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2.
Cell Mol Life Sci ; 77(1): 115-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31352534

RESUMO

Adipose tissue is located in discrete depots that are differentially associated with elevated risk of metabolic complications, with fat accretion in visceral depots being most detrimental to metabolic health. Currently, the regulation of specific adipose depot expansion, by adipocyte hypertrophy and hyperplasia and consequently fat distribution, is not well understood. However, a growing body of evidence from in vitro investigations indicates that mature adipocytes secrete factors that modulate the proliferation and differentiation of progenitor, adipose-derived stem cells (ADSCs). It is therefore plausible that endocrine communication between adipocytes and ADSCs located in different depots influences fat distribution, and may therefore contribute to the adverse health outcomes associated with visceral adiposity. This review will explore the available evidence of paracrine and endocrine crosstalk between mature adipocytes and ADSCs that affects adipogenesis, as a better understanding of the regulatory roles of the extracellular signalling mechanisms within- and between adipose depots may profoundly change the way we view adipose tissue growth in obesity and related comorbidities.


Assuntos
Adipócitos/citologia , Adipogenia , Células-Tronco/citologia , Adipócitos/metabolismo , Animais , Comunicação Celular , Humanos , Obesidade/metabolismo , Comunicação Parácrina , Transdução de Sinais , Células-Tronco/metabolismo
3.
Gut ; 69(2): 264-273, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31097538

RESUMO

OBJECTIVE: The interleukin (IL)23 pathway contributes to IBD pathogenesis and is being actively studied as a therapeutic target in patients with IBD. Unexpected outcomes in these therapeutic trials have highlighted the importance of understanding the cell types and mechanisms through which IL23 regulates immune outcomes. How IL23 regulates macrophage outcomes and the consequences of the IL23R R381Q IBD-protective variant on macrophages are not well defined; macrophages are key players in IBD pathogenesis and inflammation. DESIGN: We analysed protein and RNA expression, signalling and localisation in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR, flow cytometry, immunoprecipitation and microscopy. RESULTS: IL23R was critical for optimal levels of pattern-recognition receptor (PRR)-induced signalling and cytokines in human MDMs. In contrast to the coreceptor IL12Rß1, IL23 induced dynamic IL23R cell surface regulation and this required clathrin and dynamin-mediated endocytosis and endocytic recycling-dependent pathways; these pathways were essential for IL23R-mediated outcomes. The IBD-protective IL23R R381Q variant showed distinct outcomes. Relative to IL23R R381, HeLa cells expressing IL23R Q381 showed decreased IL23R recycling and reduced assembly of IL23R Q381 with Janus kinase/signal transducer and activator of transcription pathway members. In MDMs from IL23R Q381 carriers, IL23R accumulated in late endosomes and lysosomes on IL23 treatment and cells demonstrated decreased IL23R- and PRR-induced signalling and cytokines relative to IL23R R381 MDMs. CONCLUSION: Macrophage-mediated inflammatory pathways are key contributors to IBD pathogenesis, and we identify an autocrine/paracrine IL23 requirement in PRR-initiated human macrophage outcomes and in human intestinal myeloid cells, establish that IL23R undergoes ligand-induced recycling, define mechanisms regulating IL23R-induced signalling and determine how the IBD-protective IL23R R381Q variant modulates these processes.


Assuntos
Citocinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Macrófagos/imunologia , Receptores de Interleucina/imunologia , Comunicação Autócrina/imunologia , Endocitose/imunologia , Endossomos/imunologia , Variação Genética , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/prevenção & controle , Interleucina-23/imunologia , Janus Quinase 2/metabolismo , Comunicação Parácrina/imunologia , Receptores de Interleucina/genética , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais/imunologia
4.
EMBO J ; 38(23): e101982, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.


Assuntos
Envelhecimento/patologia , Atrofia/patologia , Senescência Celular , Melanócitos/patologia , Pele/patologia , Telômero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Atrofia/induzido quimicamente , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Comunicação Parácrina , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR4/metabolismo , Pele/metabolismo , Telômero/metabolismo , Adulto Jovem
5.
Endocrinology ; 160(12): 2849-2860, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556942

RESUMO

The gut-pancreas axis plays a key role in the regulation of glucose homeostasis and may be therapeutically exploited to treat not only type 2 diabetes but also hypoglycemia and hyperinsulinemia. We identify a novel enteroendocrine cell type expressing the peptide hormone urotensin 2B (UTS2B). UTS2B inhibits glucagon-like peptide-1 (GLP-1) secretion in mouse intestinal crypts and organoids, not by signaling through its cognate receptor UTS2R but through the activation of the somatostatin receptor (SSTR) 5. Circulating UTS2B concentrations in mice are physiologically regulated during starvation, further linking this peptide hormone to metabolism. Furthermore, administration of UTS2B to starved mice demonstrates that it is capable of regulating blood glucose and plasma concentrations of GLP-1 and insulin in vivo. Altogether, our results identify a novel cellular source of UTS2B in the gut, which acts in a paracrine manner to regulate GLP-1 secretion through SSTR5. These findings uncover a fine-tuning mechanism mediated by a ligand-receptor pair in the regulation of gut hormone secretion, which can potentially be exploited to correct metabolic unbalance caused by overactivation of the gut-pancreas axis.


Assuntos
Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Hormônios Peptídicos/metabolismo , Receptores de Somatostatina/metabolismo , Animais , Glucose/metabolismo , Jejuno/citologia , Jejuno/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Comunicação Parácrina
6.
J Vasc Res ; 56(6): 320-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550717

RESUMO

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artérias Mesentéricas/metabolismo , Comunicação Parácrina , Receptores Adrenérgicos beta 3/metabolismo , Vasoconstrição , Vasodilatação , Tecido Adiposo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Estimulação Elétrica , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
7.
Biochemistry (Mosc) ; 84(7): 762-772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509727

RESUMO

Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as example of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized.


Assuntos
Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Permeabilidade Capilar , Fator de Crescimento Epidérmico/metabolismo , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Comunicação Parácrina , Remodelação Vascular
8.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370159

RESUMO

Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, anti-oxidative, or angiogenic activity. In addition, recent studies also demonstrate that depletion and/or dysfunction of MSCs are associated with several systemic diseases, such as lupus, diabetes, psoriasis, and rheumatoid arthritis, as well as with aging and frailty syndrome. In this review, we hypothesize about the role of MSCs as keepers of tissue homeostasis as well as modulators in a variety of inflammatory and degenerative systemic diseases. This scenario opens the possibility for the use of secretome-derived products from MSCs as new therapeutic agents in order to restore tissue homeostasis, instead of the classical paradigm "one disease, one drug".


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Células-Tronco Mesenquimais/efeitos dos fármacos , Psoríase/tratamento farmacológico , Idoso , Envelhecimento/genética , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Contagem de Células , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Idoso Fragilizado , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Comunicação Parácrina/efeitos dos fármacos , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologia
9.
Nat Commun ; 10(1): 3700, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420552

RESUMO

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.


Assuntos
Ilhotas Pancreáticas/ultraestrutura , Comunicação Parácrina , Estado Pré-Diabético/patologia , Pseudópodes/ultraestrutura , Células Secretoras de Somatostatina/ultraestrutura , Animais , Glicemia/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/ultraestrutura , Microscopia Intravital , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Imagem Óptica , Optogenética , Estado Pré-Diabético/metabolismo , Pseudópodes/metabolismo , Células Secretoras de Somatostatina/citologia , Células Secretoras de Somatostatina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
J Pharmacol Exp Ther ; 370(3): 480-489, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31300611

RESUMO

Opioids promote tumor angiogenesis in mammary malignancies, but the underlying signaling mechanism is largely unknown. The current study investigated the hypothesis that stimulation of δ-opioid receptors (DOR) in breast cancer (BCa) cells activates the hypoxia-inducible factor 1α (HIF-1α), which triggers synthesis and release of diverse angiogenic factors. Immunoblotting revealed that incubation of human MCF-7 and T47D breast cancer cells with the DOR agonist d-Ala2,d-Leu5-enkephalin (DADLE) resulted in a transient accumulation and thus activation of HIF-1α DADLE-induced HIF-1α activation preceded PI3K/Akt stimulation and was blocked by the DOR antagonist naltrindole and naloxone, pertussis toxin, different phosphoinositide 3-kinase (PI3K) inhibitors, and the Akt inhibitor Akti-1/2. Whereas DADLE exposure had no effect on the expression and secretion of vascular endothelial growth factor (VEGF) in BCa cells, an increased abundance of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE2) was detected. DADLE-induced COX-2 expression was also observed in three-dimensional cultured MCF-7 cells and impaired by PI3K/Akt inhibitors and the HIF-1α inhibitor echinomycin. Supernatant from DADLE-treated MCF-7 cells triggered sprouting of endothelial (END) cells, which was blocked when MCF-7 cells were pretreated with echinomycin or the COX-2 inhibitor celecoxib. Also no sprouting was observed when END cells were exposed to the PGE2 receptor antagonist PF-04418948. The findings together indicate that DOR stimulation in BCa cells leads to PI3K/Akt-dependent HIF-1α activation and COX-2 expression, which trigger END cell sprouting by paracrine activation of PGE2 receptors. These findings provide a potential mechanism of opioid-driven tumor angiogenesis and thus therapeutic targets to combat the tumor-angiogenic opioid effect. SIGNIFICANCE STATEMENT: Opioids are indispensable analgesics for treating cancer-related pain. However, opioids were found to promote tumor growth and metastasis, which questions the use of these potent pain-relieving drugs in cancer patients. Enhanced tumor vascularization after opioid treatment implies that tumor progression results from angiogenic opioid effects. Thus, understanding the signaling mechanism of opioid-driven tumor angiogenesis helps to identify therapeutic targets to combat these undesired tumor effects. The present study reveals that stimulation of δ-opioid receptors in breast cancer cells leads to an activation of HIF-1α and expression of COX-2 via PI3K/Akt stimulation, which results in a paracrine activation of vascular endothelial cells by prostaglandin E2 receptors.


Assuntos
Neoplasias da Mama/patologia , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Receptores sigma/agonistas , Dinoprostona/metabolismo , Leucina Encefalina-2-Alanina/farmacologia , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptores sigma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357457

RESUMO

To characterize the pathobiology of solar lentigos (SLs), analyses by semiquantitative RT-PCR, Western blotting, and immunohistochemistry revealed the upregulated expression of endothelin (EDN)-1/endothelin B receptors (EDNBRs), stem cell factor (SCF)/c-KIT, and tumor necrosis factor (TNF)α in the lesional epidermis, which contrasted with the downregulated expression of interleukin (IL) 1α. These findings strongly support the hypothesis that previous repeated UVB exposure triggers keratinocytes to continuously produce TNFα. TNFα then stimulates the secretion of EDNs and the production of SCF in an autocrine fashion, leading to the continuous melanogenic activation of neighboring melanocytes, which causes SLs. A clinical study of 36 patients with SLs for six months treated with an M. Chamomilla extract with a potent ability to abrogate the EDN1-induced increase in DNA synthesis and melanization of human melanocytes in culture revealed a significant improvement in pigment scores and color differences expressed as L values. Another clinical study using a tyrosinase inhibitor L-ascorbate-2-phosphate 3 Na (ASP) demonstrated that L values of test lotion (6% APS)-treated skin significantly increased in SLs and in non-lesional skin with a significantly higher ΔL value in SLs when compared with non-lesional skin. The sum of these findings strongly suggests that combined topical treatment with EDN signaling blockers and tyrosinase inhibitors is a desirable therapeutic choice for SLs.


Assuntos
Lentigo/etiologia , Lentigo/metabolismo , Melanócitos/metabolismo , Luz Solar/efeitos adversos , Animais , Biomarcadores , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Lentigo/diagnóstico , Lentigo/terapia , Mutação , Comunicação Parácrina , Pele/metabolismo , Pele/patologia
12.
Biomed Pharmacother ; 117: 109052, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176170

RESUMO

Mesenchymal stem cells (MSCs) pretreatment is an effective route for improving cell-based therapy of endothelial cell survival, vascular stabilization, and angiogenesis. We hypothesized that the application of human umbilical cord-MSCs (hUC-MSCs) pretreated with angiotensin-II (Ang-II) might be a potential therapeutic approach for severe acute pancreatitis (SAP). Therefore, the effect of Ang-II pretreated hUC-MSCs on SAP was investigated in vitro and in vivo. METHODS: In the present study, human umbilical cord-derived MSCs pretreated with or without Ang-II were delivered through the tail vein of rats 12 h after induction of SAP. Pancreatitis severity scores and serum lipase levels, as well as the levels of VEGF and VEGFR2 were evaluated. RESULTS: We found that the administration of Ang-II-MSCs significantly inhibited pancreatic injury, as reflected by reductions of pancreatitis severity scores, serum amylase and serum lipase levels. Furthermore, the reduced apoptotic rate and increased tube formation in human umbilical vein endothelial Cells (HUVEC) were found resulting from the administration of Ang-II-MSC-CM. Moreover, knockdown of VEGFR2 can block the effect of Ang-II-MSC-CM on preventing HUVEC from apoptosis, as well as the capacity of tube formation was also suppressed. In addition, the expression of increased Bcl-2 and alleviated caspase-3 were observed in HUVEC and HUVEC transfectants exposure to Ang-II-MSC-CM. CONCLUSION: Collectively, these results elucidated that the pretreatment of hUC-MSCs with Ang-II improved the outcome of MSC-based therapy for SAP via enhancing angiogenesis and ameliorating endothelial cell dysfunction in a VEGFR2 dependent manner.


Assuntos
Angiotensina II/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pâncreas/lesões , Pâncreas/patologia , Pancreatite/terapia , Cordão Umbilical/citologia , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pancreatite/patologia , Comunicação Parácrina/efeitos dos fármacos , Ratos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Int J Cancer ; 145(9): 2521-2534, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31216364

RESUMO

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.


Assuntos
Vesículas Extracelulares/patologia , Inflamação/patologia , Melanoma/patologia , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia , Animais , Astrócitos/patologia , Exossomos/patologia , Fibroblastos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Comunicação Parácrina/fisiologia , Células Estromais/patologia
14.
Int J Mol Sci ; 20(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195598

RESUMO

Inflammatory bowel diseases increase the risk of colorectal cancer and colitis-associated colorectal cancer (CAC). Tenascin-C, a matricellular protein, is highly expressed in inflammatory bowel diseases, especially colorectal cancer. However, the role of tenascin-C in the development of CAC is not yet fully understood. We previously showed that a peptide derived from tenascin-C, peptide TNIIIA2, induces potent and sustained activation of ß1-integrin. Moreover, we recently reported that peptide TNIIIA2 promotes invasion and metastasis in colon cancer cells. Here, we show the pathological relevance of TNIIIA2-related functional site for the development of CAC. First, expression of the TNIIIA2-containing TNC peptides/fragments was detected in dysplastic lesions of an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. In vitro experiments demonstrated that conditioned medium from peptide TNIIIA2-stimulated human WI-38 fibroblasts induced malignant transformation in preneoplastic epithelial HaCaT cells. Indeed, these pro-proliferative effects stimulated by peptide TNIIIA2 were abrogated by peptide FNIII14, which has the ability to inactivate ß1-integrin. Importantly, peptide FNIII14 was capable of suppressing polyp formation in the AOM/DSS model. Therefore, tenascin-C-derived peptide TNIIIA2 may contribute to the formation of CAC via activation of stromal fibroblasts based on ß1-integrin activation. Peptide FNIII14 could represent a potential prophylactic treatment for CAC.


Assuntos
Colite/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Progressão da Doença , Fibroblastos/metabolismo , Integrina beta1/metabolismo , Peptídeos/metabolismo , Tenascina/metabolismo , Animais , Azoximetano , Células CACO-2 , Proliferação de Células , Pólipos do Colo/patologia , Meios de Cultivo Condicionados/farmacologia , Sulfato de Dextrana , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/patologia , Humanos , Masculino , Camundongos Endogâmicos ICR , Comunicação Parácrina
15.
PLoS Comput Biol ; 15(6): e1007030, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194728

RESUMO

Prolactin is a major hormone product of the pituitary gland, the central endocrine regulator. Despite its physiological importance, the cell-level mechanisms of prolactin production are not well understood. Having significantly improved the resolution of real-time-single-cell-GFP-imaging, the authors recently revealed that prolactin gene transcription is highly dynamic and stochastic yet shows space-time coordination in an intact tissue slice. However, it still remains an open question as to what kind of cellular communication mediates the observed space-time organization. To determine the type of interaction between cells we developed a statistical model. The degree of similarity between two expression time series was studied in terms of two distance measures, Euclidean and geodesic, the latter being a network-theoretic distance defined to be the minimal number of edges between nodes, and this was used to discriminate between juxtacrine from paracrine signalling. The analysis presented here suggests that juxtacrine signalling dominates. To further determine whether the coupling is coordinating transcription or post-transcriptional activities we used stochastic switch modelling to infer the transcriptional profiles of cells and estimated their similarity measures to deduce that their spatial cellular coordination involves coupling of transcription via juxtacrine signalling. We developed a computational model that involves an inter-cell juxtacrine coupling, yielding simulation results that show space-time coordination in the transcription level that is in agreement with the above analysis. The developed model is expected to serve as the prototype for the further study of tissue-level organised gene expression for epigenetically regulated genes, such as prolactin.


Assuntos
Comunicação Celular/genética , Modelos Biológicos , Comunicação Parácrina/genética , Animais , Comunicação Celular/fisiologia , Biologia Computacional , Regulação da Expressão Gênica/genética , Humanos , Masculino , Comunicação Parácrina/fisiologia , Hipófise/metabolismo , Prolactina/genética , Prolactina/metabolismo , Ratos , Ratos Transgênicos , Processos Estocásticos
16.
J Exp Clin Cancer Res ; 38(1): 241, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174567

RESUMO

BACKGROUND: Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor "stressness" represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment. METHODS: Regions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE-/- mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student's T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival. RESULTS: We show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE-/- mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival. CONCLUSIONS: Together, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.


Assuntos
Glioma/imunologia , Glioma/metabolismo , Hipóxia/metabolismo , Metabolismo dos Lipídeos , Macrófagos/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Comunicação Parácrina , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Glioma/patologia , Xenoenxertos , Humanos , Hiperlipidemias/imunologia , Hiperlipidemias/metabolismo , Hipóxia/imunologia , Macrófagos/patologia , Camundongos , Microambiente Tumoral/imunologia
17.
Immunity ; 51(1): 64-76.e7, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31231033

RESUMO

Type 1 CD8α+ conventional dendritic cells (cDC1s) are required for CD8+ T cell priming but, paradoxically, promote splenic Listeria monocytogenes infection. Using mice with impaired cDC2 function, we ruled out a role for cDC2s in this process and instead discovered an interleukin-10 (IL-10)-dependent cellular crosstalk in the marginal zone (MZ) that promoted bacterial infection. Mice lacking the guanine nucleotide exchange factor DOCK8 or CD19 lost IL-10-producing MZ B cells and were resistant to Listeria. IL-10 increased intracellular Listeria in cDC1s indirectly by reducing inducible nitric oxide synthase expression early after infection and increasing intracellular Listeria in MZ metallophilic macrophages (MMMs). These MMMs trans-infected cDC1s, which, in turn, transported Listeria into the white pulp to prime CD8+ T cells. However, this also facilitated bacterial expansion. Therefore, IL-10-mediated crosstalk between B cells, macrophages, and cDC1s in the MZ promotes both Listeria infection and CD8+ T cell activation.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Interleucina-10/metabolismo , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Macrófagos/imunologia , Baço/imunologia , Animais , Antígenos CD19/metabolismo , Antígenos CD8/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Interleucina-10/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Comunicação Parácrina , Baço/microbiologia
18.
Int J Mol Sci ; 20(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212761

RESUMO

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Neoplasias das Glândulas Endócrinas/etiologia , Obesidade/complicações , Obesidade/metabolismo , Adiponectina/química , Adiponectina/genética , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias das Glândulas Endócrinas/diagnóstico , Neoplasias das Glândulas Endócrinas/metabolismo , Neoplasias das Glândulas Endócrinas/terapia , Humanos , Insulina/metabolismo , Modelos Biológicos , Metástase Neoplásica , Comunicação Parácrina , Ligação Proteica , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Risco , Medição de Risco , Relação Estrutura-Atividade
19.
Immunity ; 51(2): 310-323.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31204070

RESUMO

The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Proliferação de Células , Sinapses Imunológicas , Ativação Linfocitária , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Comunicação Parácrina , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Imunológicos/genética , Transdução de Sinais
20.
Biomed Res Int ; 2019: 2820853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205939

RESUMO

Stem cell-based therapies exhibit profound therapeutic potential for treating various human diseases, including cancer. Among the cell types that can be used for this purpose, mesenchymal stem cells (MSCs) are considered as promising source of stem cells in personalized cell-based therapies. The inherent tumor-tropic property of MSCs can be used to target cancer cells. Although the impacts of MSCs on tumor progression remain elusive, they have been genetically modified or engineered as targeted anticancer agents which could inhibit tumor growth by blocking different processes of tumor. In addition, there are close interactions between MSCs and cancer stem cells (CSCs). MSCs can regulate the growth of CSCs through paracrine mechanisms. This review aims to focus on the current knowledge about MSCs-based tumor therapies, the opportunities and challenges, as well as the prospective of its further clinical implications.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Neoplasias , Células-Tronco Neoplásicas/metabolismo , Comunicação Parácrina , Animais , Humanos , Células-Tronco Mesenquimais/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas/patologia
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