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1.
Anticancer Res ; 41(9): 4497-4504, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475075

RESUMO

BACKGROUND/AIM: E-Cadherin has been implicated in cell-cell adhesion, and soluble E-cadherin is involved in angiogenesis and resistance to anti-angiogenic therapy in several cancer types. This study aimed to investigate the expression and clinical significance of soluble E-cadherin and other angiogenesis-related factors in plasma and malignant ascites of colorectal cancer (CRC) in patients with peritoneal carcinomatosis (PC). MATERIALS AND METHODS: Multiplex enzyme-linked immunosorbent assay was performed on 95 body fluid samples (57 plasma and 38 malignant ascites) from patients with CRC. The status of E-cadherin and angiopoietin-2 (AGNPT2) was retrospectively evaluated by immunohistochemistry in primary CRC and paired metastatic peritoneal tissues or cell blocks of malignant ascites of 30 patients with peritoneal metastases of CRC. RESULTS: The expression levels of soluble E-cadherin and ANGPT2 in plasma samples were significantly increased in patients with PC compared with those without. E-Cadherin concentration was significantly lower and ANGPT2 concentration was significantly higher in malignant ascites than plasma samples. Expression of E-cadherin was strongly positive, whilst that of ANGPT2 was negative in primary colorectal tissues, metastatic peritoneal tissues, and cell blocks of malignant ascites by immunohistochemistry. High levels of soluble E-cadherin or ANGPT2 in ascites were negatively associated with overall survival in patients with CRC with malignant ascites. CONCLUSION: Our findings suggest that soluble E-cadherin and ANGPT2 may be surrogate biomarkers for clinical outcome in patients with PC from CRC.


Assuntos
Angiopoietina-2/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/secundário , Neoplasias Peritoneais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Regulação para Cima
2.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445271

RESUMO

This study aimed to identify the proteomic changes produced by curcumin treatment following stimulation of the host immune system in a rat model of malignant mesothelioma. We analyzed the proteomes of secondary lymphoid organs from four normal rats, four untreated tumor-bearing rats, and four tumor-bearing rats receiving repeated intraperitoneal administrations of curcumin. Cross-comparing proteome analyses of histological sections of the spleen from the three groups first identified a list of eighty-three biomarkers of interest, thirteen of which corresponded to proteins already reported in the literature and involved in the anticancer therapeutic effects of curcumin. In a second step, comparing these data with proteomic analyses of histological sections of mesenteric lymph nodes revealed eight common biomarkers showing a similar pattern of changes in both lymphoid organs. Additional findings included a partial reduction of the increase in spleen-circulating biomarkers, a decrease in C-reactive protein and complement C3 in the spleen and lymph nodes, and an increase in lymph node purine nucleoside phosphorylase previously associated with liver immunodeficiency. Our results suggest some protein abundance changes could be related to the systemic, distant non-target antitumor effects produced by this phytochemical.


Assuntos
Biomarcadores Tumorais/metabolismo , Curcumina/farmacologia , Linfonodos/metabolismo , Mesotelioma , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais , Neoplasias Peritoneais , Proteoma/metabolismo , Animais , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/metabolismo , Mesotelioma/patologia , Invasividade Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Ratos , Ratos Endogâmicos F344
3.
Biochem Biophys Res Commun ; 561: 26-32, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000514

RESUMO

Peritoneal metastasis is a common mode of spread of ovarian cancer. Despite therapeutic advances, some patients have intractable peritoneal metastasis. Therefore, in-depth characterization of the molecular mechanism of peritoneal metastasis is a key imperative. Angiopoietin-like protein 2 (ANGPTL2) is an inflammatory factor which activates NF-κB signaling and plays an important role in the pathogenesis of various inflammatory diseases including cancers, such as lung and breast cancer. In this study, we examined the role of ANGPTL2 in ovarian cancer peritoneal metastasis. We observed no difference of cell proliferation between ANGPTL2-expressing and control cells. In the mouse intraperitoneal xenograft model, formation of peritoneal metastasis by ANGPTL2-expressing cells was significantly decreased compared to control. In the in vitro analysis, the expressions of integrin α5ß1, α6, and ß4, but not those of αvß3, α3, α4, and ß1, were significantly decreased in ANGPTL2-expressing cells compared to control cells. ANGPTL2-expressing cells showed significantly inhibited adherence to laminin compared to control. In addition, we observed upregulation of anoikis (a form of programmed cell death occurring under an anchorage-independent condition) and significant decrease in the expression of Bcl-2 in ANGPTL2-expressing cells as compared to control cells. These results suggest that ANGPTL2 expression in ovarian cancer cells represses peritoneal metastasis by suppressing anoikis resistance.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Animais , Anoikis/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução de Sinais
4.
Sci Rep ; 11(1): 9212, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911154

RESUMO

Peritoneal recurrence (PR) is a major relapse pattern of colorectal cancer (CRC). We investigated whether peritoneal immune cytokines can predict PR. Cytokine concentrations of peritoneal fluid from CRC patients were measured. Patients were grouped according to peritoneal cancer burden (PCB): no tumor cells (≤ pT3), microscopic tumor cells (pT4), or gross tumors (M1c). Cytokine concentrations were compared among the three groups and the associations of those in pT4 patients with and without postoperative PR were assessed. Of the ten cytokines assayed, IL6, IL10, and TGFB1 increased with progression of PCB. Among these, IL10 was a marker of PR in pT4 (N = 61) patients based on ROC curve (p = 0.004). The IL10 cut-off value (14 pg/mL) divided patients into groups with a low (7%, 2 of 29 patients) or high (45%, 16 of 32 patients) 5-year PR (p < 0.001). Multivariable analysis identified high IL10 levels as the independent risk factor for PR. Separation of patients into training and test sets to evaluate the performance of IL10 cut-off model validated this cytokine as a risk factor for PR. Peritoneal IL10 is a prognostic marker of PR in pT4 CRC. Further research is necessary to identify immune response of intraperitoneal CRC growth.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Interleucina-10/metabolismo , Recidiva Local de Neoplasia/patologia , Cavidade Peritoneal/patologia , Neoplasias Peritoneais/secundário , Idoso , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/cirurgia , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
5.
FASEB J ; 35(5): e21601, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33913201

RESUMO

Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.


Assuntos
Biomarcadores Tumorais/metabolismo , Bufanolídeos/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/genética , Óxido Nítrico Sintase Tipo III/genética , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
BMC Cancer ; 21(1): 461, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902518

RESUMO

BACKGROUND: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is an innovative treatment against peritoneal carcinomatosis. Doxorubicin is a common intra-venous chemotherapy used for peritoneal carcinomatosis and for PIPAC. This study evaluated the impact of increased PIPAC intraperitoneal pressure on the distribution and cell penetration of doxorubicin in a sheep model. METHODS: Doxorubicin was aerosolized using PIPAC into the peritoneal cavity of 6 ewes (pre-alpes breed): N = 3 with 12 mmHg intraperitoneal pressure ("group 12") and N = 3 with 20 mmHg ("group 20"). Samples from peritoneum (N = 6), ovarian (N = 1), omentum (N = 1) and caecum (N = 1) were collected for each ewe. The number of doxorubicin positive cells was determined using the ratio between doxorubicine fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (µm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei over the total number of cell nuclei that were stained with DAPI. Penetration depth (µm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei. RESULTS: DOXO+ nuclei were identified in 87% of samples. All omental samples, directly localized in front of the nebulizer head, had 100% DOXO+ nuclei whereas very few nuclei were DOXO+ for caecum. Distribution patterns were not different between the two groups but penetration depth in ovary and caecum samples was significantly deeper in group 20. CONCLUSIONS: This study showed that applying a higher intra-peritoneal pressure during PIPAC treatment leads to a deeper penetration of doxorubicin in ovarian and caecum but does not affect distribution patterns.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Peritoneais/metabolismo , Aerossóis , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/análise , Ceco/química , Ceco/metabolismo , Núcleo Celular/química , Doxorrubicina/administração & dosagem , Doxorrubicina/análise , Feminino , Omento/química , Omento/metabolismo , Ovário/química , Ovário/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/química , Peritônio/metabolismo , Pressão , Ovinos , Distribuição Tecidual
7.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921783

RESUMO

Although malignant ascites (MAs) are known to contribute to various aspects of ovarian cancer progression, knowledge regarding their role in the adhesion of cancer cells to normal peritoneal cells is incomplete. Here, we compared the effect of MAs and benign ascites (BAs) on the adhesion of A2780 and OVCAR-3 cancer cells to omentum-derived peritoneal mesothelial cells (PMCs) and peritoneal fibroblasts (PFBs). The results showed that MAs stimulated the adhesion of A2780 and OVCAR-3 cells to PMCs and PFBs more efficiently than did BAs, and the strongest binding occurred when both cancer and normal cells were exposed to the fluid. Intervention studies showed that MAs-driven adhesion of A2780 cells to PMCs/PFBs depends on the presence of TGF-ß1 and HGF, whereas binding of OVCAR-3 cells was mediated by TGF-ß1, GRO-1, and IGF-1. Moreover, MAs upregulated α5ß1 integrin expression on PFBs but not on PMCs or cancer cells, vimentin expression in all cells tested, and ICAM-1 only in cancer cells. When integrin-linked kinase was neutralized in PMCs or PFBs, cancer cell adhesion to PMCs and PFBs decreased. Collectively, our report shows that MAs may contribute to the early stages of ovarian cancer metastasis by modulating the proadhesive interplay between normal and cancer cells.


Assuntos
Ascite/metabolismo , Ascite/patologia , Adesão Celular/fisiologia , Neoplasias Ovarianas/metabolismo , Apoptose/fisiologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Citometria de Fluxo , Imunofluorescência , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia
8.
Medicine (Baltimore) ; 100(12): e25264, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761726

RESUMO

RATIONALE: Primary peritoneal epithelioid mesothelioma of clear cell type is an extremely rare entity composed of clear cytoplasm. It is challenging to diagnose because of the morphological resemblance to clear cell tumor. PATIENTS CONCERNS: A 69-year-old male patient had swollen lymph nodes in the right inguinal region for 7 months and was constipated for 1 month. DIAGNOSIS: The patient was diagnosed as peritoneal epithelioid mesothelioma of clear cell type based on computed tomography scan, pathology, immunohistochemistry, special staining and whole-exome sequencing. This patient harbored VHL gene alteration in exon 1 and homologous recombination defect (with a score of 45). This finding indicated that this patient might be sensitive to platinum-based therapy and Poly ADP-ribose Polymerase (PARP) inhibitor. This patient carried no microsatellite instability, a low level of tumor mutation burden, and a high extent of intratumoral heterogeneity. Eighteen neoantigens were detected. INTERVENTIONS: The patient received surgery-based multidisciplinary treatment by integrating cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). HIPEC was administered with docetaxel 120 mg plus cisplatin 120 mg, at 43°C, for 60 minutes. After operation, the patient received intravenous (IV) chemotherapy with docetaxel 60 mg, pemetrexed 750 mg and cisplatin 100 mg, and then intraperitoneal (IP) chemotherapy with docetaxel 40 mg. The patient received interventional therapy of hepatic artery embolization for 5 times. OUTCOMES: Regular follow-up was performed until Oct 14, 2020. The patient died 31.6 months later owing to incomplete intestinal obstruction. LESSONS: Primary peritoneal epithelioid mesothelioma of clear cell type needs to be differentiated from a variety of clear cell tumors. This disease is characterized by specific genetic alteration. Whole-exome sequencing contributes to guide individualized therapy. CRS-HIPEC helps achieve long-term overall survival.


Assuntos
Cisplatino/administração & dosagem , Procedimentos Cirúrgicos de Citorredução/métodos , Docetaxel/administração & dosagem , Quimioterapia Intraperitoneal Hipertérmica/métodos , Mesotelioma Maligno , Pemetrexede/administração & dosagem , Neoplasias Peritoneais , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Idoso , Antineoplásicos/administração & dosagem , Embolização Terapêutica/métodos , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/patologia , Mesotelioma Maligno/fisiopatologia , Mesotelioma Maligno/terapia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/fisiopatologia , Neoplasias Peritoneais/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Sequenciamento Completo do Exoma/métodos
9.
Cancer Lett ; 503: 163-173, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33524500

RESUMO

The majority of women with ovarian cancer are diagnosed with metastatic disease, therefore elucidating molecular events that contribute to successful metastatic dissemination may identify additional targets for therapeutic intervention and thereby positively impact survival. Using two human high grade serous ovarian cancer cell lines with inactive TP53 and multiple rounds of serial in vivo passaging, we generated sublines with significantly accelerated intra-peritoneal (IP) growth. Comparative analysis of the parental and IP sublines identified a common panel of differentially expressed genes. The most highly differentially expressed gene, upregulated by 60-65-fold in IP-selected sublines, was the type I transmembrane protein AMIGO2. As the role of AMIGO2 in ovarian cancer metastasis remains unexplored, CRISPR/Cas9 was used to reduce AMIGO2 expression, followed by in vitro and in vivo functional analyses. Knockdown of AMIGO2 modified the sphere-forming potential of ovarian cancer cells, reduced adhesion and invasion in vitro, and significantly attenuated IP metastasis. These data highlight AMIGO2 as a new target for a novel anti-metastatic therapeutic approach aimed at blocking cohesion, survival, and adhesion of metastatic tumorspheres.


Assuntos
Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Regulação para Cima , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Mutação , Transplante de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Proteína Supressora de Tumor p53/genética
10.
Int J Cancer ; 148(8): 2036-2047, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33403690

RESUMO

Pseudomyxoma peritonei (PMP) is a rare disorder with unique pathological and genetic changes. Although several studies have reported the clinical features and mutational changes of PMP that originates from the appendix, few studies on PMP originating from the ovary have been reported due to its extreme rarity. In order to characterize the somatic mutational landscape and to investigate the prognosis predicting factors of ovary-originating PMP, we examined 830 cases of PMP and identified 16 patients with PMP that originated from the ovary. Whole-exome sequencing (WES) was performed on 12 cases using formalin-fixed, paraffin-embedded (FFPE) tissue samples. We found that 25% (3/12) of the patients carried mutations in cancer driver genes, including TP53, ATM and SETD2, and 16.7% (2/12) of the patients carried mutations in cancer driver genes, including ATRX, EP300, FGFR2, KRAS, NOCR1 and RB1. The MUC16 (58.33%), BSN (41.67%), PCNT (41.67%), PPP2R5A (41.67%), PRSS36 (41.67%), PTPRK (41.67%) and SBF1 (41.67%) genes presented the highest mutational frequencies. The PI3K-Akt signaling pathway, human papillomavirus infection pathway, cell skeleton, cell adhesion, and extracellular matrix and membrane proteins were the major pathways or functions that were affected. Patients were followed up to 174 months (median: 48.26 months). The 5-year OS rate for all patients was 71.2% and the median OS was not reached. PTPRK mutations, presurgical CA199 level, completeness of cytoreduction (CCR) and peritoneal cancer index (PCI) were identified as potential predictive factors for patient survival. In conclusion, the mutational landscape for ovary-originating PMP was revealed and exhibited unique features distinct from appendix-originating PMP. PTPRK, CA199, CCR and PCI may predict patient survival.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Ovário/metabolismo , Neoplasias Peritoneais/genética , Pseudomixoma Peritoneal/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Idoso , Proteínas Mutadas de Ataxia Telangiectasia/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Ovário/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Prognóstico , Pseudomixoma Peritoneal/metabolismo , Pseudomixoma Peritoneal/patologia , Proteínas de Ligação a Retinoblastoma/genética , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
11.
Anticancer Res ; 41(2): 609-617, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517265

RESUMO

BACKGROUND/AIM: Disease recurrence is frequently observed after curative resection of advanced gastric cancer resulting in a poor prognosis. In the present study, we identified a candidate biomarker to predict recurrence and prognosis after curative resection of gastric cancer. MATERIALS AND METHODS: A transcriptome analysis was conducted using surgically resected cancerous tissue from patients with metastatic gastric cancer to identify genes that are upregulated in primary and metastatic tissues. RESULTS: Ring finger protein, transmembrane 2 (RNFT2) mRNA expression was upregulated in primary gastric cancer tissues and metastases compared with non-cancerous tissues. RNFT2 expression in gastric cancer cell lines was positively correlated with the EMT-related molecules GSC, MMP9, and RAC1. The RNFT2 high expression group exhibited a significantly shorter postoperative overall survival. Peritoneal recurrence was significantly higher in the RNFT2 high expression group. CONCLUSION: RNFT2 mRNA expression predicts peritoneal recurrence and is a potential prognostic biomarker for gastric cancer following curative gastrectomy.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/metabolismo , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Transição Epitelial-Mesenquimal , Feminino , Gastrectomia , Humanos , Masculino , Proteínas de Membrana/genética , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
12.
BMC Cancer ; 21(1): 102, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509150

RESUMO

BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.


Assuntos
Vesículas Extracelulares/patologia , Leucócitos Mononucleares/patologia , Macrófagos/patologia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
BMC Cancer ; 21(1): 32, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413178

RESUMO

BACKGROUND: Aberrant expression of P-cadherin has been reported in various cancers, and has been attracting attention as a target for cancer treatment. Ovarian cancer, the leading cause of death among gynecologic malignancies, is classified into four histological subtypes: serous, mucinous, endometrioid, and clear cell, and each has distinct biological behavior. Although a negative survival impact in serous ovarian cancer patients and some functional role in peritoneal dissemination have been reported, differences of P-cadherin expression in histological subtypes and the proportion and distribution of positive cells remain to be investigated. The aims of this study were to clarify the histological and distributional profiles of P-cadherin expression in ovarian cancer for development of target-therapy in near future. METHODS: A total of 162 primary, 60 metastatic, and 8 recurrent tumors (all cases from 162 ovarian cancer patients) were enrolled in the study. Immunohistochemistry was performed for P-cadherin expression. Associations with clinicopathological characteristics and survival were analyzed. RESULTS: P-cadherin expression showed a strong correlation with the FIGO stage, histological subtypes, positive peritoneal dissemination (P < 0.01), positive distant metastasis (P < 0.05), and trend toward negative overall survival probability (P = 0.050). P-cadherin was intensely and broadly expressed in mucinous, endometrioid, and serous subtypes (P < 0.01). Disseminated tumors demonstrated similar P-cadherin expression to primary tumors whereas metastatic lymph nodes demonstrated significantly decreased expression (P < 0.01). CONCLUSIONS: Mucinous, endometrioid, and serous ovarian cancer patients accompanied with peritoneal disseminations are the most potent candidates for P-cadherin targeted drug delivery strategies. P-cadherin-targeted therapy may benefit and improve survival of poor-prognosis populations.


Assuntos
Adenocarcinoma Mucinoso/patologia , Caderinas/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Terapia de Alvo Molecular , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
14.
Eur J Surg Oncol ; 47(2): 486-489, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32800401

RESUMO

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.


Assuntos
Docetaxel/administração & dosagem , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/terapia , Peritonite/terapia , Neoplasias Gástricas/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Terapia Combinada , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Gastrectomia , Humanos , Injeções Intraperitoneais , Oxaliplatina/farmacocinética , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/metabolismo , Peritonite/etiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/metabolismo
15.
Br J Cancer ; 124(3): 564-566, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33100328

RESUMO

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.


Assuntos
Antígeno B7-H1/metabolismo , Mesotelioma Maligno/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Peritoneais/metabolismo , Antineoplásicos/uso terapêutico , Regulação para Baixo , Feminino , Humanos , Masculino , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Mutação , Pemetrexede/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Compostos de Platina/uso terapêutico , Estudos Retrospectivos , Regulação para Cima
16.
Cancer Sci ; 112(2): 668-678, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33053268

RESUMO

Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX-LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.


Assuntos
Carcinoma Ductal Pancreático/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Peritoneais/secundário , Diester Fosfórico Hidrolases/metabolismo , Animais , Ascite/metabolismo , Ascite/patologia , Carcinoma Ductal Pancreático/metabolismo , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Peritoneais/metabolismo
17.
Surgery ; 169(5): 1213-1220, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33376002

RESUMO

BACKGROUND: The aim of this study was to elucidate the correlation of high-mobility group protein A2 overexpression with gastric cancer prognosis and compare its prognostic power with that of pre-existing markers. METHODS: Malignant tissues from 396 patients with gastric cancer who underwent gastrectomy from 2008 to 2012 were examined. High-mobility group protein A2 expression was assessed by immunohistochemistry and the sensitivity and specificity for predicting disease progression and overall survival of high-mobility group protein A2 and the prognostic biomarkers p53, Ki-67, human epidermal growth factor receptor 2, cyclooxygenase-2, and epidermal growth factor receptor were compared. RESULTS: A total of 95 samples (24.1%) showed high-mobility group protein A2 overexpression, which was related to advanced stage, undifferentiated histology, and lymphatic and perineural invasion. Additionally, high-mobility group protein A2 overexpression was an independent prognostic factor in multivariate analysis for disease progression and overall survival. Based on Kaplan-Meier survival analysis disease progression and overall survival, the high-mobility group protein A2-overexpressing patients showed worse survival. The recurrence pattern of peritoneal dissemination was more frequently observed in high-mobility group protein A2-positive group. Moreover, chemoresistance was more frequently observed in the high-mobility group protein A2-positive group. High-mobility group protein A2 exhibited a better ability for predicting disease progression and overall survival than other markers, and the prognostic power was enhanced when high-mobility group protein A2 was used with these markers. CONCLUSION: High-mobility group protein A2 overexpression is associated with chemoresistance and a propensity for carcinomatosis peritonei after surgery in patients with gastric cancer. The power to predict the prognosis of patients with gastric cancer can be enhanced with the use of preexisting biomarkers and high-mobility group protein A2.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteína HMGA2/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/etiologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade
18.
Int J Mol Sci ; 21(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371469

RESUMO

Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator de Transcrição Associado à Microftalmia/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Apoptose , Biomarcadores Tumorais/genética , Antígeno CD146/genética , Antígeno CD146/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Prognóstico , Células Tumorais Cultivadas
19.
Aging (Albany NY) ; 12(23): 24009-24022, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33221764

RESUMO

Peritoneal metastasis (PM) is the main cause of poor prognosis in patients with advanced gastric cancer (GC). Increasing evidence has suggested that cancer-associated EVs in body fluids may assist in the diagnosis and treatment of GC. Here, we investigated the role of GC-derived EVs in PM development. Our results demonstrate that expression of the tumor suppressor promyelocytic leukemia zinc finger (PLZF) is decreased in GC tissues and PM lesions from GC patients. PLZF suppression promoted migration and invasion of peritoneal mesothelial HMrSV5 cells, while PLZF overexpression suppressed HMrSV5 cell migration and invasion. Microarray analysis revealed significantly upregulated expression of several miRNAs in EVs isolated from GC patients with PM, including miR-544. The increased miR-544 expression was confirmed in GC tissues and PM-derived EVs. Transfection with miR-544 reduced PLZF expression in HMrSV5 cells, while miR-544 inhibition increased PLZF expression. Incubation of GC cells with peritoneal mesothelial HMrSV5 cells showed that miR-544 could be transferred from GC-derived EVs to peritoneal cells, where it suppressed the PLZF expression. These findings indicate that EV-mediated transfer of miR-544 decreases the PLZF expression in PM lesions, which suggests miR-544 could potentially serve as a diagnostic biomarker and therapeutic target for treatment of GC patients.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Neoplasias Peritoneais/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/secundário , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
20.
Cancer Res ; 80(24): 5554-5568, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33087324

RESUMO

Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin ß1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. SIGNIFICANCE: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5554/F1.large.jpg.


Assuntos
Receptores ErbB/metabolismo , Proteína Forkhead Box M1/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Receptor ErbB-2/metabolismo , Transdução de Sinais/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Proteína Forkhead Box M1/antagonistas & inibidores , Proteína Forkhead Box M1/genética , Técnicas de Silenciamento de Genes , Humanos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Camundongos , Neoplasias Peritoneais/prevenção & controle , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Tioestreptona/farmacologia , Tioestreptona/uso terapêutico , Transfecção
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