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1.
Nat Commun ; 12(1): 5232, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475402

RESUMO

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.


Assuntos
Neoplasias da Mama/patologia , Fator I de Transcrição COUP/genética , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas , Animais , Neoplasias da Mama/genética , Fator I de Transcrição COUP/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Sítios Internos de Entrada Ribossomal , Pulmão/patologia , Neoplasias Pulmonares/genética , Camundongos , Invasividade Neoplásica , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
2.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
3.
Nutrients ; 13(7)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34371939

RESUMO

A high-fat diet (HFD) and obesity are risk factors for many diseases including breast cancer. This is particularly important with close to 40% of the current adult population being overweight or obese. Previous studies have implicated that Mediterranean diets (MDs) partially protect against breast cancer. However, to date, the links between diet and breast cancer progression are not well defined. Therefore, to begin to define and assess this, we used an isocaloric control diet (CD) and two HFDs enriched with either olive oil (OOBD, high in oleate, and unsaturated fatty acid in MDs) or a milk fat-based diet (MFBD, high in palmitate and myristate, saturated fatty acids in Western diets) in a mammary polyomavirus middle T antigen mouse model (MMTV-PyMT) of breast cancer. Our data demonstrate that neither MFBD or OOBD altered the growth of primary tumors in the MMTV-PyMT mice. The examination of lung metastases revealed that OOBD mice exhibited fewer surface nodules and smaller metastases when compared to MFBD and CD mice. These data suggest that different fatty acids found in different sources of HFDs may alter breast cancer metastasis.


Assuntos
Neoplasias da Mama/patologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/toxicidade , Ácidos Graxos/toxicidade , Neoplasias Pulmonares/secundário , Leite/toxicidade , Ração Animal , Animais , Antígenos Transformantes de Poliomavirus , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Vírus do Tumor Mamário do Camundongo/genética , Azeite de Oliva/toxicidade , Medição de Risco , Fatores de Risco , Carga Tumoral , Fator de Necrose Tumoral alfa/metabolismo
4.
Medicine (Baltimore) ; 100(34): e26681, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449453

RESUMO

RATIONALE: Recently, the number of osteosarcomas has been increasing in elderly patients due to human longevity. Lung metastases are the primary cause of death from osteosarcomas. Complete resection of lung metastases can prolong the survival. However, complete resection in elderly patients is often difficult due to high risk of operative complications. Computed tomography (CT) guided radiofrequency ablation (RFA) is a minimally invasive technique to destroy tumor nodules using heat. In this report, we present the first case older than 65 years applying RFA for lung metastases due to osteosarcoma. PATIENT CONCERNS: A 74-year-old male presented with 1-year history of heel pain. A conventional high-grade osteosarcoma in his calcaneus was diagnosed. Below-knee amputation was performed. However, lung metastases were found in both lungs 1 year after amputation. CT-guided lung RFA was chosen since surgical intervention for lung metastases was abandoned because of tumor multiplicity and medical comorbidities. A total of 18 lung metastases were treated by CT-guided RFA. The most frequent complication was pneumothoraxes in 4 of 8 (50%) procedures and chest tube drainage was required in 2 of these (2 of 8 (25%) procedures). DIAGNOSES: Six lung metastases of osteosaroma were found in both lungs at 1 year after surgery. INTERVENTIONS: CT-guided lung RFA was performed. A total of 18 lung metastases were treated in 8 lung RF procedures. OUTCOMES: The patient has been alive with disease for 5.5 years after the initial surgery. LESSONS: CT-guided lung RFA is effective for elderly patients with osteosarcoma lung metastases in spite of discouragement of lung metastasectomy due to multiplicity of metastases and medical-comorbidities.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Osteossarcoma/patologia , Ablação por Radiofrequência/métodos , Idoso , Calcâneo/patologia , Humanos , Masculino , Radiografia Intervencionista , Tomografia Computadorizada por Raios X
5.
FASEB J ; 35(9): e21798, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339064

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Assuntos
COVID-19/complicações , Calgranulina A/fisiologia , Síndrome da Liberação de Citocina/etiologia , Inflamação/etiologia , Pandemias , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Antivirais/farmacologia , COVID-19/genética , COVID-19/patologia , Calgranulina A/sangue , Calgranulina A/genética , Quimiocina CXCL11/sangue , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Dissacarídeos/farmacologia , Dissacarídeos/uso terapêutico , Modelos Animais de Doenças , Descoberta de Drogas , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Inflamação/genética , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Antígeno 96 de Linfócito/fisiologia , Macaca mulatta , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Mutação , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/metabolismo , Especificidade da Espécie , Fosfatos Açúcares/farmacologia , Fosfatos Açúcares/uso terapêutico , Receptor 4 Toll-Like/fisiologia , Regulação para Cima , Internalização do Vírus
6.
Nat Commun ; 12(1): 4867, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381029

RESUMO

Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.


Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/secundário , Células Neoplásicas Circulantes/patologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Agregação Celular , Ciclo Celular , Transformação Celular Neoplásica , Humanos , Molécula 1 de Adesão Intercelular/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Células Neoplásicas Circulantes/metabolismo , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Migração Transendotelial e Transepitelial , Neoplasias de Mama Triplo Negativas/metabolismo
7.
Oncology ; 99(9): 547-554, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237725

RESUMO

PURPOSE: Esophageal cancer patients may simultaneously have resectable esophageal cancer and undiagnosable incidental minute solid pulmonary nodules. While the latter is rarely metastatic, only a few studies have reported on the outcomes of such nodules after surgery. In this retrospective study, we assessed the incidence of such nodules, the probability that they are ultimately metastatic nodules, and the prognosis of patients after esophagectomy according to the metastatic status of the nodules. METHODS: Data of 398 patients who underwent esophagectomy for resectable esophageal cancer between January 2012 and December 2016 were collected. We reviewed computed tomography (CT) images from the first visit and searched for incidental minute pulmonary nodules <10 mm in size. We followed the outcomes of these nodules and compared the characteristics of metastatic and nonmetastatic nodules. We also assessed the prognosis of patients whose minute pulmonary nodules were metastatic. RESULTS: Among the patients who underwent esophagectomy, 149 (37.4%) had one or more minute pulmonary nodules, with a total of 285 nodules. Thirteen (4.6%) of these nodules in 12 (8.1%) patients were ultimately diagnosed as being metastatic. Thirteen (8.7%) patients experienced recurrence at a different location from where the nodules were originally identified. Characteristics of the metastatic nodules were not unique in terms of size, SUVmax, or location in the lungs. Two-year and 5-year overall survival rates of patients whose nodules were metastatic were 64.2 and 32.1%, respectively. CONCLUSION: The rate of minute pulmonary nodules which were ultimately metastatic was 4.6%. Our findings suggest that esophagectomy followed by the identification of minute pulmonary nodules is an acceptable strategy even if the nodules cannot be diagnosed as being metastatic on the first visit CT due to their small size.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Achados Incidentais , Neoplasias Pulmonares/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/terapia , Esofagectomia/métodos , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X
8.
Aging (Albany NY) ; 13(13): 17462-17472, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253689

RESUMO

Propose: Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism. METHOD: TCGA database of lung squamous cell carcinoma was analyzed to explore the differentially expressed miRNAs and mRNAs and relative prognosis. RT-PCR and Western blot were performed to evaluate autophagy relative gene expression level in human lung squamous cell carcinoma cell Lines. Autophagy flux was observed using transmission electron microscopy and immunofluorescence. Meanwhile, binding relationship of potential target miRNA and mRNAs were also confirmed using Dual-luciferase reporter gene assay. Lung metastatic model was established to evaluated the effect of targeting protein and miRNA. RESULT: High level expression of ATG5 was detected in LUSC patients. Relative experiments confirmed that ATG5 silencing could decrease the autophagy flux in LUSC. In addition, our research revealed that there is a binding sites between hsa-mir-30a-5p and 3'-UTR of ATG5. Mimic miR-30a-5p suppresses ATG5-mediated autophagy in lung squamous cell carcinoma cells. The in vivo experiments confirmed that miR-30a-5p could attenuate lung squamous cell carcinoma progression through the autophagy pathway. CONCLUSION: Accordingly, the in vivo and in vitro study in our research have demonstrated that miR-30a-5p inhibits lung squamous cell carcinoma progression via ATG5-mediated autophagy.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Autofagia/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Animais , Sítios de Ligação , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Prognóstico , RNA Mensageiro/genética , Transdução de Sinais/genética
9.
Anticancer Res ; 41(8): 3933-3940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281856

RESUMO

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Idoso , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Carga Tumoral
10.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299130

RESUMO

Although cisplatin is one of most effective chemotherapeutic drugs that is widely used to treat various types of cancer, it can cause undesirable damage in immune cells and normal tissue because of its strong cytotoxicity and non-selectivity. This study was conducted to investigate the cytoprotective effects of Cudrania tricuspidata fruit-derived polysaccharides (CTPS) against cisplatin-induced cytotoxicity in macrophages, lung cancer cell lines, and a mouse model, and to explore the possibility of application of CTPS as a supplement for anticancer therapy. Both cisplatin alone and cisplatin with CTPS induced a significant cytotoxicity in A549 and H460 lung cancer cells, whereas cytotoxicity was suppressed by CTPS in cisplatin-treated RAW264.7 cells. CTPS significantly attenuated the apoptotic and necrotic population, as well as cell penetration in cisplatin-treated RAW264.7 cells, which ultimately inhibited the upregulation of Bcl-2-associated X protein (Bax), cytosolic cytochrome c, poly (adenosine diphosphateribose) polymerase (PARP) cleavage, and caspases-3, -8, and -9, and the downregulation of B cell lymphoma-2 (Bcl-2). The CTPS-induced cytoprotective action was mediated with a reduction in reactive oxygen species production and mitochondrial transmembrane potential loss in cisplatin-treated RAW264.7 cells. In agreement with the results obtained above, CTPS induced the attenuation of cell damage in cisplatin-treated bone marrow-derived macrophages (primary cells). In in vivo studies, CTPS significantly inhibited metastatic colonies and bodyweight loss as well as immunotoxicity in splenic T cells compared to the cisplatin-treated group in lung metastasis-induced mice. Furthermore, CTPS decreased the level of CRE and BUN in serum. In summation, these results suggest that CTPS-induced cytoprotective action may play a role in alleviating the side effects induced by chemotherapeutic drugs.


Assuntos
Cisplatino/toxicidade , Frutas/química , Macrófagos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Moraceae/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antineoplásicos/toxicidade , Apoptose , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Macrófagos/patologia , Melanoma Experimental/induzido quimicamente , Melanoma Experimental/patologia , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Substâncias Protetoras/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Biol Macromol ; 185: 551-561, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216657

RESUMO

Advanced melanoma patients that are not included in common genetic classificatory groups lack effective and safe therapeutic options. Chemotherapy and immunotherapy show unsatisfactory results and devastating adverse effects for these called triple wild-type patients. New approaches exploring the intrinsic antitumor properties of gold nanoparticles might reverse this scenario as a safer and more effective alternative. Therefore, we investigated the efficacy and safety of a composite made of gum arabic-functionalized gold nanorods (GA-AuNRs) against triple wild-type melanoma. The natural polymer gum arabic successfully stabilized the nanorods in the biological environment and was essential to improve their biocompatibility. In vivo results obtained from treating triple wild-type melanoma-bearing mice showed that GA-AuNRs remarkably reduced primary tumor growth by 45%. Furthermore, GA-AuNRs induced tumor histological features associated with better prognosis while also reducing superficial lung metastasis depth and the incidence of intrapulmonary metastasis. GA-AuNRs' efficacy comes from their capacity to reduce melanoma cells ability to invade the extracellular matrix and grow into colonies, in addition to a likely immunomodulatory effect induced by gum arabic. Additionally, a broad safety investigation found no evidence of adverse effects after GA-AuNRs treatment. Therefore, this study unprecedentedly reports GA-AuNRs as a potential nanomedicine for advanced triple wild-type melanomas.


Assuntos
Ouro/administração & dosagem , Goma Arábica/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melanoma/tratamento farmacológico , Animais , Células 3T3 BALB , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Ouro/química , Ouro/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Melanoma/metabolismo , Nanopartículas Metálicas , Camundongos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298975

RESUMO

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Ciclofosfamida/toxicidade , Neoplasias Pulmonares/secundário , Macrófagos/fisiologia , Neoplasias Mamárias Experimentais/genética , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Estresse Fisiológico/genética , Macrófagos Associados a Tumor/fisiologia , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Genótipo , Humanos , Neoplasias Pulmonares/metabolismo , Ativação de Macrófagos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Terapia Neoadjuvante/efeitos adversos , Metástase Neoplásica/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Macrófagos Associados a Tumor/efeitos dos fármacos
13.
Tuberk Toraks ; 69(2): 227-236, 2021 Jun.
Artigo em Turco | MEDLINE | ID: mdl-34256513

RESUMO

Introduction: Solid Pulmonary Nodule (SPN) is defined as parenchymal radiopacity smaller than 3 cm in diameter. Evaluating the metastatic nature of the SPNs detected in the thorax computed tomography (TCT) examination for staging purposes in cancer patients becomes a fundamental problem for the physician. Invasive procedures, additional imaging or follow-up imaging, are often used to differentiate metastatic and non-metastatic nodules. In this study, we aimed to distinguish SPNs detected in patients diagnosed with bladder cancer (BC) as metastatic and non-metastatic nodules by texture analysis. Materials and Methods: TCT images of patients diagnosed with BC in our hospital from January 2007 until December 2017 were retrospectively evaluated. A total of 46 patients with SPN, including metastatic (n= 19) and non-metastatic (n= 27), were included in the study. Short axis diameter, long-axis diameter, nodule volume and volume histogram values of the nodules were obtained. Chisquare test was used to evaluate dependent variables, and the Mann-Whitney U test was used to evaluate independent variables. ROC curves of the obtained data were plotted. Statistically, the significant p-value was determined as less than 0.05. Result: A significant difference was found between SPN long axis, short axis and volume values. In the volumetric histogram analysis, the maximum density value and the mean density value were found to be statistically significant. When the average of the highest densities in the volume histogram data was evaluated, the area under the curve value was 0.702 (95% CI, 519-854). The metastatic nodule could be distinguished with a sensitivity of 88% and a specificity of 70% when the volume histogram has the maximum density threshold of 50 HU. Conclusions: In this study, we concluded that SPN detected on CT images can be distinguished as metastatic and non-metastatic nodules using texture analysis method without invasive procedures.


Assuntos
Neoplasias Pulmonares/secundário , Nódulo Pulmonar Solitário/secundário , Tomografia Computadorizada por Raios X/métodos , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Nódulo Pulmonar Solitário/diagnóstico por imagem , Neoplasias da Bexiga Urinária/diagnóstico por imagem
14.
Tuberk Toraks ; 69(2): 247-252, 2021 Jun.
Artigo em Turco | MEDLINE | ID: mdl-34256516

RESUMO

The lung is the most common site of metastasis for many malignancies. Especially the gastrointestinal system, gynecological malignancies and osteosarcomas frequently metastasize to the lung. It accounts for less than 0.5% of all ovarian neoplasms. The frequency of recurrence and metastasis is less than 5%. In most cases, they are stage I tumors, limited to the ovary and carry a good prognosis. Here, while investigating the nodules in the lung that were detected incidentally at the age of 64, the rare Sertoli-Leydig cell tumor of the lung is discussed clinically, radiologically and pathologically in the presence of a 64-year-old patient who was found to have undergone ovarian surgery 9 years ago. Since imaging methods and tumor markers did not yield significant results in terms of primary malignancy, wedge resection was performed from the left lung nodules. The histology of the lung nodule was the same as the poorly differentiated foci of the ovarian tumor. The immunohistochemical profiles of the two tumors were also similar. As a result of the evaluation of the patient's old materials belonging to the ovary and the samples taken from the lung together; The diagnosis was reached by obtaining similar results with the primary tumor in the immunohistochemical examination performed for the metastatic focus. Sex cord stromal tumors of the ovary, which rarely cause lung metastasis and have a tendency to recur and metastasis in a very long time after the first diagnosis, should also be kept in mind in the elderly woman and the patient with a gynecological history.


Assuntos
Carcinoma/patologia , Neoplasias Pulmonares/secundário , Neoplasias Ovarianas/patologia , Tumor de Células de Sertoli-Leydig/patologia , Feminino , Humanos , Pessoa de Meia-Idade
16.
Cancer Treat Res Commun ; 28: 100406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34090218

RESUMO

Covid-19 Pneumonia of SARS-CoV-2 pandemic infection, persists to have high disease burden especially in cancer patients. Increased inflammation and thromboembolic processes are blamed to influence cancer patients more than the others but due to lack of knowledge regarding the pathophysiology of the both the virus itself and the response of the host, more basic and translational disease modeling research is needed to understand Cancer-Covid-19 interaction. In this study, serum samples from the patients, who were hospitalized due to Covid-19 pneumonia, applied to different cancer cells and cytotoxicity, motility, proliferation and gene expression analysis were performed. Serum samples derived from healthy volunteers and the fetal bovine serum that is used regularly in cell culture experiments used as controls. Hospitalized Covid-19 patients who had also cancer, were retrospectively screened, and their clinical course were recorded. Overall 12 Patient (PS) and 4 healthy serums (CS) were included in the experiments. PS applied cells showed increased motility in A549 cells as well as lost cell to cell connection in MCF7 and HCT116 cells, and induced expression of VIM, ZEB1 and SNAIL2 mRNA levels. Eight cancer diagnosed patients who were hospitalized due to Covid-19 between April and September 2020 were also reviewed retrospectively, which 5 of them were dead during SARS-CoV-2 infection. Thorax CT images of the 2 patients showed increased metastatic nodules in the lungs as of January 2021. The results of the study indicate that metastasis may be one of the prolonged consequences of COVID-19 pandemic in cancer sufferers.


Assuntos
COVID-19/imunologia , Transição Epitelial-Mesenquimal/fisiologia , Soros Imunes , Neoplasias/patologia , Adulto , Idoso , COVID-19/complicações , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Humanos , Soros Imunes/efeitos adversos , Soros Imunes/toxicidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia
17.
Cancer Sci ; 112(9): 3437-3454, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34152672

RESUMO

Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma-released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector-like tumor-specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD-L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD-L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD-L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis.


Assuntos
Antígeno B7-H1/metabolismo , Exossomos/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Melanoma/metabolismo , Melanoma/patologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva/métodos , Idoso , Animais , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/genética , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/deficiência , Proteínas rab27 de Ligação ao GTP/genética
18.
Cancer Sci ; 112(8): 3050-3063, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34110068

RESUMO

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH-A) is the rate-limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here show that LDH-A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH-A inhibition can improve the efficacy of PD-1 blockade in a pMMR CRC xenograft model. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH-A and dMMR status. Moreover, patients with both low LDH-A expression and dMMR exhibited better disease-free survival compared with patients with other combinations. The close correlation of LDH-A and dMMR may offer a promising therapeutic strategy in which the combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.


Assuntos
Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , L-Lactato Desidrogenase/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , L-Lactato Desidrogenase/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Transplante de Neoplasias , Prognóstico , Análise de Sobrevida
19.
Commun Biol ; 4(1): 657, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079064

RESUMO

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.


Assuntos
Biomarcadores Tumorais/fisiologia , Claudinas/fisiologia , Neoplasias Colorretais/secundário , Neoplasias Hepáticas/patologia , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Adesão Celular/genética , Adesão Celular/fisiologia , Claudinas/antagonistas & inibidores , Claudinas/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Células HT29 , Hepatócitos/patologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos SCID , Domínios PDZ/genética , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
Br J Radiol ; 94(1124): 20201391, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111978

RESUMO

OBJECTIVE: This study aims to build machine learning-based CT radiomic features to predict patients developing metastasis after osteosarcoma diagnosis. METHODS AND MATERIALS: This retrospective study has included 81 patients with a histopathological diagnosis of osteosarcoma. The entire dataset was divided randomly into training (60%) and test sets (40%). A data augmentation technique for the minority class was performed in the training set, along with feature's selection and model's training. The radiomic features were extracted from CT's image of the local osteosarcoma. Three frequently used machine learning models tried to predict patients with lung metastases (MT) and those without lung metastases (non-MT). According to the higher area under the curve (AUC), the best classifier was chosen and applied in the testing set with unseen data to provide an unbiased evaluation of the final model. RESULTS: The best classifier for predicting MT and non-MT groups used a Random Forest algorithm. The AUC and accuracy results of the test set were bulky (accuracy of 73% [ 95% coefficient interval (CI): 54%; 87%] and AUC of 0.79 [95% CI: 0.62; 0.96]). Features that fitted the model (radiomics signature) derived from Laplacian of Gaussian and wavelet filters. CONCLUSIONS: Machine learning-based CT radiomics approach can provide a non-invasive method with a fair predictive accuracy of the risk of developing pulmonary metastasis in osteosarcoma patients. ADVANCES IN KNOWLEDGE: Models based on CT radiomic analysis help assess the risk of developing pulmonary metastases in patients with osteosarcoma, allowing further studies for those with a worse prognosis.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Aprendizado de Máquina , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/secundário , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
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