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1.
Endocr Rev ; 40(2): 506-536, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657883

RESUMO

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.


Assuntos
Neoplasias do Sistema Digestório , Epigênese Genética , Tumores Neuroendócrinos , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Humanos , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia
2.
Medicine (Baltimore) ; 97(41): e12455, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30313035

RESUMO

BACKGROUND: Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers. METHODS: We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included. RESULTS: The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22-2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1-3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32-0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23-1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45-1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26-2.24, P = .62). CONCLUSION: The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/mortalidade , Proteínas de Ciclo Celular/metabolismo , Neoplasias do Sistema Digestório/diagnóstico , Neoplasias do Sistema Digestório/mortalidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Carcinoma/metabolismo , Neoplasias do Sistema Digestório/metabolismo , Regulação para Baixo , Humanos , Prognóstico , Análise de Sobrevida , Regulação para Cima
3.
J Surg Oncol ; 118(2): 315-323, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30216455
4.
Cell Prolif ; 51(4): e12446, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29484753

RESUMO

Accumulating evidence from genome-wide analysis and functional studies has begun to unveil the important role of long non-coding RNAs (lncRNAs) in cancer development. The lncRNA SPRY4-IT1 is derived from an intron of SPRY4 gene and was originally reported to be upregulated in melanoma in which it functioned as an oncogene. Since this discovery, an increasing number of studies have investigated the expression and function of SPRY4-IT1 in human cancers. Aberrant expression of SPRY4-IT1 has now been documented in different cancer types, including osteosarcoma, breast, renal, oesophageal and prostate cancers. However, its deregulation and function in lung and gastric cancers remain controversial. Pertinent to clinical practice, SPRY4-IT1 expression has been shown to predict survival of cancer patients. In this review, we summarize recent evidence concerning SPRY4-IT1 deregulation and the associated mechanisms in human cancers. We also discuss the potential clinical utilization of this lncRNA as a diagnostic and prognostic biomarker for cancer patients.


Assuntos
Neoplasias Ósseas/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/genética , Osteossarcoma/patologia , RNA Longo não Codificante/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Feminino , Humanos , Osteossarcoma/genética , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologia
5.
Anticancer Res ; 38(2): 811-816, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29374706

RESUMO

BACKGROUND: Few data are available regarding the epithelial to mesenchymal transition (EMT) /mesenchymal to epitheilal transition (MET) in the liver metastasis of digestive cancers. The aim of this study was to establish EMT/MET metastatic tumor cell plasticity according to the histological growth pattern of liver metastases. MATERIALS AND METHODS: Biopsies from 25 patients with liver metastasis (desmoplastic, replacement and pushing type) were evaluated. Double immunostaining of E-cadherin/vimentin, keratin 8,18/vimentin and E-cadherin/ keratin 8,18 were performed. RESULTS: The following cell types were noted: epithelial, mesenchymal, non-differentiated and differentiated hybrid mesenchymal/ epithelial and non-hybrid phenotype. All cases had mesenchymal/ epithelial phenotype cells. A significant correlation was found between the non-differentiated hybrid mesenchymal/ epithelial phenotype metastatic cells and histological growth pattern for gastric and colorectal cancer. CONCLUSION: A MET-targeting strategy, in conjunction with conventional chemotherapy, may be useful for the treatment of liver metastases.


Assuntos
Neoplasias do Sistema Digestório/patologia , Neoplasias Hepáticas/secundário , Antígenos CD , Caderinas/metabolismo , Plasticidade Celular/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias do Sistema Digestório/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Vimentina/metabolismo
6.
Oncotarget ; 8(19): 32332-32344, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28415659

RESUMO

Several previous studies have reported the prognostic value of hexokinase 2 (HK2) in digestive system tumors. However, these studies were limited by the small sample sizes and the results were inconsistent among them. Therefore, we conducted a meta-analysis based on 15 studies with 1932 patients to assess the relationship between HK2 overexpression and overall survival (OS) of digestive system malignancies. The relationship of HK2 and clinicopathological features was also evaluated. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CI) were calculated to estimate the effect size. Positive HK2 expression showed poor OS in all tumor types (HR = 1.75 [1.41-2.18], P < 0.001). When stratified by tumor type, the impact of HK2 overexpression on poor prognosis was observed in gastric cancer (HR = 1.77 [1.25-2.50], P < 0.001), hepatocellular carcinoma (HR = 1.87 [1.58-2.21], P < 0.001), and colorectal cancer (HR = 2.89 [1.62-5.15], P < 0.001), but not in pancreatic ductal adencarcinoma (HR = 1.11 [0.58-2.11], P = 0.763). Furthermore, high HK2 expression was significantly associated with some phenotypes of tumor aggressiveness, such as large tumor size (OR = 2.03 [1.10-3.74], P = 0.024), positive lymph node metastasis (OR = 2.05 [1.39-3.02], P < 0.001), advanced clinical stage (OR = 2.17 [1.21-3.89], P = 0.009) and high alpha fetoprotein level (OR = 1.47 [1.09-2.02] P = 0.013). In summary, HK2 might act as a prognostic indicator and a potential therapeutic target of these digestive system cancers.


Assuntos
Biomarcadores Tumorais , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/mortalidade , Expressão Gênica , Hexoquinase/genética , Animais , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Hexoquinase/metabolismo , Humanos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Razão de Chances , Prognóstico , Viés de Publicação , Carga Tumoral
7.
Anticancer Drugs ; 28(5): 551-556, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28296649

RESUMO

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/genética , Fluoruracila/efeitos adversos , Nomogramas , Farmacogenética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias do Sistema Digestório/metabolismo , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Ann R Coll Surg Engl ; 99(3): 193-197, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27490982

RESUMO

INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.


Assuntos
Neoplasias do Sistema Digestório/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/metabolismo , Adulto , Idoso , Biópsia por Agulha Fina , Biópsia com Agulha de Grande Calibre , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias do Sistema Digestório/patologia , Neoplasias do Sistema Digestório/cirurgia , Feminino , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Neoplasias do Íleo/cirurgia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
9.
Anesteziol Reanimatol ; 61: 228-232, 2017 Sep.
Artigo em Russo | MEDLINE | ID: mdl-29465210

RESUMO

The aim of this study was to determine the role remaxol in complex intensive therapy of various jorms gipoergosis dur- ing the perioperative period in patients with hepatopancreatoduodenal zone malignancies. The treatment of 48 patients was analyzed. Immediately prior to surgery, at random, patients were divided into primary (n = 26) and control group (n = 22). In the study group for compensation the energy deficient states and organ hypoxia in the pancreas and the liver during the intra- and postoperative periods remaxol was included in the infusion therapy, the introduction ofwhich had been began before the start of anesthesia. In the control group antihypoxants weren't used. Integral assessment of prognosis and severity on a scale SAPS II and APACHE II. Status of energy and the type of energy deficit was estimated by the transport of oxygen and the concentration of lactate. In order to determine the level of stress exposure and the for- mation of adaptive reactions examined quantitative and qualitative composition of the peripheral blood. The study was conducted prior to surgery, on the 2nd and 5th day perioperative period. Inclusion in the scheme of metabolic remaxol program in the perioperative period in patients with malignant diseases of hepatopancreatoduodenal zone promotes the reduction of different types ofgipoergosis, efficient delivery and oxygen consumption, the adequacy of tissue oxygenation and restoration of adaptive physiological reactions such as.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Neoplasias do Sistema Digestório/cirurgia , Metabolismo Energético/efeitos dos fármacos , Assistência Perioperatória/métodos , Succinatos/uso terapêutico , Adulto , Idoso , Neoplasias do Sistema Digestório/metabolismo , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Estudos Prospectivos , Método Simples-Cego , Succinatos/administração & dosagem , Resultado do Tratamento
10.
PLoS One ; 11(8): e0160547, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27518571

RESUMO

OBJECTIVE: There is a heated debate on whether the prognostic value of NME1 is favorable or unfavorable. Thus, we carried out a meta-analysis to evaluate the relationship between NME1 expression and the prognosis of patients with digestive system neoplasms. METHODS: We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled odd ratios (ORs) and corresponding 95%CI were calculated to evaluate the prognostic value of NME1 expression in patients with digestive system neoplasms, and the association between NME1 expression and clinicopathological factors. We also performed subgroup analyses to find out the source of heterogeneity. RESULTS: 2904 patients were pooled from 28 available studies in total. Neither the incorporative OR combined by 17 studies with overall survival (OR = 0.65, 95%CI:0.41-1.03, P = 0.07) nor the pooled OR with disease-free survival (OR = 0.75, 95%CI:0.17-3.36, P = 0.71) in statistics showed any significance. Although we couldn't find any significance in TNM stage (OR = 0.78, 95%CI:0.44-1.36, P = 0.38), elevated NME1 expression was related to well tumor differentiation (OR = 0.59, 95%CI:0.47-0.73, P<0.00001), negative N status (OR = 0.54, 95%CI:0.36-0.82, P = 0.003) and Dukes' stage (OR = 0.43, 95%CI:0.24-0.77, P = 0.004). And in the subgroup analyses, we only find the "years" which might be the source of heterogeneity of overall survival in gastric cancer. CONCLUSIONS: The results showed that statistically significant association was found between NME1 expression and the tumor differentiation, N status and Dukes' stage of patients with digestive system cancers, while no significance was found in overall survival, disease-free survival and TNM stage. More and further researches should be conducted to reveal the prognostic value of NME1.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Digestório/patologia , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Biomarcadores Tumorais/genética , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico
11.
Compr Physiol ; 6(3): 1221-37, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27347891

RESUMO

Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin [alpha]vß3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin [alpha]vß3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221-1237, 2016.


Assuntos
Apoptose/fisiologia , Neoplasias/metabolismo , Hormônios Tireóideos/fisiologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias/patologia , Receptores dos Hormônios Tireóideos/fisiologia , Transdução de Sinais/fisiologia
12.
Mol Cancer Ther ; 15(7): 1614-26, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27196767

RESUMO

Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Cetuximab/farmacologia , Neoplasias do Sistema Digestório/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Sistema Digestório/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Expressão Gênica , Humanos , Camundongos , Receptores Proteína Tirosina Quinases/genética , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo
13.
Am Surg ; 82(4): 369-75, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27097632

RESUMO

This case series demonstrates the potential of molecular profiling to improve selection of antitumor therapies in the treatment of patients with neuroendocrine and carcinoid tumors. Carcinoid tumors resected at one institution over a 3-year period were sent for molecular profiling to guide choice of treatment. Potentially beneficial therapies were identified based on the measured expression of 20 proteins and oncogenes and a comprehensive review of the chemotherapy response literature. The clinical charts of 41 patients were reviewed retrospectively, and 12 were selected as representatives of the range of effects molecular profiling has on carcinoid treatment. Their presentation, molecular profile results, treatment, and disease progression is reviewed in the following case series. A total of nine patients were treated with drugs identified as potentially beneficial by molecular profile reports. These include capecitabine, 5-fluorouracil, temozolomide, oxaliplatin, and gemcitabine. Based on clinical symptoms, serum markers of disease, and radiographic evidence five of nine patients responded to treatment, two had mixed responses, and two did not respond to treatment. At this early juncture, our critique of molecular profiling for neuroendocrine tumors is favorable, as a significant number of our patients responded to drugs identified by molecular profiling as potentially beneficial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Tomada de Decisão Clínica/métodos , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/genética , Tumor Carcinoide/metabolismo , Tumor Carcinoide/cirurgia , Quimioterapia Adjuvante , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/cirurgia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
14.
Clin Epigenetics ; 8: 33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27019673

RESUMO

BACKGROUND: An abundant class of intronic microRNAs (miRNAs) undergoes atypical Drosha-independent biogenesis in which the spliceosome governs the excision of hairpin miRNA precursors, called mirtrons. Although nearly 500 splicing-dependent miRNA candidates have been recently predicted via bioinformatic analysis of human RNA-Seq datasets, only a few of them have been experimentally validated. The detailed mechanism of miRNA processing by the splicing machinery and the roles of mirtronic miRNAs in cancer are yet to be uncovered. METHODS: We experimentally examined whether biogenesis of certain miRNAs is under a splicing control by analyzing their expression levels in response to alterations in the 5'- and 3'-splice sites of a series of intron-containing minigenes carrying appropriate miRNAs. The expression levels of the miRNAs processed from mirtrons were determined by quantitative real-time PCR in five digestive tract (pancreas PANC-1, SU.86.86, T3M4, stomach KATOIII, colon HCT116) and two excretory system (kidney CaKi-1, 786-O) carcinoma cell lines as well as in pancreatic, stomach, and colorectal tumors. Transiently expressed SRSF1 and SRSF2 splicing factors were quantified by western blotting in the nuclear fractions of HCT116 cells. RESULTS: We found that biogenesis of the human hsa-miR-1227-3p, hsa-miR-1229-3p, and hsa-miR-1236-3p is splicing-dependent; therefore, these miRNAs can be assigned to the class of miRNAs processed by a non-canonical mirtron pathway. The expression analysis revealed a differential regulation of human mirtronic miRNAs in various cancer cell lines and tumors. In particular, hsa-miR-1229-3p is selectively upregulated in the pancreatic and stomach cancer cell lines derived from metastatic sites. Compared with the healthy controls, the expression of hsa-miR-1226-3p was significantly higher in stomach tumors but extensively downregulated in colorectal tumors. Furthermore, we provided evidence that overexpression of SRSF1 or SRSF2 can upregulate the processing of individual mirtronic miRNAs in HCT116 cells. CONCLUSIONS: An interplay of different splicing factors, such as SRSF1 or SRSF2, may alter the levels of miRNAs of mirtron origin in a cell. Our findings underline the specific expression profiles of mirtronic miRNAs in colorectal, stomach, and pancreatic cancer.


Assuntos
Neoplasias do Sistema Digestório/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Renais/genética , MicroRNAs/genética , Fatores de Processamento de RNA/metabolismo , Processamento de RNA , Linhagem Celular Tumoral , Neoplasias do Sistema Digestório/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Neoplasias Renais/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo
16.
Oncotarget ; 7(19): 28736-47, 2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-26908460

RESUMO

Purinergic signaling is important for many biological processes in humans. Purinoceptors P2Y are widely distributed in human digestive system and different subtypes of P2Y receptors mediate different physiological functions from metabolism, proliferation, differentiation to apoptosis etc. The P2Y receptors are essential in many gastrointestinal functions and also involve in the occurrence of some digestive diseases. Since different subtypes of P2Y receptors are present on the same cell of digestive organs, varying subtypes of P2Y receptors may have opposite or synergetic functions on the same cell. Recently, growing lines of evidence strongly suggest the involvement of P2Y receptors in the pathogenesis of several digestive diseases. In this review, we will focus on their important roles in the development of digestive inflammation and cancer. We anticipate that as the special subtypes of P2Y receptors are studied in depth, specific modulators for them will have good potentials to become promising new drugs to treat human digestive diseases in the near future.


Assuntos
Apoptose , Proliferação de Células , Neoplasias do Sistema Digestório/fisiopatologia , Inflamação/fisiopatologia , Receptores Purinérgicos P2Y/fisiologia , Animais , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Progressão da Doença , Humanos , Inflamação/metabolismo , Inflamação/patologia , Modelos Biológicos , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , Receptores Purinérgicos P2Y/classificação , Receptores Purinérgicos P2Y/metabolismo
17.
Cancer Biomark ; 16(1): 71-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26835707

RESUMO

BACKGROUND: The Hedgehog (Hh) signaling pathway has recently been reported to be associated with the prognosis of digestive system cancers. However, the results are inconsistent. OBJECTIVE: This study aimed to investigate the association between Hh pathway components and survival outcomes in patients with digestive system cancers. METHODS: We conducted a comprehensive retrieval in PubMed, EMBASE and Cochrane library for relevant literatures until May 1st, 2015. The pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) with 95% confidence intervals (CIs) were calculated to clarify the prognostic value of Hh pathway components, including Shh, Gli1, Gli2, Smo and Ptch1. RESULTS: A total of 16 eligible articles with 3222 patients were included in the meta-analysis. Pooled HR suggested that over-expression of Shh and Gli1 were both associated with poor OS (HR = 1.87, 95% CI: 1.14-3.07 and HR = 1.96, 95% CI: 1.66-2.32, respectively) and DFS (HR = 2.37, 95% CI: 1.19-4.72 and HR = 2.18, 95% CI: 1.61-2.96, respectively). In addition, over-expression of Smo was associated with poor DFS (HR = 1.38, 95% CI: 1.08-1.75). CONCLUSIONS: This study reveals that over-expressed Hh pathway components, including Shh, Gli1 and Smo, are associated with poor prognosis in digestive system cancer patients. Hh signaling pathway may become a potential therapeutic target in digestive system cancers.


Assuntos
Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/mortalidade , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Biomarcadores , Neoplasias do Sistema Digestório/genética , Expressão Gênica , Proteínas Hedgehog/genética , Humanos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Prognóstico , Viés de Publicação , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Receptor Smoothened , Transativadores/genética , Transativadores/metabolismo , Proteína GLI1 em Dedos de Zinco
18.
Cell Metab ; 23(1): 48-62, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26771116

RESUMO

Although discussion of the obesity epidemic had become a cocktail party cliché, its impact on public health cannot be dismissed. In the past decade, cancer had joined the list of chronic debilitating diseases whose risk is substantially increased by hypernutrition. Here we discuss recent advances in understanding how obesity increases cancer risk and propose a unifying hypothesis according to which the major tumor-promoting mechanism triggered by hypernutrition is the indolent inflammation that takes place at particular organ sites, including liver, pancreas, and gastrointestinal tract. The mechanisms by which excessive fat deposition feeds this tumor-promoting inflammatory flame are diverse and tissue specific.


Assuntos
Neoplasias do Sistema Digestório/etiologia , Obesidade/complicações , Animais , Transformação Celular Neoplásica/imunologia , Neoplasias do Sistema Digestório/imunologia , Neoplasias do Sistema Digestório/metabolismo , Predisposição Genética para Doença , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Obesidade/imunologia , Obesidade/metabolismo , Especificidade de Órgãos , Fatores de Risco
19.
World J Gastroenterol ; 22(3): 906-16, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26811636

RESUMO

Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Digestório/tratamento farmacológico , Difosfonatos/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Difosfonatos/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
20.
Rom J Intern Med ; 53(3): 199-208, 2015 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26710495

RESUMO

Angiogenesis is a crucial event for tumor growth and it is regulated predominantly by several different growth factors. Vascular endothelial growth factor protein family (VEGF) and its receptors are probably the most important tissue factors responsible for angioblast differentiation and tube formation. VEGF protein family currently comprises several members: VEGF (or VEGF-A), VEGF-B, VEGF-C and VEGF-D, VEGF-F, placental growth factor (PlGF), and their receptors VEGFR-1, VEGFR-2 and VEGFR-3. VEGF is a key angiogenic growth factor and its level of expression is a critical marker for detection of the angiogenic diseases. The potent role of VEGF in tumor angiogenesis has been widely described in the past decade, being expressed in most types of nondigestive and digestive cancers. VEGF family members play an important role in the development of pancreatic cancer (especially VEGF-A, VEGF-C, VEGF-D, VEGFR-1 and VEGFR-2). VEGF-A is the most specific and prominent angiogenic factor among all family members and VEGFR-2 is the most important receptor in evaluating the angiogenesis in pancreatic cancer. Thus, VEGF overexpression may be considered as a diagnostic marker and as a poor prognostic factor of the disease.


Assuntos
Neoplasias do Sistema Digestório/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias do Sistema Digestório/genética , Neoplasias do Sistema Digestório/patologia , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/genética
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