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1.
J Surg Res ; 257: 213-220, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858322

RESUMO

Angiosarcomas (AS) are a diverse group of soft tissue sarcomas, arising from blood and lymphatic vessels. They frequently present in the elderly, and in patients with previous radiation or lymphedema. A wide range of genetic derangements contribute to their development, and AS histology is often high-grade in keeping with aggressive disease biology. The clinical presentation, while often innocuous, is marked by its infiltrative and aggressive nature, with a proclivity for metastatic spread, and outcomes are often poor. Surgery is performed for localized, resectable cases. A multidisciplinary approach, appropriately employing surgery, radiation, chemotherapy, or potentially recently approved immune-oncology agents, can result in positive outcomes.


Assuntos
Hemangiossarcoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Equipe de Assistência ao Paciente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vasos Sanguíneos/patologia , Vasos Sanguíneos/efeitos da radiação , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto , Hemangiossarcoma/genética , Hemangiossarcoma/mortalidade , Hemangiossarcoma/patologia , Humanos , Vasos Linfáticos/patologia , Vasos Linfáticos/efeitos da radiação , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Radioterapia Adjuvante , Procedimentos Cirúrgicos Operatórios
2.
J Vis Exp ; (165)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33283786

RESUMO

Lymphatic collecting vessels and lymph nodes are inevitably embedded in adipose tissue. The physiological significance of this observation remains still not elucidated. However, obesity is characterized by impaired lymphatic function and increased vessel permeability. Inversely, lymphatic dysfunction induces obesity in mice, suggesting a significant interplay between lymphatic vessels and the adipose tissue. Therefore, understanding factors leading to lymphatic dysfunction might open new therapeutic windows to prevent obesity and associated comorbidities. The first step in this process requires a precise and detailed visualization of the lymphatic network in healthy and inflamed adipose tissue. Here, we describe a rapid, inexpensive, and efficient method that allows to label and analyze lymphatic and blood vessels. This approach takes advantage of the skin-draining brachial lymph node localization within the subcutaneous adipose tissue. The lymphatic arborization of this tissue can be revealed by injecting fluorochrome-conjugated lectins subcutaneously. Moreover, the in vivo labeling approach provides a way to evaluate lymphatic vessel density and functions. Coupled to blood vessel, adipocyte and immune cell staining, the protocol allows for high-resolution mapping of the subcutaneous adipose tissue by 3D imaging.


Assuntos
Vasos Sanguíneos/patologia , Vasos Linfáticos/patologia , Obesidade/sangue , Obesidade/patologia , Animais , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Coloração e Rotulagem , Gordura Subcutânea/irrigação sanguínea
3.
Anticancer Res ; 40(12): 6923-6931, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288586

RESUMO

BACKGROUND/AIM: Examine features of blood and lymphatic vessels in ovarian tumors and their significance to prognosis of ovarian cancer. PATIENTS AND METHODS: A total of 139 women with epithelial ovarian tumors were included: 86 malignant, 17 borderline and 36 benign. Density, percentage, mean size and number of blood microvessels in tumors were measured by immunohistochemistry with antibodies against CD34 and CD105. Lymphatic vessel density was assayed using the D2-40 antibody against podoplanin. RESULTS: Angiogenesis was most profuse in malignant tumors. Small size of lymph vessels predicted 26% shorter 5-year survival of ovarian cancer patients. Further, high percentage of lymphatic vessels in tumors was associated with lymph node metastasis, and high density with cancer recurrence. Lower number of microvessels, as assessed by CD34 staining, predicted shorter progression-free survival. Additionally, the large size of microvessels assessed by CD34 and the high number of vessels assessed by CD105 were related to residual tumor >1 cm at primary surgery and also, large vessel size was associated with stage III, as assessed by CD105 staining. CONCLUSION: CD34 and CD105 define different characteristics of microvessels. Parameters of lymph vessels may predict the prognosis of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Neovascularização Patológica , Neoplasias Ovarianas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Vasos Linfáticos/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Prognóstico , Adulto Jovem
4.
Expert Rev Med Devices ; 17(12): 1277-1283, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33183101

RESUMO

INTRODUCTION: Colorectal surgery has markedly advanced due to the introduction of laparoscopic and robotic surgery. During the past 20 years, these two modalities have been further enhanced by fluorescence imaging. AREAS COVERED: This article will review the common and novel uses for fluorophores in colorectal surgery, including tissue perfusion for anastomotic creation, ureter identification, lymphatic mapping, and tumor localization. EXPERT OPINION: The versatility of this technology permeates through many aspects of colorectal procedures. The white light spectrum has historically been the only available modality to visualize tissue perfusion, tumor implants, and structures including the ureters and lymph nodes. The ability of the near-infrared spectrum to penetrate biologic tissues allows the identification of these structures with injection of fluorophores. The two most common intravenously utilized fluorophores are methylene blue and indocyanine green. Additionally, novel tumor marker-specific fluorophores are being investigated for purposes of cancer detection.


Assuntos
Cirurgia Colorretal , Imagem Óptica/métodos , Fístula Anastomótica/etiologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Cirurgia Colorretal/efeitos adversos , Feminino , Humanos , Vasos Linfáticos/diagnóstico por imagem , Vasos Linfáticos/patologia , Ureter/diagnóstico por imagem , Ureter/patologia
5.
Am J Pathol ; 190(12): 2355-2375, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33039355

RESUMO

Despite many reports about pulmonary blood vessels in lung fibrosis, the contribution of lymphatics to fibrosis is unknown. We examined the mechanism and consequences of lymphatic remodeling in mice with lung fibrosis after bleomycin injury or telomere dysfunction. Widespread lymphangiogenesis was observed after bleomycin treatment and in fibrotic lungs of prospero homeobox 1-enhanced green fluorescent protein (Prox1-EGFP) transgenic mice with telomere dysfunction. In loss-of-function studies, blocking antibodies revealed that lymphangiogenesis 14 days after bleomycin treatment was dependent on vascular endothelial growth factor (Vegf) receptor 3 signaling, but not on Vegf receptor 2. Vegfc gene and protein expression increased specifically. Extensive extravasated plasma, platelets, and macrophages at sites of lymphatic growth were potential sources of Vegfc. Lymphangiogenesis peaked at 14 to 28 days after bleomycin challenge, was accompanied by doubling of chemokine (C-C motif) ligand 21 in lung lymphatics and tertiary lymphoid organ formation, and then decreased as lung injury resolved by 56 days. In gain-of-function studies, expansion of the lung lymphatic network by transgenic overexpression of Vegfc in club cell secretory protein (CCSP)/VEGF-C mice reduced macrophage accumulation and fibrosis and accelerated recovery after bleomycin treatment. These findings suggest that lymphatics have an overall protective effect in lung injury and fibrosis and fit with a mechanism whereby lung lymphatic network expansion reduces lymph stasis and increases clearance of fluid and cells, including profibrotic macrophages.


Assuntos
Proliferação de Células/fisiologia , Fibrose/patologia , Lesão Pulmonar/patologia , Linfangiogênese/fisiologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Fibrose/metabolismo , Vasos Linfáticos/patologia , Macrófagos/metabolismo , Camundongos Transgênicos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Nat Commun ; 11(1): 4697, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943639

RESUMO

Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.


Assuntos
Linfonodos/microbiologia , Metástase Linfática , Vasos Linfáticos/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/patogenicidade , Animais , Bacteriemia/microbiologia , Bacteriemia/patologia , Modelos Animais de Doenças , Feminino , Interleucina-8/metabolismo , Linfonodos/imunologia , Linfonodos/patologia , Metástase Linfática/patologia , Sistema Linfático , Vasos Linfáticos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos/microbiologia , Fagocitose , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/patologia , Streptococcus pyogenes/genética , Virulência
8.
Cancer Res ; 80(17): 3463-3465, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32605997

RESUMO

During the growth of various cancers, primary tumors can escape antitumor immune responses of their host and eventually disseminate into distant organs. Peritumoral lymphatic vessels connect the primary tumor to lymph nodes, facilitating tumor entry into lymph nodes, systemic circulation, and metastasis. Lymph node metastases that occur frequently provide sites of tumor cell spread, whereas tumor antigen transfer into and presentation in tumor-draining lymph nodes induce activation of tumor-specific T-lymphocyte responses that can result in cytolytic targeting of the tumor. Here, we discuss the recently emerged controversial role of the lymphatic vessels in tumor dissemination and cancer immunotherapy.


Assuntos
Imunoterapia , Metástase Linfática/imunologia , Metástase Linfática/patologia , Vasos Linfáticos , Animais , Humanos , Linfangiogênese/fisiologia , Vasos Linfáticos/imunologia , Vasos Linfáticos/patologia
9.
Sci Rep ; 10(1): 12320, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704072

RESUMO

The intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 partially restored lymphatic contractile activity in MetSyn lymphatic vessel by increasing phasic contractile frequency. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.


Assuntos
Vasos Linfáticos/patologia , Síndrome Metabólica/enzimologia , Contração Muscular , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Tecido Adiposo/efeitos dos fármacos , Aminoquinolinas/farmacologia , Animais , Benzamidas/farmacologia , Composição Corporal/efeitos dos fármacos , Cardiomegalia/patologia , Dieta , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Resistência à Insulina , Vasos Linfáticos/efeitos dos fármacos , Masculino , Modelos Biológicos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Tapsigargina/farmacologia
10.
Surgery ; 168(3): 518-526, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32669204

RESUMO

BACKGROUND: It is unknown whether all thick melanomas share the same prognostic features. We present a large, multi-institutional study on thick melanoma, evaluating for factors prognostic of survival. METHODS: We queried the database of the Sentinel Lymph Node Working Group for patients with thick melanoma (>4 mm) who had a sentinel lymph node biopsy from 1993 to 2018. Clinicopathologic characteristics were correlated with overall survival. RESULTS: There were 1,235 patients with a median follow-up of 28 months. Median thickness was 5.9 mm, with 713, 356, and 166 cases having a thickness of >4 to 6, >6 to 10, and >10 mm, respectively. Ulceration was seen in 51.2% of cases, while sentinel lymph node metastases were seen in 439 of 1,235 (35.5%) cases. For melanomas >4 to 6 mm, age, thickness, ulceration, lymphovascular invasion, and sentinel lymph node metastasis were correlated with overall survival (all P < .05), but for melanomas >6 to 10 mm, only sex and sentinel lymph node metastasis were prognostic of overall survival (both P < .05). For melanomas >10 mm, only sentinel lymph node metastasis predicted overall survival on multivariable analyses (P < .05). CONCLUSION: Prognostic markers of overall survival for thick melanoma include thickness, ulceration, and sentinel lymph node metastasis, but also include other unique factors such as lymphovascular invasion. Moreover, certain prognostic markers for survival are associated with different subgroups of thick melanoma, which vary based on thickness group.


Assuntos
Procedimentos Cirúrgicos Dermatológicos , Melanoma/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Cutâneas/mortalidade , Pele/patologia , Idoso , Vasos Sanguíneos/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Vasos Linfáticos/patologia , Masculino , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Carga Tumoral
11.
PLoS One ; 15(7): e0230092, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716937

RESUMO

Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n = 10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery. This was followed by quantification of the inflammatory state (low, medium and high) and presence of cancer-infiltration of each LV using immunohistochemistry. LV miRNA expression profiling was also performed, and analysed in the context of high versus low inflammation, and cancer-infiltrated versus non-cancer-infiltrated. Results were correlated with clinical outcome data including relapse with an average follow-up time of 13.3 months. The presence of a high degree of inflammation correlated significantly with patient relapse (p = 0.033). Cancer-infiltrated LVs showed a moderate but non-significant association with relapse (p = 0.07). Differential miRNA profiles were identified in cancer-infiltrated LVs and those with high versus low inflammation. In particular, several members of the let-7 family were consistently down-regulated in highly inflamed LVs (>1.8-fold, p<0.05) compared to the less inflamed ones. Down-regulation of the let-7 family appears to be associated with inflammation, but whether inflammation contributes to or is an effect of cancer-infiltration requires further investigation.


Assuntos
Vasos Linfáticos/patologia , MicroRNAs/metabolismo , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Modelos Logísticos , Vasos Linfáticos/metabolismo , Aprendizado de Máquina , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Análise de Componente Principal , Prognóstico , Risco
12.
Medicine (Baltimore) ; 99(24): e20432, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541464

RESUMO

To ascertain the relationship between the perimetric differences obtained between the limbs and the type of fluoroscopic pattern observed by Indocyanine green (ICG) lymphography in patients with upper limb lymphedema.A correlational descriptive study was carried out in 19 patients with upper limb lymphedema secondary to breast cancer. The perimetric increase was recorded in 11 anatomical regions after ICG injection, fluoroscopic patterns were identified using an infrared camera. The ICG patterns were categorized into worse (stardust, diffuse) or better (linear, splash) patterns.The pattern coincidence between the anterior and posterior regions of the edematous extremities was 45%. At the wrist level, a difference of 2 cm was associated with the presence of a worse fluoroscopic pattern, whereas perimeter differences of 4.25 cm in the elbow and 2.25 cm in the arm (12 cm from the epicondyle) were associated with the presence of a better fluoroscopic pattern.The perimetric differences observed between the healthy and affected upper limbs in 4 specific anatomical areas allowed us to predict the type of fluoroscopic pattern. ICG lymphography has facilitated the study of the posterior regions of edema, which are difficult to visualize using other imaging techniques.


Assuntos
Verde de Indocianina/administração & dosagem , Vasos Linfáticos/diagnóstico por imagem , Linfedema/etiologia , Linfografia/métodos , Testes de Campo Visual/métodos , Adulto , Idoso , Neoplasias da Mama/complicações , Estudos de Casos e Controles , Estudos de Avaliação como Assunto , Feminino , Fluoroscopia/métodos , Fluoroscopia/estatística & dados numéricos , Humanos , Vasos Linfáticos/patologia , Linfedema/classificação , Linfedema/patologia , Pessoa de Meia-Idade , Espanha/epidemiologia , Extremidade Superior/anatomia & histologia , Extremidade Superior/diagnóstico por imagem
13.
Cancer Sci ; 111(8): 2837-2849, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32539229

RESUMO

Accumulating evidence on the association of VEGF-C with lymphangiogenesis and lymph node metastasis implicates lymphatic vessels as a potential target in anti-cancer therapy. To evaluate whether blocking VEGF-C and VEGFR-3 signaling can inhibit multi-organ metastases, a mouse metastatic mammary cancer model was subjected to gene therapy using a soluble VEGFR-3 expression vector (psVEGFR-3). We showed that psVEGFR-3 significantly diminished cell growth in vitro with or without added VEGF-C, and significantly reduced primary tumor growth and tumor metastases to wide-spectrum organs in vivo. Although apoptotic cell death and angiogenesis levels did not differ between the control and psVEGFR-3 groups, cell proliferation and lymphangiogenesis in the mammary tumors were significantly decreased in the psVEGFR-3 group. Furthermore, lymphatic vessel invasion was significantly inhibited in this group. Real-time RT-PCR analysis revealed significantly high expression of the Vegfr3 gene due to gene therapy, and the transcriptional levels of Pcna and Lyve1 tended to decrease in the psVEGFR-3 group. Immunofluorescence staining indicated that phospho-tyrosine expression was considerably lower in tumor cells of psVEGFR-3-treated mammary carcinomas than those of control tumors. Double immunofluorescence staining indicated that phospho-tyrosine+ /LYVE-1+ (a lymphatic vessel marker) tended to decrease in psVEGFR-3-treated mammary carcinomas compared with control mice, indicating a decline in the activity of the VEGF-C/VEGFR-3 axis. These findings showed that a blockade of VEGF-C/VEGFR-3 signaling caused by sVEGFR-3 sequestered VEGF-C and prevented the side-effects of anti-angiogenesis and suppressed overall metastases, suggesting their high clinical significance.


Assuntos
Terapia Genética/métodos , Neoplasias Mamárias Experimentais/terapia , Metástase Neoplásica/terapia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Linhagem Celular Tumoral/transplante , Feminino , Vasos Linfáticos/patologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/genética , Fator C de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Nat Commun ; 11(1): 2869, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513927

RESUMO

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.


Assuntos
Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Vasos Linfáticos/anormalidades , Mutação/genética , Transdução de Sinais , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Criança , Células Endoteliais/metabolismo , Ativação Enzimática , Feminino , Humanos , Vasos Linfáticos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Serina-Treonina Quinases TOR/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Hum Cell ; 33(4): 930-937, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32507979

RESUMO

The tumor microenvironment (TME) plays a crucial role in tumor progression, therapeutic response, and patient outcomes. TME includes immune cells, blood and lymphatic vessels, and so on. There are anti-cancer and pro-cancer immune cells. In general, infiltration of anti-cancer immune cells, such as cytotoxic T cells (CTLs), is associated with a favorable patient prognosis. In contrast, infiltration of pro-cancer immune cells, such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), is associated with a worse prognosis. However, some immune cells, which play an ambivalent role in cancer immunity, have demonstrated contradictory impacts on patient prognosis. Blood and lymphatic vessels play crucial roles in TME not only as delivery and draining systems of fluid and molecules, but also allowing cancer cells access to systematic circulation to metastasize. Angiogenesis promotes cancer aggressiveness and is associated with a worse prognosis. Its targeted therapy shows a benefit in some cancers, however, because the target can vary by caner type, a benefit of anti-angiogenesis therapy is limited in the current standard of care. Lymphangiogenesis plays a role in lymph node metastasis, thus, it is associated with a poor prognosis in some cancers. To study TME, the mouse model is one of the most commonly used tools. The choice of appropriate mouse model depends on the hypothesis being tested and the scientific question being asked. Here, we review recent studies that investigated the clinical relevance of TME components and introduce mouse models to study TME.


Assuntos
Modelos Animais de Doenças , Vasos Linfáticos/fisiopatologia , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Microambiente Tumoral , Animais , Progressão da Doença , Humanos , Vasos Linfáticos/patologia , Macrófagos/imunologia , Camundongos , Neoplasias/patologia , Neoplasias/fisiopatologia , Neovascularização Patológica , Prognóstico , Linfócitos T Reguladores/imunologia
16.
J Histochem Cytochem ; 68(8): 553-560, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32589075

RESUMO

Crohn's disease (CD) is a gastrointestinal disorder of unknown etiology. CD-specific longitudinal ulcers show an association between disease pathogenesis and vasculature dysfunction. Granulomatous lymphangitis may also contribute to CD pathogenesis; meanwhile, vasculitis is the primary CD lesion. We investigated the association between granulomas and lymphatic and blood vessels to assess the role of vasculature in CD pathogenesis. Two small and large intestine specimens were obtained from four CD patients. From each specimen, 160 sequential sections were obtained and double immunohistochemical stained to label lymphatic and blood vessels in association with granulomas. We found that 289 of 342 granulomas (85%) were associated with a lymphatic vessel and 313 of 364 granulomas (86%) were associated with a blood vessel. Although intrablood vessel granulomas were not detected, intralymphatic vessel granulomas were. In the internal region of the granuloma, we found more blood vessels than lymphatic vessels. Hence, these results cumulatively demonstrate that CD epithelioid cell granulomas are differentially associated with lymphatic and blood vessels, suggesting both as essential for the formation and maintenance of these granulomas. Moreover, both lymphatic and blood vessels may participate in granulomatous inflammation in the primary CD lesions; however, additional studies with larger numbers of participants are required to validate our findings.


Assuntos
Vasos Sanguíneos/patologia , Doença de Crohn/complicações , Células Epitelioides/patologia , Granuloma/complicações , Granuloma/patologia , Vasos Linfáticos/patologia , Coloração e Rotulagem , Adulto , Feminino , Histiócitos/patologia , Humanos , Masculino , Adulto Jovem
17.
Cancer Res ; 80(15): 3130-3144, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32518204

RESUMO

Kaposi sarcoma is the most common cancer in human immunodeficiency virus-positive individuals and is caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is believed that a small number of latently infected Kaposi sarcoma tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here, we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BECs progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LECs predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Because of the strong propensity of LECs toward lytic replication, LECs maintained virus as a population, despite the death of individual host cells from lytic lysis. The master regulator of lymphatic development, Prox1, bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LECs may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BECs and mesenchymal stem cells, which give rise to Kaposi sarcoma tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in Kaposi sarcoma tumors. SIGNIFICANCE: This study defines the mechanism by which Kaposi's sarcoma could be maintained by virus constantly produced by lymphatic cells in HIV-positive individuals.


Assuntos
Herpesvirus Humano 8/fisiologia , Proteínas de Homeodomínio/fisiologia , Vasos Linfáticos/virologia , Sarcoma de Kaposi , Microambiente Tumoral/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Liberação de Vírus/genética , Replicação Viral/genética , Transformação Celular Viral/genética , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/virologia , Regulação Viral da Expressão Gênica , Células HEK293 , HIV/fisiologia , Humanos , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Latência Viral/genética
18.
J Plast Reconstr Aesthet Surg ; 73(9): 1622-1629, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32591265

RESUMO

BACKGROUND: Indocyanine green (ICG) lymphography gained widespread acceptance as a gold standard in lymphatic surgery, although this imaging modality has several limitations. Ultrasound is progressively emerging as a powerful tool in LVA preoperative planning, as it expands the available knowledge for both lymphatic channels and recipient venules. The purpose of this study is to evaluate the accuracy of ultrahigh frequency ultrasound (UHFUS) in detecting the lymphatic vessels and in evaluating their degeneration status, including wall and lumen characteristics, compared with direct histology observation. PATIENTS AND METHODS: From May 2018 to November 2018, 26 consecutive patients affected by extremities lymphedema who underwent LVA were prospectively assessed. For each patient, we evaluated the lymphatic vessels suitable for LVA by UHFUS preoperatively, intraoperatively, and by histology. Qualitative and quantitative data of lymphatic channels were analyzed for each evaluation including lymphatic outer diameter, inner diameter, and wall thickness. Quantitative outcome analysis after LVA was also performed. RESULTS: On a total of 26 patients, 14 were upper limb lymphedema (ULL) and 12 lower limb lymphedema (LLL). All cases were secondary lymphedema. The qualitative and the quantitative analysis showed significant correlation and agreement between ultrasound and histological measurements. CONCLUSIONS: UHFUS preoperative and intraoperative analysis of lymphatic channel strongly correlates with their histology. By coupling this high detailed information on lymphatic channels with the ability to dynamically study preoperative recipient venules, UHFUS represents the quintessence in lymphatic surgery, and it should be considered as the new gold standard in the preoperative planning of LVA. Level of Evidence II (diagnostic).


Assuntos
Anastomose Cirúrgica , Vasos Linfáticos/diagnóstico por imagem , Vasos Linfáticos/cirurgia , Linfedema/cirurgia , Ultrassonografia/métodos , Veias/cirurgia , Adulto , Idoso , Extremidades/cirurgia , Feminino , Humanos , Cuidados Intraoperatórios , Vasos Linfáticos/patologia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Estudos Prospectivos
19.
Eur J Surg Oncol ; 46(7): 1225-1232, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360066

RESUMO

BACKGROUND: Minimally invasive surgery has achieved great success in the surgical treatment of many kinds of cancer. This study aimed to systematically review the available evidence evaluating the effects of the use of uterine manipulators in minimally hysterectomies for endometrial cancer patients. METHODS: We searched the CENTRAL, MEDLINE, PubMed, EMBASE and ClinicalTrials.gov databases to Sep. 12, 2019 to identify relevant prospective or retrospective studies, using the intersection of "endometrial neoplasms", "endometrial carcinoma", "endometrial cancer"; "uterine manipulator", and "intrauterine manipulator". The initial search identified 251 items in total. The main outcomes of interest were the presence of LVSI (lymphovascular space invasion), the incidence of positive peritoneal cytology, and the presence of recurrence during follow-up. RESULTS: After screening for eligibility, 11 studies were included in the meta-analysis finally. The timing of uterine manipulators insertion during MIS for endometrial cancer was not associated with an increased risk of positive peritoneal cytology (RR: 1.21, 95% CI, 0.68 to 2.16). Moreover, there was no significant difference for the rate of positive peritoneal cytology (RR: 1.53, 95% CI, 0.85 to 2.77), LVSI (RR: 1.18, 95% CI, 0.66 to 2.11) or the rate of recurrence (RR: 1.25, 95% CI, 0.89 to 1.74) regarding the use of uterine manipulators for laparoscopic surgery in the treatment of endometrial cancer patients. CONCLUSION: We found that the use of uterine manipulators is not associated with an increased incidence of positive peritoneal cytology, LVSI, or recurrence among patients with endometrial cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020147111.


Assuntos
Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Histerectomia/instrumentação , Recidiva Local de Neoplasia , Inoculação de Neoplasia , Peritônio/patologia , Vasos Sanguíneos/patologia , Feminino , Humanos , Histerectomia/métodos , Vasos Linfáticos/patologia , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia
20.
J Pathol ; 251(3): 323-335, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32418202

RESUMO

The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. The effects of lymphatic drainage dysfunction on periodontitis have not been well studied. Here we show that lymphatic vessel endothelial receptor 1 (LYVE1)+ /podoplanin (PDPN)+ lymphatic vessels (LVs) are increased in the periodontal tissues, with accumulation close to the alveolar bone surface, in two murine periodontitis models: rheumatoid arthritis (RA)-associated periodontitis and ligature-induced periodontitis. Further, PDPN+ /alpha-smooth muscle actin (αSMA)- lymphatic capillaries are increased, whereas PDPN+ /αSMA+ collecting LVs are decreased significantly in the inflamed periodontal tissues. Both mouse models of periodontitis have delayed lymph flow in periodontal tissues, increased TRAP-positive osteoclasts, and significant alveolar bone loss. Importantly, the local administration of adeno-associated virus for vascular endothelial growth factor C, the major growth factor that promotes lymphangiogenesis, increases the area and number of PDPN+ /αSMA+ collecting LVs, promotes local lymphatic drainage, and reduces alveolar bone loss in both models of periodontitis. Lastly, LYVE1+ /αSMA- lymphatic capillaries are increased, whereas LYVE1+ /αSMA+ collecting LVs are decreased significantly in gingival tissues of patients with chronic periodontitis compared with those of clinically healthy controls. Thus, our findings reveal an important role of local lymphatic drainage in periodontal inflammation-mediated alveolar bone loss. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Processo Alveolar/metabolismo , Periodontite Crônica/terapia , Terapia Genética , Linfa/metabolismo , Vasos Linfáticos/metabolismo , Maxila/metabolismo , Fator C de Crescimento do Endotélio Vascular/biossíntese , Fator C de Crescimento do Endotélio Vascular/genética , Perda do Osso Alveolar/genética , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Processo Alveolar/patologia , Animais , Estudos de Casos e Controles , Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Periodontite Crônica/patologia , Modelos Animais de Doenças , Humanos , Vasos Linfáticos/patologia , Masculino , Maxila/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoclastos/metabolismo , Osteoclastos/patologia , Fator de Necrose Tumoral alfa/genética
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