RESUMEN
Objective: This investigation sought to delineate the associations among colorectal adenomatous polyps, diabetes, and biomolecules involved in glucose metabolism. Method: Data were collected from 40 patients who underwent endoscopic polypectomy at the Endoscopy Department of Shandong Cancer Hospital between June 2019 and September 2021. This cohort included 27 patients with inflammatory polyps and 13 with adenomatous polyps. We assessed fasting insulin (Fins), fasting blood glucose (FBG), and the mRNA expressions of fibroblast growth factor 19 (FGF-19) and insulin-like growth factor 1 (IGF-1) in the polyp tissues. Both univariate and multivariate logistic regression analyses were employed to ascertain the determinants influencing the emergence of adenomatous polyps. From these analyses, a predictive nomogram was constructed to forecast the occurrence of adenomatous polyps, and evaluations on the discriminative capacity, calibration, and clinical utility of the model were conducted. Results: The adenomatous polyp group exhibited markedly elevated levels of glucose, insulin, FGF-19, and IGF-1, with respective concentrations of (8.67±2.70) mmol/L, (12.72±7.69) µU/L, 2.20±1.88, and 1.36±0.69. These figures were significantly higher compared to the inflammatory polyp group, which showed levels of (5.51±0.72) mmol/L, (5.49±2.68) µU/L, 0.53±0.97, and 0.41±0.46, respectively, P=0.001. Multivariate logistic regression revealed that the relative expression of IGF-1 served as an independent risk factor for the development of colorectal adenomatous polyps (OR=5.622, 95% CI:1.085-29.126). The nomogram displayed a C-index of 0.849, indicating substantial discriminative capability. The calibration curve affirmed the model's accuracy in aligning predicted probabilities with actual outcomes, and the clinical decision curve demonstrated thepractical clinical applicability of the model. Conclusions: There was a significant correlation between the occurrence of colorectal adenomatous polyps and glucose metabolic pathways. Individuals with diabetes showed a higher propensity to develop such polyps.
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Pólipos Adenomatosos , Glucemia , Neoplasias Colorrectales , Factores de Crecimiento de Fibroblastos , Factor I del Crecimiento Similar a la Insulina , Insulina , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Colorrectales/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Glucemia/metabolismo , Insulina/metabolismo , Pólipos Adenomatosos/metabolismo , Pólipos del Colon/metabolismo , Masculino , Femenino , Adenoma/metabolismo , Persona de Mediana Edad , Modelos Logísticos , Nomogramas , Péptidos Similares a la InsulinaRESUMEN
Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of ß-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00; p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73; 95% CI: 0.50-1.08; p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.
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Pólipos Adenomatosos/prevención & control , Antocianinas/farmacología , Neoplasias Colorrectales/prevención & control , Curcumina/farmacología , Suplementos Dietéticos , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Antígeno Ki-67/genética , Masculino , Persona de Mediana Edad , FN-kappa B/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Complex interrelationships govern the dynamic interactions between gut microbes, the host, and exogenous drivers of disease outcome. A multi-omics approach to cancer prevention by spinach (SPI) was pursued for the first time in the polyposis in rat colon (Pirc) model. SPI fed for 26 weeks (10% w/w, freeze-dried in the diet) exhibited significant antitumor efficacy and, in the Apc-mutant genetic background, ß-catenin remained highly overexpressed in adenomatous polyps. However, in both wild type and Apc-mutant rats, increased gut microbiome diversity after SPI consumption coincided with reversal of taxonomic composition. Metagenomic prediction implicated linoleate and butanoate metabolism, tricarboxylic acid cycle, and pathways in cancer, which was supported by transcriptomic and metabolomic analyses. Thus, tumor suppression by SPI involved marked reshaping of the gut microbiome along with changes in host RNA-miRNA networks. When colon polyps were compared with matched normal-looking tissues via metabolomics, anticancer outcomes were linked to SPI-derived linoleate bioactives with known anti-inflammatory/ proapoptotic mechanisms, as well as N-aceto-2-hydroxybutanoate, consistent with altered butanoate metabolism stemming from increased α-diversity of the gut microbiome. In colon tumors from SPI-fed rats, L-glutamate and N-acetylneuraminate also were reduced, implicating altered mitochondrial energetics and cell surface glycans involved in oncogenic signaling networks and immune evasion. In conclusion, a multi-omics approach to cancer prevention by SPI provided mechanistic support for linoleate and butanoate metabolism, as well as tumor-associated changes in L-glutamate and N-acetylneuraminate. Additional factors, such as the fiber content, also warrant further investigation with a view to delaying colectomy and drug intervention in at-risk patients.
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Proteína de la Poliposis Adenomatosa del Colon/genética , Pólipos Adenomatosos/metabolismo , Neoplasias del Colon/dietoterapia , Microbioma Gastrointestinal/fisiología , Spinacia oleracea , Animales , Ácido Butírico/metabolismo , Ciclo del Ácido Cítrico/fisiología , Neoplasias del Colon/patología , Dieta , Ácido Glutámico/metabolismo , Ácido Linoleico/metabolismo , Masculino , Mitocondrias/metabolismo , Ácidos Neuramínicos/metabolismo , Ratas , Ratas Endogámicas F344 , VerdurasRESUMEN
Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.
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Carcinoma/prevención & control , Transformación Celular Neoplásica , Neoplasias del Colon/prevención & control , Pólipos del Colon/terapia , Terapia Molecular Dirigida/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/prevención & control , Adenoma/genética , Adenoma/metabolismo , Adenoma/patología , Adenoma/prevención & control , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Pólipos Adenomatosos/prevención & control , Antineoplásicos/uso terapéutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Pólipos del Colon/genética , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/fisiología , Genes de Cambio/efectos de los fármacos , Humanos , Mapas de Interacción de Proteínas/efectos de los fármacos , Mapas de Interacción de Proteínas/genética , Proteómica , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Studies have found a positive association between metabolic risk factors, such as obesity and diabetes, and adenomatous polyps (AP). However, fewer studies have assessed the association between sessile serrated polyps (SSP) or synchronous diagnosis of APs and SSPs (synch polyps). Study participants (N = 1,370; ages 40-85) undergoing screening colonoscopy were enrolled between August 2016 and February 2020. Self-reported metabolic risk factors, including diabetes, hypertension, hyperlipidemia, and overweight/obesity, were evaluated for associations with new diagnoses of APs, SSPs, and synch polyps at the present colonoscopy. Average participant age was 60.73 ± 8.63 (SD) years; 56.7% were female and 90.9% white. In an assessment of individual metabolic risk factors, adjusted for age, sex, race, and smoking status, increased body mass index (BMI; overweight or obese vs. normal BMI of <25 kg/m2) was associated with an increased odds for new onset of colon APs (P trend < 0.001) as was a diagnosis of diabetes [adjusted conditional OR (aCOR) = 1.59 (1.10-2.29)]. No associations were seen between the metabolic risk factors and onset of SSPs. Being obese or hypertensive each increased the odds of new onset of synch polyps with aCOR values of 2.09 (1.01-4.32) and 1.79 (1.06-3.02), respectively. Self-reported risk factors may help assess polyp type risk. Because SSPs and synch polyps are rare, larger studies are needed to improve our understanding of the contribution of these factors to polyp risk. These data lead us to hypothesize that differences in observed metabolic risk factors between polyp types reflect select metabolic impact on pathways to colorectal cancer. PREVENTION RELEVANCE: Self-reported medical history provides valuable insight into polyp risk, potentially enabling the use of larger retrospective studies of colonoscopy populations to assess knowledge gaps. More aggressive colonoscopy screening, critical to colorectal cancer prevention, may be considered in populations of individuals with metabolic risk factors and modifiable lifestyle risk factors.
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Pólipos Adenomatosos/epidemiología , Pólipos del Colon/epidemiología , Neoplasias Colorrectales/prevención & control , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Adulto , Anciano , Anciano de 80 o más Años , Pólipos del Colon/diagnóstico , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Colonoscopía , Neoplasias Colorrectales/patología , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Femenino , Humanos , Hiperlipidemias/epidemiología , Hiperlipidemias/metabolismo , Hipertensión/epidemiología , Hipertensión/metabolismo , Masculino , Anamnesis/estadística & datos numéricos , Persona de Mediana Edad , Obesidad/epidemiología , Obesidad/metabolismo , Estudios Prospectivos , Factores de Riesgo , Autoinforme/estadística & datos numéricosAsunto(s)
Pólipos Adenomatosos , Hematopoyesis Extramedular , Trastornos Mieloproliferativos , Neoplasias Gástricas , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Pólipos Adenomatosos/fisiopatología , Anciano , Femenino , Humanos , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Trastornos Mieloproliferativos/fisiopatología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/fisiopatologíaRESUMEN
AIMS: Helicobacter pylori (Hp) infection plays an important role in the development of gastric cancer. Hp can secrete gamma-glutamyltransferase (GGT), however, the impact of GGT of Hp on the human gastric cells is not clear. Although it has been demonstrated that ten-eleven translocation 1 (TET1) is overexpressed in gastric cancer, the relationship between the GGT of Hp and TET1 has not been studied. The aim of this study was to explore the relationship between GGT and TET1, and the role of TET1 in the development of gastric cancer induced by Hp was also explored. MATERIALS AND METHODS: The correlation between TET1 and prognosis of gastric adenoma cancer was analyzed by bioinformatics. The GGT gene of Hp26695 was knocked out by electroporation with plasmid to construct the GGT knockout strain of Hp (Hp-KS-1). The shTET1 lentivirus transfected GES-1, MGC-803 and SGC-7901 cell lines were constructed. The biological characteristics of the three kind of cells were detected. KEY FINDINGS: TET1 was overexpressed in gastric tissues of Hp infected patients and mice. Bioinformatics analysis showed that in patients with gastric cancer, higher TET1 expression would result in poorer prognosis. The GGT gene of Hp can lead to overexpression of TET1 in GES-1, MGC-803 and SGC-7901 cells, along with the activation of Wnt/ß-catenin signaling pathway, and then promoting tumorigenesis. After silencing TET1, the Wnt/ß-catenin signaling pathway which was activated by GGT of Hp was inhibited. SIGNIFICANCE: GGT of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt/ß-catenin signaling pathway trough up-regulating TET1.
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Infecciones por Helicobacter/microbiología , Helicobacter pylori/enzimología , Helicobacter pylori/genética , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Gástricas/microbiología , Vía de Señalización Wnt , gamma-Glutamiltransferasa/genética , Pólipos Adenomatosos/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transformación Celular Neoplásica , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Helicobacter pylori/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Gástricas/metabolismo , Activación Transcripcional , beta Catenina/metabolismo , gamma-Glutamiltransferasa/metabolismoRESUMEN
PURPOSE: IGF-1Ec is an isoform of Insulin-like growth factor 1 (IGF-1) and has recently been identified to be overexpressed in cancers including prostate and neuroendocrine tumours. The aim of this paper is to investigate the expression of IGF-1Ec in colorectal cancer and polyps compared to normal colon tissues and its association with recurrent disease using semi-quantitative immunohistochemistry. METHODS: Immunohistochemistry for IGF-1Ec expression was performed for colorectal cancer, colorectal polyps and normal colonic tissues. The quantification of IGF-1Ec expression was performed with the use of Image J software and the IHC profiler plugin. Following ethics approval from the National Research Ethics Service (Reference 11/LO/1521), clinical information including recurrent disease on follow-up was collected for patients with colorectal cancer. RESULTS: Immunohistochemistry was performed in 16 patients with colorectal cancer and 11 patients with colonic polyps and compared to normal colon tissues and prostate adenocarcinoma (positive control) tissues. Significantly increased expression of IGF-1Ec was demonstrated in colorectal cancer (p < 0.001) and colorectal polyps (p < 0.05) compared to normal colonic tissues. Colonic adenomas with high-grade dysplasia had significantly higher expression of IGF-1Ec compared to low-grade dysplastic adenomas (p < 0.001). Colorectal cancers without lymph node metastases at the time of presentation had significantly higher IGF-1Ec expression compared to lymph node-positive disease (p < 0.05). No correlation with recurrent disease was identified with IGF-1Ec expression. CONCLUSION: IGF-1Ec is significantly overexpressed in colorectal cancer and polyps compared to normal colon tissues offering a potential target to improve colonoscopic identification of colorectal polyps and cancer and intraoperative identification of colorectal tumours.
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Pólipos Adenomatosos/diagnóstico , Pólipos del Colon/diagnóstico , Neoplasias Colorrectales/diagnóstico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunohistoquímica/métodos , Factor I del Crecimiento Similar a la Insulina/análisis , MasculinoRESUMEN
BACKGROUND AND AIMS: The importance of sessile serrated lesions (SSLs) in the pathogenesis of colorectal carcinoma has been recently established. These are supposed to cause the so-called "interval cancer", having a rapidly progressive growth and being difficult to detect and to obtain an endoscopic complete resection. We aimed to establish the most important metabolic risk factors for sessile serrated lesions. METHODS: We performed a retrospective case-control study, on a series of 2918 consecutive patients who underwent colonoscopy in Gastroenterology and Endoscopy Unit, County Clinical Emergency Hospital, Târgu-MureÈ, Romania between 1 st of January 2015-31 th of December 2017. In order to evaluate the metabolic risk factors for polyps' development, enrolled participants were stratified in two groups, a study group, 33 patients with SSLs lesions, and a control group, 138 patients with adenomatous polyps, selected by systematic sampling for age and anatomical site. Independent variables investigated were: gender, smoking, alcohol consumption, obesity, arterial hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, hyperuricemia, nonalcoholic liver disease. RESULTS: For SSLs the most common encountered localization was the right colon in 30.55% of cases. By comparative bivariate analysis between SSLs group and control group, it was observed that hypertension (p=0.03, OR 2.33, 95 %CI 1.03-5.24), obesity (p=0.03, OR 2.61, 95 %CI 1.08-6.30), hyperuricemia (p=0.04, OR 2.72, 95 %CI 1.28-7.55), high cholesterol (p=0.002, OR 3.42; 95 %CI 1.48-7.87), and high triglycerides level (p=0.0006, OR 5.75; 95 %CI 1.92-17.2) were statistically associated with SSLs development. By multivariate analysis hypertension and hypertriglyceridemia retained statistical significance. CONCLUSIONS: Our study showed that the highest prevalence of SSLs was in the right colon and hypertension and increased triglycerides levels were associated with the risk of SSLs development. These risk factors are easy to detect in clinical practice and may help identifying groups with high risk for colorectal cancer, where screening is recommended.
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Pólipos Adenomatosos , Carcinogénesis/metabolismo , Colon Ascendente/patología , Pólipos del Colon , Neoplasias Colorrectales/diagnóstico , Hipertensión/epidemiología , Hipertrigliceridemia/metabolismo , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/epidemiología , Pólipos Adenomatosos/metabolismo , Estudios de Casos y Controles , Pólipos del Colon/diagnóstico , Pólipos del Colon/epidemiología , Pólipos del Colon/metabolismo , Colonoscopía/métodos , Colonoscopía/estadística & datos numéricos , Correlación de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Factores de Riesgo , Rumanía/epidemiologíaRESUMEN
ApcMin/+ mice are regarded as a standard animal model of colorectal cancer (CRC). Tensin4 (TNS4 or Cten) is a putative oncogene conferring features of stemness and promoting motility. Our objective was to assess TNS4 expression in intestinal adenomas and determine whether TNS4 is upregulated by Wnt signalling. ApcMin/+ mice (n = 11) were sacrificed at approximately 120 days old at the onset of anaemia signs. Small intestines were harvested, and Swiss roll preparations were tested for TNS4 expression by immunohistochemistry (IHC). Individual polyps were also separately collected (n = 14) and tested for TNS4 mRNA expression and Kras mutation. The relationship between Wnt signalling and TNS4 expression was tested by Western blotting in the human CRC cell line HCT116 after inhibition of ß-catenin activity with MSAB or its increase by transfection with a Flag ß-catenin expression vector. Overall, 135/148 (91.2%) of the total intestinal polyps were positive for TNS4 expression by IHC, whilst adjacent normal areas were negative. RT-qPCR analysis showed approximately 5-fold upregulation of TNS4 mRNA in the polyps compared to adjacent normal tissue and no Kras mutations were detected. In HCT116, ß-catenin inhibition resulted in reduced TNS4 expression, and conversely, ß-catenin overexpression resulted in increased TNS4 expression. In conclusion, this is the first report linking aberrant Wnt signalling to upregulation of TNS4 both during initiation of intestinal adenomas in mice and in in vitro models. The exact contribution of TNS4 to adenoma development remains to be investigated, but the ApcMin/+ mouse represents a good model to study this.
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Pólipos Adenomatosos/metabolismo , Genes APC , Neoplasias Intestinales/metabolismo , Intestino Delgado/metabolismo , Tensinas/metabolismo , Vía de Señalización Wnt , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patología , Animales , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Intestino Delgado/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Tensinas/genética , Regulación hacia Arriba , beta Catenina/metabolismoRESUMEN
OBJECTIVES: Conventional colonoscopy with white light illumination detects colonic adenomas based on structural changes alone and is limited by a high miss rate. We aim to demonstrate an integrated imaging strategy that combines wide-field endoscopy and confocal endomicroscopy in real time to visualize molecular expression patterns in vivo to detect premalignant colonic mucosa. METHODS: A peptide specific for claudin-1 is labeled with Cy5.5 and administrated intravenously in genetically engineered mice that develop adenomas spontaneously in the distal colon. Wide-field endoscopy is used to identify the presence of nonpolypoid and polypoid adenomas. Anatomic landmarks are used to guide placement of a confocal endomicroscope with side-view optics to visualize claudin-1 expression patterns with subcellular resolution. RESULTS: Wide-field fluorescence images show peak uptake in colon adenoma at â¼1 hour after systemic peptide administration, and lesion margins are clearly defined. Further examination of the lesion using a confocal endomicroscope shows dysplastic crypts with large size, elongated shape, distorted architecture, and variable dimension compared with normal. The mean fluorescence intensity is significantly higher for dysplasia than normal. Increased claudin-1 expression in dysplasia vs normal is confirmed ex vivo, and the binding pattern is consistent with the in vivo imaging results. DISCUSSION: Wide-field endoscopy can visualize molecular expression of claudin-1 in vivo to localize premalignant colonic mucosa, and confocal endomicroscopy can identify subcellular feature to distinguish dysplasia from normal.
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Adenoma/metabolismo , Claudina-1/metabolismo , Pólipos del Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Adenoma/diagnóstico , Adenoma/genética , Adenoma/patología , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Animales , Animales Modificados Genéticamente , Carbocianinas , Claudina-1/genética , Pólipos del Colon/diagnóstico , Pólipos del Colon/genética , Pólipos del Colon/patología , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Técnica del Anticuerpo Fluorescente , Colorantes Fluorescentes , Genes APC , Inmunohistoquímica , Ratones , Microscopía Confocal , Péptidos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Approximately 15% to 20% of colorectal cancers are developed through the serrated pathway of tumorigenesis, which is associated with BRAF mutation, CpG island methylation phenotype, and MLH1 methylation. However, the detailed process of progression from sessile serrated adenoma (SSA) to dysplasia and carcinoma has not been elucidated. To further characterize mechanisms involved in the dysplastic progression of SSA, we investigated differential expressions of mRNAs between areas with and without dysplasia within the same SSA polyps. Significantly dysregulated genes in paired samples were applied for functional annotation and biological significance. The same lysates from a subset of matched samples were subjected for miRNA expression profiling. Differentially expressed miRNAs were determined, and their targeted mRNAs were compared in parallel to the list of differentially expressed mRNAs from an RNA sequencing study. Fourteen common mRNA targets were identified, which include AXIN2, a known indicator of WNT/ß-catenin pathway activation. Together, in this study, different genes, pathways, and biological processes involved in the initiation and progression of dysplasia in the serrated pathway are documented. One of the most significant findings is the involvement of the WNT/ß-catenin pathway in the dysplastic progression of SSAs with different genes being targeted in early versus advanced dysplasia.
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Adenoma/patología , Pólipos Adenomatosos/patología , Mutación , Vía de Señalización Wnt , Adenoma/genética , Adenoma/metabolismo , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Anciano , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , MasculinoRESUMEN
BACKGROUND: Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs. METHODS: Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis. FINDINGS: ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1â¯cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression. INTERPRETATION: ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs.
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Adenocarcinoma/metabolismo , Pólipos Adenomatosos/metabolismo , Neoplasias Colorrectales/metabolismo , Metabolismo Energético , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/genética , Adenocarcinoma/patología , Pólipos Adenomatosos/diagnóstico por imagen , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patología , Anciano , Anciano de 80 o más Años , Biomarcadores , Línea Celular Tumoral , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , ADN Mitocondrial , Femenino , Fluorodesoxiglucosa F18 , Humanos , Mucosa Intestinal , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Mutación , Estadificación de Neoplasias , Fosforilación Oxidativa , Consumo de Oxígeno , Tomografía Computarizada por Tomografía de Emisión de Positrones , Carga TumoralRESUMEN
AIMS: Dysplasia in colonic sessile serrated adenomas (SSAs)/sessile serrated polyps often shows loss of MLH1 expression as determined with immunohistochemistry, but the significance of loss of MLH1 expression in non-dysplastic crypts in these polyps is less well studied. The purpose of this study was to evaluate the prevalence of loss of MLH1 expression in non-dysplastic crypts in SSAs, and to evaluate its significance with regard to progression of these polyps. METHODS AND RESULTS: Four hundred SSAs, including 158 SSAs without dysplasia, 219 SSAs with dysplasia (SSAD), and 23 SSAs with invasive adenocarcinoma (SSAC), were evaluated immunohistochemically for loss of MLH1 expression in both non-dysplastic and dysplastic portions of the polyps. Seventy-one of 400 (18%) SSAs showed loss of MLH1 expression in non-dysplastic crypts. The prevalence of MLH1-deficient non-dysplastic crypts was higher in polyps with dysplasia or carcinoma (7%, 22%, and 52% in SSAs, SSADs, and SSACs, respectively; P < 0.0001). When SSAs with MLH1-deficient dysplasia and those with MLH-1-proficient dysplasia were compared, those with MLH1-deficient dysplasia were more likely to have MLH1-deficient non-dysplastic crypts (66% versus 8.1%, P < 0.0001) and a greater number of discrete foci (3.6 foci versus 1.1 foci, P = 0.008). Also, non-dysplastic crypts with loss of MLH1 expression were more likely to be contiguous with the dysplasia when the dysplasia also showed loss of MLH1 expression (26% versus 0%, P = 0.02). CONCLUSIONS: Our results suggest that loss of MLH1 expression in non-dysplastic crypts in SSAs precedes the development of MLH1-deficient dysplasia and adenocarcinoma, and may be a biomarker of an advanced serrated polyp even in the absence of dysplasia.
Asunto(s)
Pólipos Adenomatosos/patología , Neoplasias del Colon/patología , Pólipos del Colon/patología , Homólogo 1 de la Proteína MutL/biosíntesis , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Pólipos Adenomatosos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias del Colon/metabolismo , Pólipos del Colon/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS: Sessile serrated lesions (SSL) with dysplasia are uncommon polyps with a high risk of rapid malignant transformation. Most of these lesions have a BRAF mutation and 75% show loss of MLH1 expression in their dysplastic component. Different morphological patterns of dysplasia occurring in these polyps have recently been described. We hypothesised that a subset of SSLs with dysplasia mimicking the dysplasia seen in conventional adenoma (adenomatous dysplasia) may represent a collision lesion between an ordinary SSL and a conventional adenoma. METHODS AND RESULTS: We selected 80 SSLs with dysplasia, including 19 with adenomatous dysplasia, 18 with serrated dysplasia and 43 with dysplasia not otherwise specified (NOS). BRAF mutation analysis was performed using molecular testing (allelic discrimination) and the mutation-specific BRAF-V600E immunohistochemistry (clone VE1). The overall BRAF-V600E mutation rate was 84% in all lesions, 68% in SSLs with adenomatous dysplasia, 89% in SSLs with serrated dysplasia and 88% in SSLs with dysplasia NOS. From the 63 SSLs with dysplasia that were positive for the BRAF-V600E mutation, a negative BRAF-V600E immunostaining was observed in the dysplastic component of 83% of SSLs with adenomatous dysplasia, 0% of SSLs with serrated dysplasia and 3% of SSLs with dysplasia NOS (P < 0.001). CONCLUSIONS: These findings suggest that SSLs with adenomatous dysplasia may not represent advanced SSLs, but instead may be a collision between a non-dysplastic SSL and a conventional adenoma.
Asunto(s)
Adenoma/genética , Adenoma/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Pólipos Intestinales/genética , Pólipos Intestinales/patología , Proteínas Mutantes/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adenoma/metabolismo , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Pólipos Intestinales/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Mutantes/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Invasive colonoscopy is the gold standard for patients at risk for colorectal cancer. However, the need for non-invasive and specific markers is required. OBJECTIVE: To evaluate the sensitivity of the glycolytic pyruvate kinase isoenzyme type M2 dimer (M2PK) as a diagnostic biomarker for colorectal cancer (CRC) and adenomatous colorectal polyps (CRP) screening. DESIGN: Case-control. PATIENTS: Twenty patients with CRC, 20 patients with CRP (lack criteria for colonic cancer by biopsy), and 20 normal subjects. OUTCOME: Complete blood count (CBC), erythrocyte sedimentation rate (ESR), tumor markers: carcino embryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), fecal occult blood test (FOBT), and fecal M2PK. Pelvic and abdominal ultrasound (US), colonoscopy, and a histopathological examination. RESULTS: Only weight loss and cachexia were significantly associated with CRC than CRP or control groups. M2PK was the most sensitive and specific test in differentiating CRC from CRP and the control subjects (sensitivity = 75%, specificity = 100%). LIMITATIONS: (1) The selection of cases for three well-matched groups, as to perform colonoscopy in well-prepared cases and conditions. (2) Replicates in more than 20 cases for confirmation at the expense of enrolling new patients. (3) The cost associated with tumor markers analysis. CONCLUSION: Fecal M2PK can be used as a precolonoscopy screening test for CRC patients, and is superior to other tumor markers, and in indicating the progress of colorectal adenomas > 1 cm. Thus being cost-effective and easy-to-perform test, it is a feasible tool to preselect patients who require colonoscopy.
Asunto(s)
Pólipos Adenomatosos/diagnóstico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Heces/enzimología , Piruvato Quinasa/metabolismo , Pólipos Adenomatosos/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Colonoscopía , Neoplasias Colorrectales/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Sangre Oculta , Pronóstico , Curva ROCRESUMEN
Colorectal cancer (CRC) placed among the most common neoplasm. Survivin is a member of the inhibitor apoptosis gene family. This gene could be associated with aggressive behavior in numerous types of cancers. The aim of the present study was to evaluate the immunohistochemical expression of survivin gene and its correlation with -31G/C polymorphism in CRC patients. This case-control study was performed on 90 cases: 30 adenocarcinoma, 30 adenomatous polyp, and 30 normal colon. Immunohistochemical expression of survivin evaluated on formalin-fixed paraffin-embedded tissue and -31G/C polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. Results showed that the subjects carrying C/C genotype with 43.3% (p = 0.002' OR = 12.188, CI = 2.530-58.720) and G/C genotype with 43.3% (p = 0.032' OR = 4.432, CI = 1.133-17.341) significantly had increased risk of CRC compared with subjects carrying GG genotype. Allelic frequencies showed statistically significant difference (p = 0.001) among adenocarcinoma (G = 35%, C = 65%), adenomatous (G = 43.3, C = 56.7), and normal group (G = 68.3, C = 31.7). Immunohistological evaluation showed nuclear survivin protein expression in patients with the CC genotype higher than in patient with the GG and GC genotypes (p = 0.002). The results suggest that C allele of - 31G/C polymorphism in survivin might be cooperative in CRC development.
Asunto(s)
Adenocarcinoma/genética , Pólipos Adenomatosos/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Survivin/genética , Adenocarcinoma/metabolismo , Pólipos Adenomatosos/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Survivin/biosíntesisRESUMEN
The trans-sulfuration enzyme cystathionine-ß-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-κB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/- ) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis. Cancer Res; 77(21); 5741-54. ©2017 AACR.
Asunto(s)
Pólipos Adenomatosos/genética , Colon/metabolismo , Cistationina betasintasa/genética , Mucosa Intestinal/metabolismo , Regulación hacia Arriba , Pólipos Adenomatosos/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Línea Celular , Movimiento Celular/genética , Colon/patología , Cistationina betasintasa/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Sulfuro de Hidrógeno/metabolismo , Mucosa Intestinal/patología , Masculino , Metabolómica/métodos , Ratones Noqueados , Ratones Desnudos , Trasplante HeterólogoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is one of the more intensively studied human malignancies. For many years, the general view has been that the vast majority of CRCs in humans evolve from conventional (tubular or villous) adenomas via the adenoma-carcinoma pathway. More recently, serrated colorectal polyps (hyperplastic polyps, sessile serrated polyps and traditional serrated adenomas) have emerged as an alternative pathway of colorectal carcinogenesis in humans. Archival sections from early experiments in Sprague-Dawley (SD) rats injected with dimethylhydrazine (DMH) were reviewed and the histology of colonic neoplasias was re-evaluated. Out of 215 colonic neoplasias, 9% were serrated adenomas and 6% serrated carcinomas, 11% conventional adenomas, 39% highly differentiated carcinomas, 21% gut-associated lymphoid tissue (GALT) carcinomas, 13% signet-ring cell carcinomas, and 1% villous carcinomas. In a more recent review of archived sections from DMH-treated rats with colonic GALT follicles, dysplastic crypts exhibiting asymmetrical bifurcations in GALT mucosa were found in 49% and colonic GALT carcinomas in 53% of 276 DMH-treated rats. Histology of the 146 colonic GALT-carcinomas revealed highly differentiated carcinoma in 75%, signet-ring cell carcinoma in 20%, mucinous carcinomas in 3% and mixed in the remaining 2%. Highly differentiated carcinomas were seen to evolve from dysplastic crypts with asymmetric bifurcations and from adenomas and signet-ring cell carcinomas, and from non-dysplastic crypts having goblet cells with marked anisocytosis. It is apparent that DMH treatment in SD rats induced conventional adenomas, conventional carcinomas, serrated adenomas, serrated carcinomas and GALT carcinomas. The paradigm permits to monitor in detail the early histological steps that epitomize the three alternative pathways of colonic carcinogenesis in SD rats. This model might be useful for analyzing different molecular aberrations evolving during the conventional adenoma-carcinoma pathway, the serrated carcinoma pathway, and the GALT carcinoma pathway of colonic carcinogenesis, under standard laboratory conditions.
Asunto(s)
Pólipos Adenomatosos/patología , Carcinoma/patología , Transformación Celular Neoplásica/patología , Colon/patología , Neoplasias del Colon/patología , Pólipos del Colon/patología , Neoplasias Experimentales/patología , Pólipos Adenomatosos/inducido químicamente , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma/inducido químicamente , Carcinoma/genética , Carcinoma/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Colon/metabolismo , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Pólipos del Colon/inducido químicamente , Pólipos del Colon/genética , Pólipos del Colon/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Tejido Linfoide/metabolismo , Tejido Linfoide/patología , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Previous studies have shown a higher prevalence of malignancy in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). The purpose of this study was to investigate the prevalence of adenomatous colon polyps (ACP) as they occur in subjects with DM and coexisting CKD. This is a retrospective cohort study of patients with DM (n=565) who had undergone colonoscopy between 2000-2010. The cohort was further bifurcated into those with CKD (n=296) and those with normal renal function (n=269). Presence or absence of ACP was measured in both groups. Concentrations of serum parathyroid hormone (PTH), Calcium (Ca), and phosphorous (P) were recorded for the CKD group. The levels of these variables in patients with ACP (n=171) were compared with the levels from those without ACP (n=175). Nonparametric statistical methods were applied with statistical significance suggested by p<0.05 (two-sided). The presence of CKD in this cohort demonstrated a significant association with ACP (OR: 2.96; 95% CI: 2.02 to 4.34; p<0.0001). We did not detect a statistically significant difference in P or Ca between the groups. There was, however, a statistically significant difference in PTH; for the group with ACP, PTH: 387.7±351.3 ng/L vs. 172.2±196.7 ng/L; p<0.0001. This data suggests that CKD is associated with ACP in subjects with DM and those with ACP exhibit higher PTH levels when compared to those without ACP.