorded. A quantitative analysis of residual tumor was performed on the slide with the highest tumor burden to derive a tumor to tumor bed ratio. RESULTS: On univariate analysis, only lymph node status (p=0.043), and CAP TRG (p=0.038) correlated with OS. Sixteen percent of patients showed complete pathologic response. The optimal tumor to tumor bed ratio cut point was 11.6% and on a multivariate model was the only pathologic parameter that correlated with OS (p=0.016) (Hazard Ratio 2.27). CONCLUSIONS: The high proportion of patients with PDAC showing complete and near complete pathologic response supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation while a quantitative tumor to tumor bed ratio is a powerful predictor of OS. The data supports a two-tiered approach to TRG based on tumor to tumor bed ratio and quantitative analysis merits further consideration.

3.
Cancer Res ; 80(7): 1461-1474, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32029550

RESUMO

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. SIGNIFICANCE: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

4.
Clin Cancer Res ; 26(6): 1277-1287, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31852835

RESUMO

PURPOSE: Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. EXPERIMENTAL DESIGN: Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. RESULTS: Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. CONCLUSIONS: Muscularis mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.

5.
Cell Tissue Res ; 379(1): 45-62, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31858241

RESUMO

Lipid droplet (LD) binding proteins in mammary glands and in adipocytes were previously compared and striking similar sets of these specific proteins demonstrated. Xanthine oxidoreductase (XOR) together with perilipins and the lactating mammary gland protein butyrophilin play an important role in the secretion process of LDs into milk ducts. In contrast, in adipose tissue and in adipocytes, mainly perilipins have been described. Moreover, XOR was reported in mouse adipose tissue and adipocyte culture cells as "novel regulator of adipogenesis". This obvious coincidence of protein sets prompted us to revisit the formation of LDs in human-cultured adipocytes in more detail with special emphasis on the possibility of a LD association of XOR. We demonstrate by electron and immunoelectron microscopy new structural details on LD formation in adipocytes. Surprisingly, by immunological and proteomic analysis, we identify in contrast to previous data showing the enzyme XOR, predominantly the expression of aldehyde oxidase (AOX). AOX could be detected tightly linked to LDs when adipocytes were treated with starvation medium. In addition, the majority of cells show an enormous interconnected, tubulated mitochondria network. Here, we discuss that (1) XOR is involved-together with perilipins-in the secretion of LDs in alveolar epithelial cells of the lactating mammary gland and is important in the transcytosis pathway of capillary endothelial cells. (2) In cells, where LDs are not secreted, XOR cannot be detected at the protein level, whereas in contrast in these cases, AOX is often present. We detect AOX in adipocytes together with perilipins and find evidence that these proteins might direct LDs to mitochondria. Finally, we here report for the first time the exclusive and complementary localization of XOR and AOX in diverse cell types.


Assuntos
Adipócitos/metabolismo , Aldeído Oxidase/biossíntese , Gotículas Lipídicas/metabolismo , Adipócitos/enzimologia , Adipócitos/ultraestrutura , Animais , Células Cultivadas , Meios de Cultura , Humanos , Perilipinas/metabolismo , Xantina Desidrogenase/metabolismo
6.
Cell Stress ; 3(11): 348-360, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31799501

RESUMO

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug's mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315's multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.

7.
Proc Natl Acad Sci U S A ; 116(39): 19609-19618, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31484774

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.

8.
Cell ; 178(5): 1115-1131.e15, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31442404

RESUMO

Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (ßOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ßOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous ßOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, ßOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through ßOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of ßOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.

9.
Proc Natl Acad Sci U S A ; 116(28): 14181-14190, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31068469

RESUMO

Extracellular matrix (ECM) deposition is a hallmark of many diseases, including cancer and fibroses. To exploit the ECM as an imaging and therapeutic target, we developed alpaca-derived libraries of "nanobodies" against disease-associated ECM proteins. We describe here one such nanobody, NJB2, specific for an alternatively spliced domain of fibronectin expressed in disease ECM and neovasculature. We showed by noninvasive in vivo immuno-PET/CT imaging that NJB2 detects primary tumors and metastatic sites with excellent specificity in multiple models of breast cancer, including human and mouse triple-negative breast cancer, and in melanoma. We also imaged mice with pancreatic ductal adenocarcinoma (PDAC) in which NJB2 was able to detect not only PDAC tumors but also early pancreatic lesions called pancreatic intraepithelial neoplasias, which are challenging to detect by any current imaging modalities, with excellent clarity and signal-to-noise ratios that outperformed conventional 2-fluorodeoxyglucose PET/CT imaging. NJB2 also detected pulmonary fibrosis in a bleomycin-induced fibrosis model. We propose NJB2 and similar anti-ECM nanobodies as powerful tools for noninvasive detection of tumors, metastatic lesions, and fibroses. Furthermore, the selective recognition of disease tissues makes NJB2 a promising candidate for nanobody-based therapeutic applications.

10.
Nat Commun ; 10(1): 1486, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940805

RESUMO

Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models. These anticancer effects are linked to increased T lymphocyte infiltration and are abolished by T cell depletion or interferon-γ neutralization. Crizotinib plus cisplatin leads to an increase in the expression of PD-1 and PD-L1 in tumors, coupled to a strong sensitization of NSCLC to immunotherapy with PD-1 antibodies. Hence, a sequential combination treatment consisting in conventional chemotherapy together with crizotinib, followed by immune checkpoint blockade may be active against NSCLC.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Crizotinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Linhagem Celular Tumoral , Feminino , Humanos , Interferon gama/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia
11.
Proc Natl Acad Sci U S A ; 116(16): 7624-7631, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30936321

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing VHH-based, single-domain antibody (nanobody) CAR T cells that target aspects of the tumor microenvironment conserved across multiple cancer types. Many solid tumors evade immune recognition through expression of checkpoint molecules, such as PD-L1, that down-regulate the immune response. We therefore targeted CAR T cells to the tumor microenvironment via the checkpoint inhibitor PD-L1 and observed a reduction in tumor growth, resulting in improved survival. CAR T cells that target the tumor stroma and vasculature through the EIIIB+ fibronectin splice variant, which is expressed by multiple tumor types and on neovasculature, are likewise effective in delaying tumor growth. VHH-based CAR T cells can thus function as antitumor agents for multiple targets in syngeneic, immunocompetent animal models. Our results demonstrate the flexibility of VHH-based CAR T cells and the potential of CAR T cells to target the tumor microenvironment and treat solid tumors.

13.
Matrix Biol ; 71-72: 10-27, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29730502

RESUMO

The diversity of extracellular matrix (ECM) proteins encoded in mammalian genomes and detected by proteomic analyses generates a need for well validated antibodies against these proteins. We present characterization of a large number of antibodies against ECM proteins, from both commercial and academic sources, together with discussion of methods and strategies for their effective use in immunohistochemistry and illustrations of their efficacy. These data should be of value to investigators seeking well validated antibodies to ECM proteins of interest and save significant time and money tracking down effective reagents.


Assuntos
Anticorpos/metabolismo , Proteínas da Matriz Extracelular/imunologia , Animais , Indústria Farmacêutica , Matriz Extracelular/metabolismo , Humanos , Imuno-Histoquímica
15.
Science ; 358(6367)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29191879

RESUMO

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.


Assuntos
Adenocarcinoma/patologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Osso e Ossos/patologia , Lectinas/metabolismo , Neoplasias Pulmonares/patologia , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Neutrófilos/patologia , Osteoblastos/patologia , Adenocarcinoma de Pulmão , Animais , Densidade Óssea , Células da Medula Óssea/patologia , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/patologia , Neoplasias Experimentais/patologia , Osteocalcina/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo
16.
Nat Biotechnol ; 35(6): 569-576, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28459449

RESUMO

In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.


Assuntos
Neoplasias Colorretais/genética , Modelos Animais de Doenças , Edição de Genes/métodos , Genes Neoplásicos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Transplante de Órgãos/métodos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Metástase Neoplásica
17.
Cell Rep ; 17(7): 1764-1772, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27829148

RESUMO

Co-option of host components by solid tumors facilitates cancer progression and can occur in both local tumor microenvironments and remote locations. At present, the signals involved in long-distance communication remain insufficiently understood. Here, we identify platelet factor 4 (PF4, CXCL4) as an endocrine factor whose overexpression in tumors correlates with decreased overall patient survival. Furthermore, engineered PF4 over-production in a Kras-driven lung adenocarcinoma genetic mouse model expanded megakaryopoiesis in bone marrow, augmented platelet accumulation in lungs, and accelerated de novo adenocarcinogenesis. Additionally, anti-platelet treatment controlled mouse lung cancer progression, further suggesting that platelets can modulate the tumor microenvironment to accelerate tumor outgrowth. These findings support PF4 as a cancer-enhancing endocrine signal that controls discrete aspects of bone marrow hematopoiesis and tumor microenvironment and that should be considered as a molecular target in anticancer therapy.


Assuntos
Plaquetas/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Fator Plaquetário 4/metabolismo , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Células da Medula Óssea/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem da Célula , Proliferação de Células , Progressão da Doença , Humanos , Megacariócitos/metabolismo , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Análise de Sobrevida
18.
Immunity ; 44(2): 343-54, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26872698

RESUMO

Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.


Assuntos
Adenocarcinoma/terapia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Adenocarcinoma/imunologia , Animais , Linhagem Celular Tumoral , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Tratamento Farmacológico/métodos , Genes cdc/efeitos dos fármacos , Humanos , Imunidade Inata , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Receptor 4 Toll-Like/metabolismo
19.
Nat Med ; 21(9): 1076-84, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26280121

RESUMO

Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.


Assuntos
Queratina-18/fisiologia , Queratina-8/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Cardiomegalia/prevenção & controle , Desmina/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia
20.
Cell Tissue Res ; 359(3): 779-97, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25501894

RESUMO

Proteins of the striatin family (striatins 1-4; sizes ranging from 90 to 110 kDa on SDS-polyacrylamide gel electrophoresis) are highly homologous in their amino acid sequences but can differ in their cell-type-specific gene expression patterns and biological functions. In various cell types, we have found one, two or three polypeptides of this evolutionarily old and nearly ubiquitous family of proteins known to serve as scaffold proteins for diverse protein complexes. Light and electron microscopic immunolocalization methods have revealed striatins in mammalian cell-cell adherens junctions (AJs). In simple epithelia, we have localized striatins as constitutive components of the plaques of the subapical zonulae adhaerentes of cells, including intestinal, glandular, ductal and urothelial cells and hepatocytes. Striatins colocalize with E-cadherin or E-N-cadherin heterodimers and with the plaque proteins α- and ß-catenin, p120 and p0071. In some epithelia and carcinomas and in cultured cells derived therefrom, striatins are also seen in lateral AJs. In stratified epithelia and in corresponding squamous cell carcinomas, striatins can be found in plaques of some forms of tessellate junctions. Moreover, striatins are major plaque proteins of composite junctions (CJs; areae compositae) in the intercalated disks connecting cardiomyocytes, colocalizing with other CJ molecules, including plectin and ankyrin-G. We discuss the "multimodulator" scaffold roles of striatins in the initiation and regulation of the formation of various complex particles and structures. We propose that striatins are included in the diagnostic candidate list of proteins that, in the CJs of human hearts, can occur in mutated forms in the pathogeneses of hereditary cardiomyopathies, as seen in some types of genetically determined heart damage in boxer dogs.


Assuntos
Junções Aderentes/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Epitélio/metabolismo , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Junções Aderentes/ultraestrutura , Animais , Anticorpos/metabolismo , Bovinos , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Enterócitos/metabolismo , Epitélio/ultraestrutura , Imunofluorescência , Humanos , Miocárdio/citologia , Ratos
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