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1.
J Pathol ; 254(1): 46-56, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33512712

RESUMO

Renal cell carcinoma (RCC) is the most predominant type of kidney cancer in adults and is responsible for approximately 85% of clinical cases. The tumor-specific microenvironment includes both cellular and physical factors, and it regulates the homeostasis and function of cancer cells. Perirenal adipose tissue and tumor-associated macrophages are the major cellular components of the RCC microenvironment. The RCC microvasculature network generates interstitial fluid flow, which is the movement of fluid through the extracellular compartments of tissues. This fluid flow is a specific physical characteristic of the microenvironment of RCC. We hypothesized that there may be an interaction between the cellular and physical microenvironments and that these two factors may play an important role in regulating the behavior of RCC. To elucidate the effects of adipose tissue, macrophages, and fluid flow stimulation on RCC and to investigate the relationships between these factors, we used a collagen gel culture method to generate cancer-stroma interactions and a gyratory shaker to create fluid flow stimulation. Adipose-related cells, monocytes, and fluid flow influenced the proliferative potential and invasive capacity of RCC cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by both fluid flow and cellular interactions between RCC and adipose tissue fragments or macrophages. Fluid flow stimulation synergistically enhanced the anti-proliferative effect of sunitinib on RCC cells, but macrophages abolished the synergistic anti-proliferative effect related to fluid flow stimulation. In conclusion, we established a reconstructed model to investigate the cellular and physical microenvironments of RCC in vitro. Our alternative culture model may provide a promising tool for further therapeutic investigations into many types of cancer. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma de Células Renais/patologia , Técnicas de Cultura de Células/métodos , Neoplasias Renais/patologia , Microambiente Tumoral/fisiologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Resistencia a Medicamentos Antineoplásicos/fisiologia , Líquido Extracelular/fisiologia , Humanos , Ratos , Sunitinibe/farmacologia , Microambiente Tumoral/efeitos dos fármacos
2.
BMC Cancer ; 21(1): 434, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879104

RESUMO

BACKGROUND: Interactions between adipocyte and breast cancer (BC) cells have yet to be fully elucidated. Here we investigated the prognostic impact of marginal adipose tissue invasion in both luminal breast cancer (HR+/HER2-) and triple-negative breast cancer (TNBC) (HR-/HER2-). METHODS: A total of 735 patients with early-stage invasive BC (1999-2014) were retrospectively registered. Median length of patient follow-up was 8.9 years. Survival curves were calculated using a Kaplan-Meier cumulative survival plot. The prognostic difference between two groups were assessed by the univariate Cox-proportional hazard regression model. RESULTS: Patients with adipose tissue invasion (n = 614) had a significantly poorer prognosis than those without adipose tissue invasion (n = 121) in overall survival (OS) (hazard ratio, 2.1; 95% Confidence interval [CI], 1.1 to 4.0; P = 0.025). While a poorer prognosis was observed in TNBC (n = 137) than in luminal BC patients (n = 496) (hazard ratio, 0.45; 95% CI, 0.30 to 0.68, P < 0.001), this aggressive nature of TNBC was noted in node-positive disease (hazard ratio, 0.3; 95% CI, 0.18 to 0.5, P < 0.001) but not in node-negative disease (hazard ratio, 0.78; 95% CI, 0.39 to 1.55, P = 0.472), and also noted in adipose tissue invasion-positive patients (hazard ratio, 0.4; 95% CI, 0.26 to 0.6, P < 0.001) but not in adipose tissue invasion-negative patients (hazard ratio, 0.73; 95% CI, 0.16 to 3.24, P = 0.675). In addition, although patients suffering from TNBC with adipose tissue invasion had a poorer outcome than those without adipose tissue invasion (hazard ratio, 3.63; 95% CI, 1.11 to 11.84; P = 0.033), the difference was not observed in luminal BC (hazard ratio, 1.75; 95% CI, 0.64 to 4.82; P = 0.277). CONCLUSIONS: Adipose tissue invasion was correlated with poor survival in TNBC. Cancer cell invasion into local fat may be a first step on cancer progression and systemic disease in TNBC.


Assuntos
Tecido Adiposo/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Comunicação Celular , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral
3.
Tohoku J Exp Med ; 252(2): 153-157, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33028760

RESUMO

Membranous nephropathy (MN) is a common glomerular disease that is characterized by diffuse thickening of the glomerular basement membrane, and a common cause of nephrotic syndrome (NS). MN is often accompanied with malignant disease; The solid tumors are commonly associated with MN, whereas hematological malignancies are rarely found in patients with MN. A 68-year-old man with a history of diabetes mellitus visited a hospital with a chief complaint of general fatigue. He was previously not diagnosed with any complications of diabetes. Computed tomography revealed a pancreatic tumor, and the pathological findings of the biopsied tumor revealed the tumor was diffuse large B-cell lymphoma (DLBCL). Concurrently, he developed severe proteinuria, hypoalbuminemia, systemic edema and hyperlipidemia, consistent with the diagnosis of NS. The biopsied renal specimen revealed minute spike lesions of glomerular basement membrane, and abnormal lymphocytes infiltrated in the kidney interstitially. Anti-glomerular basement membrane antibody, proteinase-3-/myeloperoxidase antineutrophil cytoplasmic antibody and hepatitis B antigenemia, are absent in the patient. Serum anti-phospholipase A2 receptor (PLA2R) antibody (marker for primary MN) was not detected. A diagnosis of secondary MN induced by DLBCL was made. He received rituximab containing chemotherapy for DLBCL, resulting in amelioration of both DLBCL and MN. We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Síndrome Nefrótica/diagnóstico por imagem , Idoso , Membrana Basal/patologia , Terapia Combinada , Complicações do Diabetes , Humanos , Imunoterapia , Inflamação , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Síndrome Nefrótica/complicações , Síndrome Nefrótica/patologia , Síndrome Nefrótica/terapia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Receptores da Fosfolipase A2/imunologia , Rituximab/farmacologia , Tomografia Computadorizada por Raios X
4.
Int J Mol Sci ; 21(7)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32225099

RESUMO

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-ß (Aß) protein in Aß Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aß. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aß deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aß-positive vessels × severity of amyloid burden of Aß-positive vessels) were evaluated in the brain of mice aged 15 and 21-23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21-23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann-Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral/tratamento farmacológico , Cilostazol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Fosfodiesterase 3/uso terapêutico , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Cilostazol/administração & dosagem , Feminino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Inibidores da Fosfodiesterase 3/administração & dosagem
5.
Graefes Arch Clin Exp Ophthalmol ; 257(9): 1915-1924, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31321523

RESUMO

PURPOSE: In vivo microenvironments are critical to tissue homeostasis and wound healing, and the cornea is regulated by a specific microenvironment complex that consists of cell-cell interactions, air-liquid interfaces, and fluid flow stimulation. In this study, we aimed to clarify the effects of and the correlations among these three component factors on the cell kinetics of corneal epithelial cells. METHODS: Human corneal epithelial-transformed (HCE-T) cells were cocultured with either primary rat corneal fibroblasts or NIH 3T3 fibroblasts. We employed a double-dish culture method to create an air-liquid interface and a gyratory shaker to create fluid flow stimulation. Morphometric and protein expression analyses were performed for the HCE-T cells. RESULTS: Both the primary rat fibroblasts and the NIH 3T3 cells promoted HCE-T cell proliferation, and the presence of fluid flow synergistically enhanced this effect and inhibited the apoptosis of HCE-T cells. Moreover, fluid flow enhanced the emergence of myofibroblasts when cocultured with primary rat fibroblasts or NIH 3T3 cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by both fluid flow and cellular interaction between the HCE-T and NIH 3T3 cells. CONCLUSION: The cell-cell interaction and fluid flow stimulation in the air-liquid interface synergistically or independently regulated the behavior of HCE-T cells. Fluid flow accelerated the phenotypic change from corneal fibroblasts and NIH 3T3 cells to myofibroblasts. Elucidation of the multicomponent interplay in this microenvironment will be critical to the homeostasis and regeneration of the cornea and other ocular tissues.


Assuntos
Lesões da Córnea/metabolismo , Epitélio Corneano/metabolismo , Células-Tronco Mesenquimais/citologia , Cicatrização/fisiologia , Animais , Western Blotting , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Lesões da Córnea/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Epitélio Corneano/patologia , Homeostase , Humanos , Imuno-Histoquímica , Ratos , Ratos Wistar , Transdução de Sinais
6.
Gastric Cancer ; 21(6): 946-955, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29696406

RESUMO

BACKGROUND: Early local tumor invasion in gastric cancer results in likely encounters between cancer cells and submucosal and subserosal adipose tissue, but these interactions remain to be clarified. Microenvironmental mechanical forces, such as fluid flow, are known to modulate normal cell kinetics, but the effects of fluid flow on gastric cancer cells are poorly understood. We analyzed the cell kinetics and chemosensitivity in gastric cancer using a simple in vitro model that simultaneously replicated the cancer-adipocyte interaction and physical microenvironment. METHODS: Gastric cancer cells (MKN7 and MKN74) were seeded on rat adipose tissue fragment-embedded discs or collagen discs alone. To generate fluid flow, samples were placed on a rotatory shaker in a CO2 incubator. Proliferation, apoptosis, invasion, and motility-related molecules were analyzed by morphometry and immunostaining. Proteins were evaluated by western blot analysis. Chemosensitivity was investigated by trastuzumab treatment. RESULTS: Adipose tissue and fluid flow had a positive synergistic effect on the proliferative potential and invasive capacity of gastric cancer cells, and adipose tissue inhibited apoptosis in these cells. Adipose tissue upregulated ERK1/2 signaling in gastric cancer cells, but downregulated p38 signaling. Notably, adipose tissue and fluid flow promoted membranous and cytoplasmic HER2 expression and modulated chemosensitivity to trastuzumab in gastric cancer cells. CONCLUSION: We have demonstrated that cancer-adipocyte interaction and physical microenvironment mutually modulate gastric cancer cell kinetics. Further elucidation of the microenvironmental regulation in gastric cancer will be very important for the development of strategies involving molecular targeted therapy.


Assuntos
Tecido Adiposo/patologia , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Trastuzumab/farmacologia , Animais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Am J Pathol ; 186(5): 1180-94, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26952643

RESUMO

Esophageal squamous cell carcinoma (ESCC) develops within the squamous epithelial layer and invades the submucosa to the subadventitia that has adipose tissue (AT). AT seems critical to ESCC progression, but the underlying mechanism is unknown. We aimed to address the association between ESCC and AT in vitro. ESCC cells were cultured on rat or human subcutaneous AT-embedded or -non-embedded collagen gel. AT promoted the growth of ESCC cells and inhibited their apoptosis. AT promoted the expression of the squamous differentiation marker involucrin in ESCC cells. AT accelerated the expression of invasion-related factors in poorly differentiated ESCC cells only. AT promoted the expression of phosphorylated-insulin-like growth factor-1 receptor in ESCC cells, whereas it inhibited that of the human epidermal growth factor receptor 2. Insulin-like growth factor-1, but not leptin, adiponectin, or resistin, promoted and inhibited the growth and apoptosis of ESCC cells, respectively. In turn, ESCC cells decreased the production of these adipokines in AT and the number of preadipocytes and mesenchymal stem cell-like cells, which developed from AT. These results suggest that i) AT may influence the progression of ESCC with increased growth or invasion and decreased apoptosis through insulin-like growth factor-1/insulin-like growth factor-1 receptor signaling, ii) AT may affect human epidermal growth factor receptor 2-targeted therapy; and iii) the cancer cells may affect adipokine production in AT.


Assuntos
Tecido Adiposo/fisiologia , Carcinoma de Células Escamosas/fisiopatologia , Neoplasias Esofágicas/fisiopatologia , Adiponectina/farmacologia , Animais , Apoptose/fisiologia , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Carcinoma de Células Escamosas do Esôfago , Filaminas/metabolismo , Humanos , Hipertrofia/fisiopatologia , Fator de Crescimento Insulin-Like I , Metabolismo dos Lipídeos/fisiologia , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Microscopia Eletrônica , Precursores de Proteínas/metabolismo , Ratos Wistar , Receptor ErbB-2/metabolismo , Resistina/farmacologia , Células Estromais/fisiologia , Células Tumorais Cultivadas , Calinina
8.
Gastrointest Endosc ; 85(5): 1076-1085, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27751874

RESUMO

BACKGROUND AND AIMS: Extensive excision of the esophageal mucosa by endoscopic submucosal dissection (ESD) frequently evokes a luminal stricture. This study aimed to determine the efficacy of a high-density collagen patch for the prevention of esophageal stricture in extensive ESD. METHODS: Six pigs underwent circumferential esophageal ESD under general anesthesia. In 3 pigs, artificial ulcers were covered by 2 collagen patches. The other 3 pigs underwent circumferential ESD only. RESULTS: The 2 collagen patches were settled onto the ulcer surface using a general endoscope and instruments. The collagen patch-treated group showed significantly better patency rates on both the oral and anal sides of the wound area compared with the control group at day 14. The mucosal re-epithelization ratio was significantly promoted, and the extent of mucosal inflammation and fibrosis was significantly decreased with the collagen patch treatment in the wound area. The frequency of cells positive α-smooth muscle actin was significantly reduced in the collagen patch-treated group compared with the control group. CONCLUSIONS: We have established a high-density collagen device that can reduce the esophageal stricture associated with extensive ESD. This easy-to-handle device would be useful during superficial esophageal cancer treatment by ESD.


Assuntos
Colágeno/uso terapêutico , Ressecção Endoscópica de Mucosa/métodos , Mucosa Esofágica/cirurgia , Estenose Esofágica/prevenção & controle , Esofagoscopia/métodos , Esôfago/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Cicatrização , Animais , Mucosa Esofágica/metabolismo , Mucosa Esofágica/patologia , Esôfago/metabolismo , Esôfago/patologia , Feminino , Géis , Imuno-Histoquímica , Modelos Anatômicos , Reepitelização , Suínos , Úlcera
9.
Pathol Int ; 66(10): 554-562, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27477924

RESUMO

Cell culture is a well-established standard technique and a fundamental tool in biology and medicine. Establishment of a novel culture method by meeting various challenges can sometimes open up new fields of cell biology and medicine. An artificial microenvironment for cultured cells is made up of complicated factors, including cytokines, scaffold material type, cell-cell interactions, and physical stress. To replicate the tissue architecture, cell-cell interactions, and specific physical microenvironment, we previously demonstrated the effectiveness of a three-dimensional culture system, and further established two simple culture systems: air-liquid interface (ALI) and fluid flow stress (FFS). A three-dimensional collagen gel culture system can replicate cell-cell interactions in vitro. As skin is constantly exposed to air, the ALI system closely mimicked the skin microenvironment and maintained the homeostasis of the epidermis and dermis. The ALI culture system also revealed the possibility of skin regeneration through ectopic mesenchymal cell involvement. Fluid streaming and shear stress were recently demonstrated to constitute the critical microenvironment for various cell types. The FFS system demonstrated that fluid streaming induced epithelial-mesenchymal transition of mesothelial cells, leading to peritoneal fibrosis. Our novel culture systems will hopefully open up new fields of regenerative medicine and pathological research.


Assuntos
Técnicas de Cultura de Células/métodos , Patologia/métodos , Animais , Técnicas de Cultura de Células/tendências , Humanos , Pesquisa
10.
Pathol Int ; 66(3): 148-157, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26811269

RESUMO

Adipose tissue (AT)-thyrocyte interaction is largely unknown. Here we described the interaction in a co-culture system, in which thyrocytes were cultured on AT fragment (ATF)-embedded collagen gel, using electron microscopy, immunocytochemistry, real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). ATFs promoted the hypertrophy, polarization and lipid accumulation of thyrocytes. ATFs did not affect the growth of thyroyctes, and inhibited their apoptosis. ATFs increased the protein expression of thyroglobulin (Tg) and paired box gene 8 (PAX8) in thyrocytes. In turn, thyrocytes decreased the concentration of leptin and adiponectin, and increased the expression of these mRNAs in ATFs. Thyrotropin (TSH) enhanced the ATF-induced nuclear hypertrophy and Tg protein expression in thyrocytes, while TSH enhanced the thyrocyte-induced expression of leptin and adiponectin mRNAs in ATFs. Finally, leptin promoted the hypertrophy and Tg protein expression in thyrocytes. TSH enhanced these leptin-induced effects. The data indicate an active interaction between thyrocytes and AT, suggesting that (i) ATFs may serve to regulate the morphology, survival and differentiation of thyrocytes probably through lipid accumulation partly in a TSH-synergistic way; (ii) thyrocytes may affect adipokine production from ATFs in a TSH-independent manner; and (3) leptin may be related to the hypertrophy and differentiation of thyrocytes in a TSH-synergistic way.


Assuntos
Tecido Adiposo/fisiologia , Tireoglobulina/metabolismo , Células Epiteliais da Tireoide/fisiologia , Tireotropina/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/citologia , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Colágeno , Humanos , Hipertrofia , Leptina/genética , Leptina/metabolismo , Metabolismo dos Lipídeos , Masculino , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo , RNA Mensageiro/genética , Ratos Wistar , Células Epiteliais da Tireoide/citologia
11.
Pathol Int ; 66(2): 75-82, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26753834

RESUMO

Tumor budding is a major risk factor for T1 colorectal cancer. Quality control of the pathological diagnosis of budding is crucial, irrespective of the pathologist's experience. This study examines the interobserver variability according to pathologists' experience and evaluates the influence of cytokeratin (CK) immunostaining in the assessment of budding. Hematoxylin-eosin (HE) and CK-immunostained slides of 40 cases with T1 primary colorectal cancer were examined. Budding grades were individually evaluated by 12 pathologists who we categorized into three groups by their experience (expert, with >10 years of experience (n = 4), senior, with 5-10 years (n = 4), and junior, < 5 years (n = 4)). The results revealed a tendency for the more experienced pathologists to assign higher budding grades compared to the less-experienced pathologists. In the junior group, the interobserver variability obtained with HE slides was poor, but it was markedly improved in the evaluation using CK-immunostained slides. The benefit of CK immunostaining was only slight in the expert group. CK immunostaining would be useful when a pathologist is not experienced enough or does not have enough confidence in the assessment of budding.


Assuntos
Neoplasias Colorretais/patologia , Queratinas/metabolismo , Neoplasias Colorretais/metabolismo , Humanos , Imuno-Histoquímica , Metástase Linfática , Gradação de Tumores , Variações Dependentes do Observador , Reprodutibilidade dos Testes
12.
J Artif Organs ; 19(1): 87-96, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26318752

RESUMO

Peritoneal fluid dwell impacts the peritoneum by creating an abnormal physiological microenvironment. Little is known about the precise effects of fluid dwell on the peritoneum, and no adequate in vitro models to analyze the impact of fluid dwell have been established. In this study, we developed a peritoneal fluid dwell model combined with an artificial peritoneal cavity and fluid stirring generation system to clarify the effects of different dwelling solutions on the peritoneum over time. To replicate the peritoneal cavity, we devised a reconstructed peritoneal cavity utilizing a mesothelial layer, endothelial layer, and collagen membrane chamber. The reconstructed peritoneal cavity was infused with Dulbecco's modified Eagle's medium, saline, lactated Ringer's solution or peritoneal dialysis solution with repeated 4-h dwells for 10 or 20 consecutive days. The above-described solutions induced epithelial-mesenchymal transition (EMT) and hyperplasia of mesothelial cells. All solution types modulated nitric oxide synthase activities in mesothelial and endothelial cells and nitric oxide concentrations in dwelling solutions. Inhibition of nitric oxide synthase activity acted synergistically on mesothelial EMT and hyperplasia. The present findings suggest that solutions infused into the peritoneal cavity are likely to affect nitric oxide production in the peritoneum and promote peritoneal fibrosis. Our newly devised peritoneal cavity model should be a promising tool for understanding peritoneal cellular kinetics and homeostasis.


Assuntos
Líquido Ascítico/patologia , Cavidade Peritoneal/patologia , Fibrose Peritoneal/patologia , Peritônio/patologia , Células Endoteliais/patologia , Células Epiteliais/patologia , Humanos , Modelos Teóricos , Óxido Nítrico/metabolismo , Diálise Peritoneal
13.
Int J Urol ; 23(6): 510-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27020040

RESUMO

OBJECTIVES: To clarify the interaction between adipose tissue stromal cells and bladder cancer cells. METHODS: Superficial (RT4) and invasive (EJ) urothelial carcinoma cells were cultured on adipose tissue stromal cell-embedded or non-embedded collagen gel. Cells were analyzed by immunohistochemistry, western blot and real-time reverse transcription polymerase chain reaction. RESULTS: Adipose tissue stromal cells inhibited growth of RT4, while they promoted the apoptosis. In contrast, adipose tissue stromal cells promoted growth of EJ, but they did not affect the apoptosis. Adipose tissue stromal cells slightly promoted expression of mitogen-activated protein kinase cascade in RT4 and EJ. Adipose tissue stromal cells promoted display of the molecular-targeted agent human epidermal growth factor receptor-2 in only RT4. In turn, RT4 and EJ enhanced α-smooth muscle actin (myofibroblast marker) and S-100 protein (adipocyte marker) expression of adipose tissue stromal cells, respectively. CONCLUSIONS: These findings suggest that: (i) adipose tissue stromal cells might suppress the progression of superficial-type cancer, whereas they might promote that of invasive type; (ii) adipose tissue stromal cell-activated mitogen-activated protein kinase pathway might play differential roles in both types of bladder cancer; (iii) human epidermal growth factor receptor-2 could represent a critical therapeutic agent for the superficial type under adipose tissue stromal cells-cancer interaction; and (iv) superficial bladder cancer might promote myofibroblast differentiation of adipose tissue stromal cells as a cancer-associate phenotype, whereas invasive bladder cancer might promote their adipocyte differentiation.


Assuntos
Apoptose , Carcinoma de Células de Transição/patologia , Invasividade Neoplásica , Células Estromais , Neoplasias da Bexiga Urinária/patologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Humanos
15.
Wound Repair Regen ; 23(6): 819-29, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26036768

RESUMO

Engineered skin substitutes are widely used in skin wound management. However, no currently available products satisfy all the criteria of usability in emergency situations, easy handling, and minimal scar formation. To overcome these shortcomings, we designed a cell-free bandage-type artificial skin, named "VitriBand" (VB), using adhesive film dressing, silicone-coated polyethylene terephthalate film, and collagen xerogel membrane defined as a dried collagen vitrigel membrane without free water. We analyzed its advantages over in-line products by comparing VB with hydrocolloid dressing and collagen sponge. For evaluation, mice inflicted with full-thickness skin defects were treated with VB, hydrocolloid dressing, and collagen sponge. A plastic film group treated only with adhesive film dressing and silicone-coated polyethylene terephthalate film, and a no treatment group were also compared. VB promoted epithelization while inhibiting the emergence of myofibroblasts and inflammation in the regenerating tissue more effectively than the plastic film, hydrocolloid dressing, and collagen sponge products. We have succeeded in establishing a cell-free bandage-type artificial skin that could serve as a promising first-line medical biomaterial for emergency treatment of skin injuries in various medical situations.


Assuntos
Cicatriz/patologia , Tecido de Granulação/patologia , Neutrófilos/metabolismo , Pele Artificial , Pele/lesões , Lesões dos Tecidos Moles/patologia , Cicatrização , Animais , Colágeno , Modelos Animais de Doenças , Camundongos , Camundongos Nus , Pele/patologia
16.
Am J Dermatopathol ; 37(3): e31-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25699980

RESUMO

We describe a unique case of Merkel cell carcinoma (MCC) with a heterogeneous differentiation exhibiting distinct triphasic phenotypic differentiation features: small cells typical of MCC, sweat gland carcinoma (sweat gland Ca.) with possible decapitation secretion, and spindle cell carcinoma (spindle cell Ca.). The patient was an 84-year-old Japanese woman. We evaluated the present case immunohistochemically with various antibodies. The histological features showed a gradual transition from MCC to sweat gland Ca. and spindle cell Ca. For clarifying the histogenesis, immunophenotypic analysis of the 3 different components of the carcinoma was performed using hair follicle stem cell markers (eg, CK15, CK19, and CD200) that have been identified as biomarkers of human bulge cells. The triphasic components immunohistochemically shared the characteristic feature of CK19 and CD200 expression. We posit that the MCC arose from hair follicle stem cells residing within the bulge area where Merkel cells are preferentially situated. Based on our findings, we recommend adding this rare neoplasm to the expanding morphological spectrum of MCC.


Assuntos
Carcinoma de Célula de Merkel/patologia , Diferenciação Celular , Folículo Piloso/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Carcinoma de Apêndice Cutâneo/patologia , Feminino , Humanos , Células-Tronco/patologia , Neoplasias das Glândulas Sudoríparas/patologia
17.
Am J Physiol Renal Physiol ; 306(1): F116-22, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24197067

RESUMO

Peritoneal dysfunction is a major factor leading to treatment failure of peritoneal dialysis (PD). However, the precise mechanism of the peritoneal diffusion changes related to PD remains to be elucidated. To this end, we have established a novel peritoneal diffusion model in vitro, which consists of a three-dimensional culture system using a collagen vitrigel membrane chamber and a fluid-stream generation system. This artificial peritoneal model revealed that high-glucose culture medium and fluid flow stress promoted the epithelial-mesenchymal transition (EMT) process of mesothelial cells and that endothelial cells inhibited this mesothelial EMT process. Mesothelial cells in the EMT state showed high expression of connective tissue growth factor and low expression of bone morphogenic protein-7, while non-EMT mesothelial cells showed the opposite expression pattern of these two proteins. In addition, these protein expressions were dependent on the presence of endothelial cells in the model. Our model revealed that the endothelial slit function was predominantly dependent on the covering surface area, while the mesothelial layer possessed a specific barrier function for small solutes independently of the surface area. Notably, a synergic barrier effect of mesothelial cells and endothelial cells was present with low-glucose pretreatment, but high-glucose pretreatment abolished this synergic effect. These findings suggest that the mesothelial slit function is not only regulated by the high-glucose-induced EMT process but is also affected by an endothelial paracrine effect. This peritoneal diffusion model could be a promising tool for the development of PD.


Assuntos
Comunicação Celular/fisiologia , Colágeno/química , Células Endoteliais/citologia , Células Epiteliais/citologia , Células-Tronco Mesenquimais/citologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Colágeno/metabolismo , Células Endoteliais/fisiologia , Células Epiteliais/fisiologia , Humanos , Células-Tronco Mesenquimais/fisiologia , Modelos Biológicos , Peritônio
18.
J Cutan Pathol ; 41(5): 469-74, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24499097

RESUMO

We present a rare case of Merkel cell carcinoma (MCC) with heterologous differentiation. The patient was an 86-year-old female patient with MCC who presented with a forearm skin tumor and left axillary lymph node swelling. Histopathologically, the malignant components of the primary and metastatic lesions showed the intermingled features of triphasic phenotype differentiation, which had distinct cell populations; MCC, sweat gland carcinoma (SGC) and malignant poorly differentiated spindle cells with myogenic differentiation were immunohistochemically showed. Moreover, an electron microscopic observation of the tumor cells revealed intracytoplasmic canaliculi and junctional structures that indicated ductal differentiation. To our knowledge, this is the first case of MCC admixed with SGC and sarcomatous components in both the primary and metastatic lesions. An immunohistochemical study, using several stem cell markers, indicated that the MCC arose from pluripotent epidermal stem cells.


Assuntos
Carcinoma de Célula de Merkel/patologia , Metástase Linfática/patologia , Neoplasias Complexas Mistas/patologia , Neoplasias Cutâneas/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica , Metástase Neoplásica
19.
Pathol Int ; 64(6): 276-82, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24965110

RESUMO

Stenosing flexor tenosynovitis, trigger finger, is a common clinical disorder causing painful locking or contracture of the involved digits, and most instances are idiopathic. This problem is generally caused by a size mismatch between the swollen flexor tendon and the thickened first annular pulley. Although hypertrophic pulleys have been histologically and ultrasonographically detected, little is known about the histopathology of the tenosynovium covering the tendons of trigger fingers. We identified chondrocytoid cells that produced hyaluronic acid in 23 (61%) fingers and hypocellular collagen matrix in 32 (84%) fingers around the tenosynovium among 38 specimens of tenosynovium from patients with trigger fingers. These chondrocytoid cells expressed the synovial B cell marker CD44, but not the chondrocyte marker S-100 protein. The incidence of these findings was much higher than that of conventional findings of synovitis, such as inflammatory infiltrate (37%), increased vascularity (37%), hyperplasia of synovial lining cells (21%), or fibrin exudation (5%). We discovered the following distinctive histopathological features of trigger finger: hyaluronic acid-producing chondrocytoid cells originated from fibroblastic synovial B cells, and a hypocellular collagen matrix surrounding the tenosynovium. Thus, an edematous extracellular matrix with active hyaluronic acid synthesis might increase pressure under the pulley and contribute to the progression of stenosis.


Assuntos
Membrana Sinovial/patologia , Tendões/patologia , Dedo em Gatilho/patologia , Adulto , Idoso , Feminino , Humanos , Ácido Hialurônico/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas S100/metabolismo , Membrana Sinovial/metabolismo , Tendões/metabolismo , Dedo em Gatilho/metabolismo
20.
Ann Otol Rhinol Laryngol ; 123(4): 247-51, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24671480

RESUMO

OBJECTIVE: This study was undertaken to elucidate the mechanisms underlying laryngeal granuloma formation in a rat model of gastroesophageal reflux disease (GERD) with mechanically injured vocal cord mucosa. METHODS: The rat model of GERD was surgically created by tying the pyloric sphincter and ligating the transitional region between the forestomach and the glandular portion (limiting ridge). The control rats received only a midline incision. In all the animals, a plastic bar was inserted into the trachea, and moved vertically thrice in 3 seconds to cause mechanical injury of the vocal cord mucosa. The rats were sacrificed 2 weeks postsurgically, and their pharynx and larynx were observed histologically. RESULTS: Granulomas were observed in the vocal cord mucosa of the GERD group (3 of 5 animals); they presented a similar pathological structure to that of human laryngeal granulomas. In contrast, only abrasions and blisters were observed on the vocal cord mucosa in the control group (all 5 animals). CONCLUSIONS: The development of laryngeal granuloma may involve both mechanical injury and gastric acid reflux.


Assuntos
Refluxo Gastroesofágico/complicações , Granuloma Laríngeo/etiologia , Prega Vocal/lesões , Animais , Modelos Animais de Doenças , Granuloma Laríngeo/patologia , Masculino , Mucosa/lesões , Ratos Wistar
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