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1.
Artigo em Inglês | MEDLINE | ID: mdl-33475878

RESUMO

PURPOSE: The purpose of this review is to clarify the association of body composition with breast cancer risk and treatment, including physiological mechanisms, and to elucidate strategies for overcoming unfavorable body composition changes that relate to breast cancer progression. METHODS: We have summarized updated knowledge regarding the mechanism of the negative association of altered body composition with breast cancer risk and treatment. We also review strategies for reversing unfavorable body composition based on the latest clinical trial results. RESULTS: Body composition changes in patients with breast cancer typically occur during menopause or as a result of chemotherapy or endocrine therapy. Dysfunction of visceral adipose tissue (VAT) in the setting of obesity underlies insulin resistance and chronic inflammation, which can lead to breast cancer development and progression. Insulin resistance and chronic inflammation are also observed in patients with breast cancer who have sarcopenia or sarcopenic obesity. Nutritional support and a personalized exercise program are the fundamental interventions for reversing unfavorable body composition. Other interventions that have been explored in specific situations include metformin, testosterone, emerging agents that directly target the adipocyte microenvironment, and bariatric surgery. CONCLUSIONS: A better understanding of the biology of body composition phenotypes is key to determining the best intervention program for patients with breast cancer.

2.
Cells ; 9(12)2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317052

RESUMO

Proper processing of collagens COL1 and COL6 is required for normal function of adipose tissue and skeletal muscle. Proteoglycan decorin (DCN) regulates collagen fiber formation. The amino-terminus of DCN is modified with an O-linked glycosaminoglycan (GAG), the function of which has remained unclear. Previously, non-glycanated DCN (ngDCN) was identified as a marker of adipose stromal cells. Here, we identify MMP14 as the metalloprotease that cleaves DCN to generate ngDCN. We demonstrate that mice ubiquitously lacking DCN GAG (ngDCN mice) have reduced matrix rigidity, enlarged adipocytes, fragile skin, as well as skeletal muscle hypotrophy, fibrosis, and dysfunction. Our results indicate that DCN deglycanation results in reduced intracellular DCN-collagen binding and increased production of truncated COL6 chains, leading to aberrant procollagen processing and extracellular localization. This study reveals that the GAG of DCN functions to regulate collagen assembly in adipose tissue and skeletal muscle and uncovers a new mechanism of matrix dysfunction in obesity and aging.

3.
Nat Metab ; 2(12): 1482-1497, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33324010

RESUMO

White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra+ cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb+ lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.


Assuntos
Adipócitos/patologia , Envelhecimento/patologia , Doenças Metabólicas/patologia , Células-Tronco/patologia , Homeostase do Telômero , Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula/genética , Proliferação de Células , Dieta Hiperlipídica , Feminino , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologia , Telomerase/genética , Telomerase/metabolismo
4.
Cell Rep ; 33(2): 108253, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33053339

RESUMO

While plasminogen activator inhibitor-1 (PAI-1) is known to potentiate cellular migration via proteolytic regulation, this adipokine is implicated as an oncogenic ligand in the tumor microenvironment. To understand the underlying paracrine mechanism, here, we conduct transcriptomic analysis of 1,898 endometrial epithelial cells (EECs) exposed and unexposed to PAI-1-secreting adipose stromal cells. The PAI-1-dependent action deregulates crosstalk among tumor-promoting and tumor-repressing pathways, including transforming growth factor ß (TGF-ß). When PAI-1 is tethered to lipoprotein receptor-related protein 1 (LRP1), the internalized signaling causes downregulation of SMAD4 at the transcriptional and post-translational levels that attenuates TGF-ß-related transcription programs. Repression of genes encoding the junction and adhesion complex preferentially occurs in SMAD4-underexpressed EECs of persons with obesity. The findings highlight a role of PAI-1 signaling that renders ineffective intercellular communication for the development of adiposity-associated endometrial cancer.

5.
Mol Ther Oncolytics ; 18: 579-586, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32995482

RESUMO

Adipose stromal cells (ASCs) recruited by tumors contribute to the population of cancer-associated fibroblasts. ASCs have been reported to induce tumor growth and chemotherapy resistance. The effect of ASCs on metastasis has not been explored. Here, we investigated the role of ASCs in cancer aggressiveness and tested them as a therapy target. We show that ASCs promote the epithelial-mesenchymal transition and invasiveness of triple-negative breast cancer cells. In human cell lines derived from various types of breast tumors, ASCs suppressed cytotoxicity of cisplatin and paclitaxel. D-CAN, a proapoptotic peptide targeting ASC, suppressed spontaneous breast cancer lung metastases in a mouse allograft model when combined with cisplatin. Moreover, in a human breast cancer xenograft model, treatment with D-CAN alone was sufficient to suppress lung metastases. This study improves our understanding of how tumor stromal cells recruited from fat tissue stimulate carcinoma progression to chemotherapy resistance/metastasis and outlines a new approach to combination cancer treatment.

6.
Cells ; 9(4)2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252348

RESUMO

Adipose tissue (AT) is comprised of a diverse number of cell types, including adipocytes, stromal cells, endothelial cells, and infiltrating leukocytes. Adipose stromal cells (ASCs) are a mixed population containing adipose progenitor cells (APCs) as well as fibro-inflammatory precursors and cells supporting the vasculature. There is growing evidence that the ability of ASCs to renew and undergo adipogenesis into new, healthy adipocytes is a hallmark of healthy fat, preventing disease-inducing adipocyte hypertrophy and the spillover of lipids into other organs, such as the liver and muscles. However, there is building evidence indicating that the ability for ASCs to self-renew is not infinite. With rates of ASC proliferation and adipogenesis tightly controlled by diet and the circadian clock, the capacity to maintain healthy AT via the generation of new, healthy adipocytes appears to be tightly regulated. Here, we review the contributions of ASCs to the maintenance of distinct adipocyte pools as well as pathogenic fibroblasts in cancer and fibrosis. We also discuss aging and diet-induced obesity as factors that might lead to ASC senescence, and the consequences for metabolic health.

7.
Nat Rev Cancer ; 20(3): 174-186, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31980749

RESUMO

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Biomarcadores , Fibroblastos Associados a Câncer/efeitos dos fármacos , Plasticidade Celular , Ensaios Clínicos como Assunto , Suscetibilidade a Doenças , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Resultado do Tratamento
8.
Mol Cell Biol ; 40(8)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-31988105

RESUMO

Fibrosis is recognized as the major pathological change in adipose tissue during the development of obesity. However, the detailed mechanisms governing the interactions between the fibrotic components and their modifiers remain largely unclear. Here, we reported that matrix metalloproteinase 14 (MMP14), a key pericellular collagenase, is dramatically upregulated in obese adipose tissue. We generated a doxycycline-inducible adipose tissue-specific MMP14 overexpression model to study its regulatory function. We found that overexpression of MMP14 in the established obese adipose tissue leads to enlarged adipocytes and increased body weights in transgenic mice. Furthermore, the mice exhibited decreased energy expenditure, impaired lipid metabolism, and insulin resistance. Mechanistically, we found that MMP14 digests collagen 6α3 to produce endotrophin, a potent costimulator of fibrosis and inflammation. Unexpectedly, when overexpressing MMP14 in the early-stage obese adipose tissue, the transgenic mice showed a healthier metabolic profile, including ameliorated fibrosis and inflammation, as well as improved lipid and glucose metabolism. This unique metabolic phenotype is likely due to digestion/modification of the dense adipose tissue extracellular matrix by MMP14, thereby releasing the mechanical stress to allow for its healthy expansion. Understanding these dichotomous impacts of MMP14 provides novel insights into strategies to treat obesity-related metabolic disorders.


Assuntos
Tecido Adiposo/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Obesidade/enzimologia , Adipócitos/enzimologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Adiposidade , Animais , Linhagem Celular , Metabolismo Energético , Feminino , Fibrose/metabolismo , Células HEK293 , Humanos , Inflamação/genética , Insulina/metabolismo , Resistência à Insulina , Masculino , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima , Ganho de Peso
9.
Cancer Res ; 79(22): 5860-5873, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31575546

RESUMO

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC. SIGNIFICANCE: This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.


Assuntos
Carcinoma Hepatocelular/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
10.
Stem Cells ; 37(12): 1615-1628, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31574188

RESUMO

Although the lack of dystrophin expression in muscle myofibers is the central cause of Duchenne muscular dystrophy (DMD), accumulating evidence suggests that DMD may also be a stem cell disease. Recent studies have revealed dystrophin expression in satellite cells and demonstrated that dystrophin deficiency is directly related to abnormalities in satellite cell polarity, asymmetric division, and epigenetic regulation, thus contributing to the manifestation of the DMD phenotype. Although metabolic and mitochondrial dysfunctions have also been associated with the DMD pathophysiology profile, interestingly, the role of dystrophin with respect to stem cells dysfunction has not been elucidated. In the past few years, editing of the gene that encodes dystrophin has emerged as a promising therapeutic approach for DMD, although the effects of dystrophin restoration in stem cells have not been addressed. Herein, we describe our use of a clustered regularly interspaced short palindromic repeats/Cas9-based system to correct the dystrophin mutation in dystrophic (mdx) muscle progenitor cells (MPCs) and show that the expression of dystrophin significantly improved cellular properties of the mdx MPCs in vitro. Our findings reveal that dystrophin-restored mdx MPCs demonstrated improvements in cell proliferation, differentiation, bioenergetics, and resistance to oxidative and endoplasmic reticulum stress. Furthermore, our in vivo studies demonstrated improved transplantation efficiency of the corrected MPCs in the muscles of mdx mice. Our results indicate that changes in cellular energetics and stress resistance via dystrophin restoration enhance muscle progenitor cell function, further validating that dystrophin plays a role in stem cell function and demonstrating the potential for new therapeutic approaches for DMD. Stem Cells 2019;37:1615-1628.


Assuntos
Distrofina/genética , Terapia Genética/métodos , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular de Duchenne/terapia , Células Satélites de Músculo Esquelético/patologia , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular/genética , Polaridade Celular/fisiologia , Proliferação de Células/genética , Modelos Animais de Doenças , Distrofina/metabolismo , Estresse do Retículo Endoplasmático/genética , Metabolismo Energético/genética , Epigênese Genética , Edição de Genes , Camundongos , Camundongos Endogâmicos mdx , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Estresse Oxidativo/genética , Células-Tronco/fisiologia
11.
Transl Androl Urol ; 8(Suppl 3): S348-S350, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31392166
12.
Oncogene ; 38(11): 1979-1988, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30361686

RESUMO

Fat tissue, overgrowing in obesity, promotes the progression of various carcinomas. Clinical and animal model studies indicate that adipose stromal cells (ASC), the progenitors of adipocytes, are recruited by tumors and promote tumor growth as tumor stromal cells. Here, we investigated the role of ASC in cancer chemoresistance and invasiveness, the attributes of tumor aggressiveness. By using human cell co-culture models, we demonstrate that ASC induce epithelial-mesenchymal transition (EMT) in prostate cancer cells. Our results for the first time demonstrate that ASC interaction renders cancer cells more migratory and resistant to docetaxel, cabazitaxel, and cisplatin chemotherapy. To confirm these findings in vivo, we compared cancer aggressiveness in lean and obese mice grafted with prostate tumors. We show that obesity promotes EMT in cancer cells and tumor invasion into the surrounding fat tissue. A hunter-killer peptide D-CAN, previously developed for targeted ASC ablation, suppressed the obesity-associated EMT and cancer progression. Importantly, cisplatin combined with D-CAN was more effective than cisplatin alone in suppressing growth of mouse prostate cancer allografts and xenografts even in non-obese mice. Our data demonstrate that ASC promote tumor aggressiveness and identify them as a target of combination cancer therapy.


Assuntos
Tecido Adiposo/patologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias da Próstata/patologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Camundongos , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nat Commun ; 9(1): 4349, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341289

RESUMO

Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Carcinoma Hepatocelular/metabolismo , Fator 4 Nuclear de Hepatócito/fisiologia , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição ARNTL/genética , Transporte Ativo do Núcleo Celular , Carcinoma Hepatocelular/patologia , Relógios Circadianos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/patologia , Isoformas de Proteínas/fisiologia
14.
Mol Cell Biol ; 38(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30126894

RESUMO

Adipose-derived vascular endothelial growth factor A (VEGF-A) stimulates functional blood vessel formation in obese fat pads, which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose tissue-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high-fat diet (HFD) feeding. We found that local overexpression of VEGF-A in adipose tissue stimulated lipolysis and browning rapidly after Dox induction. Immunofluorescence staining against tyrosine hydroxylase (TH) indicated higher levels of sympathetic innervation in adipose tissue of transgenic mice. In response to an increased norepinephrine (NE) level, expression of ß3-adrenoceptor was significantly upregulated, and the downstream protein kinase A (PKA) pathway was activated, as indicated by enhanced phosphorylation of whole PKA substrates, in particular, the hormone-sensitive lipase (HSL) in adipocytes. As a result, the adipose tissue exhibited increased lipolysis, browning, and energy expenditure. Importantly, all of these effects were abolished upon treatment with the ß3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates the sympathetic nervous system, which hence promotes lipolysis and browning in adipose tissue.


Assuntos
Tecido Adiposo/metabolismo , Metabolismo Energético/fisiologia , Sistema Nervoso Simpático/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adipócitos/metabolismo , Adipócitos/fisiologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Lipólise/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Norepinefrina/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosforilação/fisiologia , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais/fisiologia , Esterol Esterase/metabolismo , Sistema Nervoso Simpático/fisiologia
15.
Trends Cancer ; 4(5): 374-384, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29709261

RESUMO

Obesity has been linked to the increased risk and aggressiveness of many types of carcinoma. A state of chronic inflammation in adipose tissue (AT), resulting in genotoxic stress, may contribute to carcinogenesis and cancer initiation. Evidence that AT plays a role in cancer aggressiveness is solid and mounting. During cancer progression, tumor cells engage in a metabolic symbiosis with adjacent AT. Mature adipocytes provide adipokines and lipids to cancer cells, while stromal and immune cells from AT infiltrate carcinomas and locally secrete paracrine factors within the tumor microenvironment. This review focuses on the crosstalk between AT and tumor cells that promotes tumor growth and increases cellular lipid metabolism, metastasis, and chemoresistance.


Assuntos
Tecido Adiposo , Neoplasias , Adipócitos , Animais , Comunicação Celular , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucócitos , Obesidade
16.
Methods Mol Biol ; 1773: 147-154, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29687387

RESUMO

White adipose tissue (WAT) has attracted interest for tissue engineering and cell-based therapies as an abundant source of adipose stem/stromal cells (ASC). However, technical challenges in WAT cell culture have limited its applications in regenerative medicine. Traditional two-dimensional (2D) cell culture models, which are essentially monolayers of cells on glass or plastic substrates, inadequately represent tissue architecture, biochemical concentration gradients, substrate stiffness, and most importantly for WAT research, cell phenotypic heterogeneity. Physiological cell culture platforms for WAT modeling must recapitulate the native diversity of cell types and their coordination within the organ. For this purpose, we developed a three-dimensional (3D) model using magnetic levitation. Here, we describe our protocol that we successfully employed to build adipose tissue organoids (adipospheres) that preserve the heterogeneity of the constituent cell types in vitro. We demonstrate the capacity of assembling adipospheres from multiple cell types, including ASCs, endohtelial cells, and leukocytes that recreate tissue organization. These adipospheres mimicked WAT organogenesis in that they enabled the formation of vessel-like endothelial structures with lumens and differentiation of unilocular adipocytes. Altogether, magnetic levitation is a cell culture platform that recreates tissue structure, function, and heterogeneity in vitro, and serves as a foundation for high-throughput WAT tissue culture and analysis.


Assuntos
Adipócitos/química , Tecido Adiposo Branco/química , Nanopartículas de Magnetita/química , Organoides/química , Esferoides Celulares/química , Células 3T3-L1 , Adipócitos/citologia , Tecido Adiposo Branco/citologia , Animais , Diferenciação Celular , Linhagem Celular , Terapia Baseada em Transplante de Células e Tecidos , Técnicas de Cocultura , Camundongos , Organoides/citologia , Cultura Primária de Células , Engenharia Tecidual
17.
Sci Signal ; 11(527)2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29692362

RESUMO

Inflammatory signaling has been implicated in adipose tissue remodeling and metabolism. In this issue of Science Signaling, Babaei et al report that lipolysis induced by ß3-adrenergic signaling triggers transient inflammation that directs progenitor cells toward beige adipogenesis.


Assuntos
Adipogenia , Fator de Crescimento Transformador beta , Tecido Adiposo , Humanos , Inflamação , Transdução de Sinais
18.
Development ; 145(1)2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29158445

RESUMO

The relative abundance of thermogenic beige adipocytes and lipid-storing white adipocytes in adipose tissue underlie its metabolic activity. The roles of adipocyte progenitor cells, which express PDGFRα or PDGFRß, in adipose tissue function have remained unclear. Here, by defining the developmental timing of PDGFRα and PDGFRß expression in mouse subcutaneous and visceral adipose depots, we uncover depot specificity of pre-adipocyte delineation. We demonstrate that PDGFRα expression precedes PDGFRß expression in all subcutaneous but in only a fraction of visceral adipose stromal cells. We show that high-fat diet feeding or thermoneutrality in early postnatal development can induce PDGFRß+ lineage recruitment to generate white adipocytes. In contrast, the contribution of PDGFRß+ lineage to beige adipocytes is minimal. We provide evidence that human adipose tissue also contains distinct progenitor populations differentiating into beige or white adipocytes, depending on PDGFRß expression. Based on PDGFRα or PDGFRß deletion and ectopic expression experiments, we conclude that the PDGFRα/PDGFRß signaling balance determines progenitor commitment to beige (PDGFRα) or white (PDGFRß) adipogenesis. Our study suggests that adipocyte lineage specification and metabolism can be modulated through PDGFR signaling.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Adipogenia/fisiologia , Diferenciação Celular/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Adipócitos Bege/citologia , Adipócitos Brancos/citologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Humanos , Camundongos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Células-Tronco/citologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-29202102

RESUMO

High-throughput screening of a natural compound library was performed to identify the most efficacious combinatorial treatment on prostate cancer. Ursolic acid, curcumin and resveratrol were selected for further analyses and administered in vivo via the diet, either alone or in combination, in a mouse allograft model of prostate cancer. All possible combinations of these natural compounds produced synergistic effects on tumor size and weight, as predicted in the screens. A subsequent untargeted metabolomics and metabolic flux analysis using isotopically labeled glutamine indicated that the compound combinations modulated glutamine metabolism. In addition, ASCT2 levels and STAT3, mTORC1 and AMPK activity were modulated to a greater extent by the combinations compared to the individual compounds. Overall, this approach can be useful for identifying synergistic combinations of natural compounds for chemopreventive and therapeutic interventions.

20.
Cancer Res ; 77(18): 5158-5168, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28687617

RESUMO

Obesity is a prognostic risk factor in the progression of prostate cancer; however, the molecular mechanisms involved are unclear. In this study, we provide preclinical proof of concept for the role of a proinflammatory CXCL12-CXCR4/CXCR7 signaling axis in an obesity-driven mouse model of myc-induced prostate cancer. Analysis of the stromal vascular fraction from periprostatic white adipose tissue from obese HiMyc mice at 6 months of age revealed a dramatic increase in mRNAs encoding various chemokines, cytokines, growth factors, and angiogenesis mediators, with CXCL12 among the most significantly upregulated genes. Immunofluorescence staining of ventral prostate tissue from obese HiMyc mice revealed high levels of CXCL12 in the stromal compartment as well as high staining for CXCR4 and CXCR7 in the epithelial compartment of tumors. Prostate cancer cell lines derived from HiMyc tumors (HMVP2 and derivative cell lines) displayed increased protein expression of both CXCR4 and CXCR7 compared with protein lysates from a nontumorigenic prostate epithelial cell line (NMVP cells). CXCL12 treatment stimulated migration and invasion of HMVP2 cells but not NMVP cells. These effects of CXCL12 on HMVP2 cells were inhibited by the CXCR4 antagonist AMD3100 as well as knockdown of either CXCR4 or CXCR7. CXCL12 treatment also produced rapid activation of STAT3, NFκB, and MAPK signaling in HMVP2 cells, which was again attenuated by either AMD3100 or knockdown of CXCR4 or CXCR7. Collectively, these data suggest that CXCL12 secreted by stromal cells activates invasiveness of prostate cancer cells and may play a role in driving tumor progression in obesity. Targeting the CXCL12-CXCR4/CXCR7 axis could lead to novel approaches for offsetting the effects of obesity on prostate cancer progression. Cancer Res; 77(18); 5158-68. ©2017 AACR.


Assuntos
Quimiocina CXCL12/metabolismo , Inflamação/complicações , Obesidade/complicações , Neoplasias da Próstata/etiologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Animais , Apoptose , Movimento Celular , Proliferação de Células , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Obesos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Receptores CXCR/genética , Receptores CXCR4/genética , Células Tumorais Cultivadas
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