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1.
Nature ; 610(7930): 190-198, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36131018

RESUMO

Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.


Assuntos
Proliferação de Células , Melanoma , Metástase Neoplásica , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula , Rastreamento de Células , Reprogramação Celular , Células Endoteliais , Melanoma/genética , Melanoma/patologia , Mesoderma/patologia , Camundongos , Metástase Neoplásica/patologia , Crista Neural/embriologia , Fenótipo , Análise de Célula Única , Transcriptoma , Microambiente Tumoral
2.
J Ovarian Res ; 15(1): 104, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114551

RESUMO

BACKGROUND: Ovarian malignant mesoderm mixed tumor (OMMMT) is a rare clinical entity. To provide reference for the treatment and prognosis of OMMMT, we analyzed the clinical features, pathology and molecular biology characteristic of published cases. METHODS: The English and Chinese reported cases of OMMMT were selected from PubMed, Clinical Trials.gov and CNKI database from 2000 to December 15th, 2021 following the PRISMA guidelines. RESULTS: A total of 63 literatures including 199 OMMMT cases were included. The average age of patients at diagnosis was 56.46 years, the highest incidence age was 60-65 years, and 82% of them were menopausal women. Most patients were diagnosed in FIGO III stage (59.64%). The most common symptom of OMMMT was abdominal pain (60.5%). 61.6% of patients were accompanied by ascites, while ascites was not associated with metastatic tumor and local recurrence. The CA125 of 88.68% patients increased. The most common reported carcinomatous component and sarcomatous component were serous adenocarcinoma (44.96%) and chondrosarcoma (24.81%), respectively. Initial treatment included surgery (94.97%) and taxanes-based (55.10%) or platinum-based (85.71%) chemotherapy regimens. The median survival time of patients was 20 months. Heterologous sarcoma component did not shorten life expectancy. The optimal ovarian tumor cell debulking surgery (OOTCDS), radiotherapy and chemotherapy could significantly prolong the median survival time of patients. Furthermore, platinum drugs could significantly prolong the survival time after comparing various chemotherapy schemes. Besides, the combination of platinum and taxanes was therapeutically superior to the combination of platinum and biological alkylating agents. CONCLUSION: The OOTCDS and platinum-based chemotherapy regimen can improve the prognosis of OMMMT. Targeted therapy might become a new research direction in the future. Since the elderly patients are the majority, the toxicity of new drugs on the elderly patients is more noteworthy.


Assuntos
Carcinoma , Neoplasias Ovarianas , Idoso , Alquilantes/uso terapêutico , Feminino , Humanos , Mesoderma/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Taxoides/uso terapêutico
3.
Nature ; 607(7917): 163-168, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35768509

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1-4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3-5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1 inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1 overexpression caused an almost complete 'epithelialization' of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1 was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial-mesenchymal transition transcription factors Snai1 (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial-mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.


Assuntos
Transição Epitelial-Mesenquimal , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/patologia , Camundongos , Neoplasias Pancreáticas/patologia , Fatores de Transcrição da Família Snail
4.
Indian J Ophthalmol ; 70(3): 921-929, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35225544

RESUMO

PURPOSE: This study aimed to investigate the efficacy of human-derived umbilical cord mesenchymal stem cells (HDUMSC) and human-derived umbilical cord mesenchymal stem cells expressing erythropoietin (HDUMSC-EPO) to rescue total degenerated retina in a rat model. METHODS: The study included four treatment groups, namely negative control using normal saline (HBSS) injection, positive control using sodium iodide 60 mg/kg (SI), SI treated with HDUMSC, and SI treated with HDUMSC-EPO given via subretinal and intravenous routes, to test the efficacy of retinal regeneration following SI-induced retinal degeneration. Retinal function in both phases was tested via electroretinography (ERG) and histological staining examining the outer nuclear layer (ONL). RESULTS: There was a statistically significant result (P < 0.05) in the SI treated with HDUMSC-EPO only when comparing day 11 (mean = 23.6 µv), day 18 (mean = 25.2 µv), day 26 (mean = 26.3 µv), and day 32 (mean = 28.2 µv) to the b-wave ERG on day 4 rescue injection day (mean = 12.5 µv). The SI treated with HDUMSC-EPO showed significant improvement in b-wave ERG readings in the Sprague-Dawley (SD) rat but did not restore baseline readings prior to degeneration (day 0). Both treated groups' ONL thicknesses did not show significant changes compared to the negative control group (HBSS) following rescue therapy. CONCLUSION: Total retinal degeneration following intravenous SI injection was observed at 60 mg/kg. SI treated with HDUMSC and HDUMSC-EPO showed no regenerative potential compared to baseline in SI-induced total retina degeneration on ERG or histology, whereas SI treated with HDUMSC-EPO group showed a substantial increase in b-wave ERG amplitude over time.


Assuntos
Eritropoetina , Degeneração Retiniana , Animais , Modelos Animais de Doenças , Eletrorretinografia , Humanos , Mesoderma/patologia , Ratos , Ratos Sprague-Dawley , Retina/patologia , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/terapia , Células-Tronco/patologia
5.
Cell Rep ; 38(7): 110385, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35172160

RESUMO

Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression roadmap for the analysis of different 2D and 3D NF models. The best model consists of generating heterotypic spheroids (neurofibromaspheres) composed of iPSC-derived differentiating NF1(-/-) SCs and NF1(+/-) pNF-derived fibroblasts (Fbs). Neurofibromaspheres form by maintaining highly proliferative NF1(-/-) cells committed to the NC-SC axis due to SC-SC and SC-Fb interactions, resulting in SC linage cells at different maturation points. Upon engraftment on the mouse sciatic nerve, neurofibromaspheres consistently generate human NF-like tumors. Analysis of expression roadmap genes in human pNF single-cell RNA-seq data uncovers the presence of SC subpopulations at distinct differentiation states.


Assuntos
Células-Tronco Pluripotentes Induzidas/patologia , Neurofibroma Plexiforme/patologia , Células de Schwann/patologia , Adolescente , Adulto , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Criança , Feminino , Humanos , Masculino , Mesoderma/patologia , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Crista Neural/patologia , Nervo Isquiático/patologia , Esferoides Celulares/patologia , Adulto Jovem
6.
Indian J Pathol Microbiol ; 65(1): 181-183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35074991

RESUMO

Tumor-induced osteomalacia is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. Phosphaturic mesenchymal tumors represent a rare etiology of tumor-induced osteomalacia. They are exceptionally rare, probably accounting for < 0.01% of all soft tissue tumors. Most PMTs present as small inapparent lesions that require very careful clinical examination and radionucleotide scan for localization. Here we describe a case in a 65 years old woman with recurrent multiple bone fractures and subsequent detection of a tumor involving right femur and adjacent soft tissue, low phosphate level and elevated serum Fibroblast growth factor-23 (FGF-23).


Assuntos
Mesoderma/patologia , Fosfatos/sangue , Neoplasias de Tecidos Moles/diagnóstico por imagem , Idoso , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Fatores de Crescimento de Fibroblastos/sangue , Técnicas Histológicas , Humanos , Imageamento por Ressonância Magnética , Mesoderma/cirurgia , Tomografia por Emissão de Pósitrons , Neoplasias de Tecidos Moles/cirurgia
7.
Am J Physiol Lung Cell Mol Physiol ; 322(1): L162-L173, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851724

RESUMO

Most lung development occurs in the context of cyclic stretch. Alteration of the mechanical microenvironment is a common feature of many pulmonary diseases, with congenital diaphragmatic hernia (CDH) and fetal tracheal occlusion (FETO, a therapy for CDH) being extreme examples with changes in lung structure, cell differentiation, and function. To address limitations in cell culture and in vivo mechanotransductive models, we developed two mouse lung organoid (mLO) mechanotransductive models using postnatal day 5 (PND5) mouse lung CD326-positive cells and fibroblasts subjected to increased, decreased, and cyclic strain. In the first model, mLOs were exposed to forskolin (FSK) and/or disrupted (DIS) and evaluated at 20 h. mLO cross-sectional area changed by +59%, +24%, and -68% in FSK, control, and DIS mLOs, respectively. FSK-treated organoids had twice as many proliferating cells as other organoids. In the second model, 20 h of 10.25% biaxial cyclic strain increased the mRNAs of lung mesenchymal cell lineages compared with static stretch and no stretch. Cyclic stretch increased TGF-ß and integrin-mediated signaling, with upstream analysis indicating roles for histone deacetylases, microRNAs, and long noncoding RNAs. Cyclic stretch mLOs increased αSMA-positive and αSMA-PDGFRα-double-positive cells compared with no stretch and static stretch mLOs. In this PND5 mLO mechanotransductive model, cell proliferation is increased by static stretch, and cyclic stretch induces mesenchymal gene expression changes important in postnatal lung development.


Assuntos
Pulmão/patologia , Organoides/patologia , Estresse Mecânico , Animais , Colforsina/farmacologia , Fibroblastos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Mecanotransdução Celular/genética , Mesoderma/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos
8.
Int J Gynecol Pathol ; 41(1): 45-50, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33900230

RESUMO

Complete hydatidiform mole (CHM) is a premalignant proliferative disease of the placenta characterized by misexpression of imprinted gene products, most notably p57. The majority of CHM exhibit immunohistochemical absence of p57 protein in villous mesenchyme (VM) and cytotrophoblast (CT) and are thus p57 VM/CT concordant. However, some gestations show loss of p57 in only VM or CT, either in all chorionic villi or a subset thereof (VM/CT discordant). Here, we present a rare case of a p57 VM/CT-discordant CHM with diffuse retention of p57 expression in VM but complete absence in CT. Histologically, the case exhibited typical features of CHM including trophoblast hyperplasia and severe nuclear atypia, but was unusual in the presence of gestational membranes identified ultrasonographically and histologically. Ploidy determination by FISH and genotyping by short tandem repeat analyses showed that this was a diploid gestation with variable allelic ratios and with an androgenetic lineage, similar to previously reported p57 VM/CT-discordant cases.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Mola Hidatiforme/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagem , Adulto , Vilosidades Coriônicas/diagnóstico por imagem , Vilosidades Coriônicas/patologia , Inibidor de Quinase Dependente de Ciclina p57/genética , Feminino , Técnicas de Genotipagem , Humanos , Mola Hidatiforme/patologia , Imuno-Histoquímica , Mesoderma/diagnóstico por imagem , Mesoderma/patologia , Placenta/diagnóstico por imagem , Placenta/patologia , Gravidez , Trofoblastos/patologia , Neoplasias Uterinas/patologia
9.
Cells ; 10(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944071

RESUMO

Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFß inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins via activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Células Endoteliais/patologia , Mesoderma/patologia , Transdução de Sinais , Proteína Smad5/metabolismo , Estresse Mecânico , Varizes/metabolismo , Varizes/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neointima/patologia , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Reologia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
10.
Cells ; 10(11)2021 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-34831274

RESUMO

The well documented decline in the regenerative ability of ageing human skin has been attributed to many factors including genomic instability, telomere shortening, poor nutrient sensing, cellular senescence, and stem cell exhaustion. However, a role for the dermal cellular and molecular microenvironment in skin ageing is just emerging. We previously showed that dermal pericytes co-operate with fibroblasts to improve human skin regeneration in an organotypic skin culture model, and even do so in the absence of fibroblasts. Here, we report that the number of dermal cells, particularly pericytes, declines significantly in human skin of donors aged > 50 years. Notably, aged pericytes promoted epidermal regeneration of neonatal keratinocytes in organotypic cultures and the resulting epithelium exhibited a Ki67+/ΔNp63+ basal layer and terminal differentiation. However, the epithelium lacked several features of homeostasis displaying lower levels of ΔNp63 expression, decreased LAMA5 deposition at the dermo-epidermal junction, and the absence of basement membrane and hemi-desmosome assembly. We conclude that a decline in pericyte incidence and function contribute to an impaired epidermal microenvironment and poor skin regeneration with ageing in the human skin.


Assuntos
Técnicas de Cultura de Células , Senescência Celular , Derme/patologia , Pericitos/patologia , Regeneração , Epiderme/patologia , Fibroblastos/patologia , Homeostase , Humanos , Recém-Nascido , Masculino , Mesoderma/patologia , Pericitos/ultraestrutura
11.
Cells ; 10(11)2021 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-34831282

RESUMO

We have investigated motility in breast cancer cell lines in association with the expression of Transglutaminase type 2 (TG2) as well as upon the administration of Doxorubicin (Dox), an active cytotoxic agent that is employed in chemotherapy. The exposure of MCF-7 cells to the drug increased TG2 levels, triggering epithelial-mesenchymal transition (EMT), thereby supporting cell motility. The effects of Dox on the movement of MCF-7 cells were counteracted by treatment with NC9, a TG2 inhibitor, which induced morphological changes and also reduced the migration of MDA-MB-231 cells exhibiting high levels of TG2. The physical association of TG2 with the cytoskeletal component vimentin appeared pivotal both in drug-treated MCF-7 and in MDA-MB-231 cells and seemed to be independent of the catalytic activity of TG2. NC9 altered the subcellular distribution of TG2 and, consequently, the co-localization of TG2 with vimentin. Furthermore, NC9 induced a nuclear accumulation of TG2 as a prelude to TG2-dependent gene expression modifications. Since enzyme activity can affect both motility and nuclear functions, targeting of this protein could represent a method to improve therapeutic interventions in breast tumors, particularly those to control progression and to limit drug resistance.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Movimento Celular , Espaço Intracelular/metabolismo , Mesoderma/patologia , /metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Forma Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Doxorrubicina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fluorescência , Humanos , Invasividade Neoplásica , Transcrição Genética , Vimentina/metabolismo
12.
Indian J Pathol Microbiol ; 64(4): 837-838, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673619

RESUMO

Leiomyoma is a benign smooth muscle cell tumor commonly occurring in the uterine myometrium. Extra-uterine tumors are infrequent and those occurring in an intracranial location are extremely rare. We report a primary intracranial leiomyoma as an incidental autopsy finding in a 60-year-old woman, who died of acute myocardial infarction.


Assuntos
Neoplasias Encefálicas/diagnóstico , Achados Incidentais , Leiomioma/diagnóstico , Autopsia , Neoplasias Encefálicas/patologia , Feminino , Humanos , Leiomioma/patologia , Mesoderma/patologia , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Miométrio/patologia , Neoplasias Uterinas/patologia
13.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623323

RESUMO

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-ß signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-ß pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-ß signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Animais , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Masculino , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Camundongos Knockout , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Remodelação Vascular
14.
Sci Rep ; 11(1): 17764, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493753

RESUMO

Endothelial-mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFß1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease.


Assuntos
Transdiferenciação Celular/fisiologia , Doença da Artéria Coronariana/patologia , Endotélio Vascular/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Mesoderma/patologia , Proteína Quinase 7 Ativada por Mitógeno/fisiologia , Transdução de Sinais/fisiologia , Túnica Íntima/patologia , Regiões 3' não Traduzidas/genética , Doença da Artéria Coronariana/enzimologia , Estenose Coronária/enzimologia , Estenose Coronária/patologia , Fosfatase 1 de Especificidade Dupla/biossíntese , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 6 de Especificidade Dupla/biossíntese , Fosfatase 6 de Especificidade Dupla/genética , Endotélio Vascular/enzimologia , Ativação Enzimática , Regulação da Expressão Gênica , Genes Reporter , Código das Histonas , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperplasia , Mesoderma/enzimologia , MicroRNAs/biossíntese , MicroRNAs/genética , Túnica Média/patologia
15.
Diagn Cytopathol ; 49(10): E400-E404, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34264026

RESUMO

Fine-needle aspiration cytology (FNAC) is an effective tool for early and quick diagnosis of malignant and metastatic liver masses. However, diagnosing a benign liver tumor on cytology is a challenging task as they are rarely assessed on cytology and also due to the limitations of the procedure. Mesenchymal hamartoma is an uncommon benign pediatric liver tumor and difficult to diagnose on cytology. We describe here a case of a child who presented with a huge liver mass and clinical suspicion of hepatoblastoma. The child underwent blind FNA, and was diagnosed as mesenchymal hamartoma based on the cytological features. A biopsy was performed subsequently which confirmed the same and then he underwent surgical resection of the tumor. The patient had an uneventful recovery and is disease free on follow up.


Assuntos
Citodiagnóstico , Hamartoma/diagnóstico , Hamartoma/patologia , Hepatoblastoma/diagnóstico , Hepatoblastoma/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Mesoderma/patologia , Biópsia por Agulha Fina , Diagnóstico Diferencial , Células Epiteliais/patologia , Hamartoma/diagnóstico por imagem , Hepatoblastoma/diagnóstico por imagem , Humanos , Lactente , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
16.
Nat Commun ; 12(1): 4262, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253738

RESUMO

The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Mamárias Animais/patologia , Mesoderma/patologia , Organoides/patologia , Animais , Azacitidina/farmacologia , Benzamidas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Processamento de Imagem Assistida por Computador , Neoplasias Mamárias Animais/genética , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Organoides/efeitos dos fármacos , Pirimidinas/farmacologia , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Cell Death Dis ; 12(8): 721, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285192

RESUMO

Brain metastases remain a major problem in patients with advanced non-small cell lung cancer (NSCLC). The permeability of the blood-brain barrier (BBB) is highly increased during lung cancer brain metastasis; however, the underlying mechanism remains largely unknown. We previously found that lnc-MMP2-2 is highly enriched in tumor growth factor (TGF)-ß1-mediated exosomes and regulates the migration of lung cancer cells. This study aimed to explore the role of exosomal lnc-MMP2-2 in the regulation of BBB and NSCLC brain metastasis. Here, using endothelial monolayers and mouse models, we found that TGF-ß1-mediated NSCLC-derived exosomes efficiently destroyed tight junctions and the integrity of these natural barriers. Overexpression of lnc-MMP2-2 in human brain microvascular endothelial cells increased vascular permeability in endothelial monolayers, whereas inhibition of lnc-MMP2-2 alleviated these effects. Furthermore, lnc-MMP2-2 knockdown markedly reduced NSCLC brain metastasis in vivo. Mechanistically, through luciferase reporter assays, RNA pull-down assay, and Ago2 RNA immunoprecipitation assay, we showed that lnc-MMP2-2 served as a microRNA sponge or a competing endogenous RNA for miR-1207-5p and consequently modulated the derepression of EPB41L5. In conclusion, TGF-ß1-mediated exosomal lnc-MMP2-2 increases BBB permeability to promote NSCLC brain metastasis. Thus, exosomal lnc-MMP2-2 may be a potential biomarker and therapeutic target against lung cancer brain metastasis.


Assuntos
Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Exossomos/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio/patologia , Exossomos/ultraestrutura , Feminino , Humanos , Neoplasias Pulmonares/patologia , Mesoderma/patologia , Camundongos Nus , RNA Longo não Codificante/genética , Proteínas de Junções Íntimas/metabolismo
18.
Nat Commun ; 12(1): 3709, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140509

RESUMO

Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies.


Assuntos
Colágeno/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Queloide/metabolismo , Mesoderma/citologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Colágeno/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Ontologia Genética , Humanos , Queloide/genética , Queloide/patologia , Ligantes , Mesoderma/metabolismo , Mesoderma/patologia , RNA-Seq , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Análise de Célula Única , Dermatopatias/genética , Dermatopatias/metabolismo , Dermatopatias/patologia
19.
Chem Biol Interact ; 345: 109562, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34153226

RESUMO

Advanced glycation end products (AGEs) are associated with the pathogenesis of diabetic vascular complications. Induction of the endothelial-to-mesenchymal transition (EndMT) is associated with the pathogenesis of fibrotic diseases. The roles of AGEs in islet EndMT induction and diabetes-related islet microvasculopathy and fibrosis remain unclear. This study investigated the pathological roles of AGEs in islet EndMT induction and fibrosis in vitro and in vivo. Non-cytotoxic concentrations of AGEs upregulated the protein expression of fibronectin, vimentin, and α-smooth muscle actin (α-SMA) (mesenchymal/myofibroblast markers) and downregulated the protein expression of vascular endothelial (VE)-cadherin and cluster of differentiation (CD) 31 (endothelial cell markers) in cultured mouse pancreatic islet endothelial cells, which was prevented by the AGE cross-link breaker alagebrium chloride. In streptozotocin-induced diabetic mice, the average islet area and islet immunoreactivities for insulin and CD31 were decreased and the islet immunoreactivities for AGEs and α-SMA and fibrosis were increased, which were prevented by the AGE inhibitor aminoguanidine. Immunofluorescence double staining showed that α-SMA-positive staining co-localized with CD31-positive staining in the diabetic islets, which was effectively prevented by aminoguanidine. These results demonstrate that AGEs can induce EndMT in islet endothelial cells and islet fibrosis in diabetic mice, suggesting that AGE-induced EndMT may contribute to islet fibrosis in diabetes.


Assuntos
Diabetes Mellitus Experimental/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Produtos Finais de Glicação Avançada/farmacologia , Ilhotas Pancreáticas/patologia , Mesoderma/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Mesoderma/efeitos dos fármacos , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo
20.
Cells ; 10(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066078

RESUMO

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.


Assuntos
Envelhecimento , Hormônio do Crescimento Humano/metabolismo , Dente/embriologia , Dente/crescimento & desenvolvimento , Animais , Osso e Ossos/metabolismo , Cartilagem , Esmalte Dentário/embriologia , Esmalte Dentário/crescimento & desenvolvimento , Polpa Dentária/metabolismo , Dentina/fisiologia , Perfilação da Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Fator de Crescimento Insulin-Like II/biossíntese , Mesoderma/patologia , Ortodontia , Osseointegração , Ligamento Periodontal/metabolismo , Proteínas Recombinantes/uso terapêutico , Regeneração , Engenharia Tecidual
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