Adenocarcinoma Sequence Research Articles

Grades of Poorly Differentiated Clusters are Associated with Lymph Node and the Tumour, Node and Metastasis Stages in Colorectal Carcinoma.

Colorectal carcinoma (CRC) is the third most common cancer globally. In Malaysia, CRC is most prevalent among males and the second most common cancer among females. The CRC arises mainly from the adenocarcinoma sequence. Poorly differentiated clusters (PDCs) and tumour budding (TB) are believed to represent sequential steps in tumour growth. Therefore, this study analysed the association between PDC grades with clinicopathological and demographic characteristics of CRC. A total of 47 CRC cases previously diagnosed by histopathological examination were reviewed for the presence of PDCs and graded accordingly. The association between PDC grades with clinicopathological and demographic characteristics was statistically analysed. Out of the 47 cases with PDCs, most of them were of grade 3 (G3) (n = 27, 57.4%), followed by grade 2 (G2) (n = 13, 27.7%) and grade 1 (G1) (n = 7, 14.9%). Higher PDC grades (G2 and G3) were mainly observed in higher tumour stage (T); T3 (n = 26, 83.9%), T4 (n = 12, 92.3%), N1 (n = 20, 86.9%), N2 (n = 15, 100%). In addition, there was a significant association between PDC grades with the nodal stage (N) (P = 0.013) and the tumour, node and metastasis (TNM) stages (P = 0.012). The PDC grades are useful for assessing the disease prognosis in CRC. A statistically significant association between PDC grades with N and TNM stages suggested that PDC grades are potential predictive parameters for invasive and metastatic risks in CRC.

Significance of (IMP3) In Dysplasia- Adenocarcinoma Sequence in Barrett's Esophagus. (Immunohistochemical Study)

Significance of (IMP3) In Dysplasia- Adenocarcinoma Sequence in Barrett's Esophagus. (Immunohistochemical Study)

Exploration of the Key Proteins of High-Grade Intraepithelial Neoplasia to Adenocarcinoma Sequence Using In-Depth Quantitative Proteomics Analysis.

Purpose In this study, we aimed to provide a comprehensive description of typical features and identify key proteins associated with the high-grade intraepithelial neoplasia- (HIN-) adenocarcinoma (AC) sequence. Methods We conducted tandem mass tag-based quantitative proteomic profiling of normal mucosa, HIN, and AC tissues. Protein clusters representative of the HIN-AC sequence were identified using heatmaps based on Pearson's correlation analysis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, ClueGO plugin in Cytoscape, and the Metascape database. The prognostic value of the key proteins and their effects on the tumor microenvironment and consensus molecular subtype were explored based on The Cancer Genome Atlas. Results We identified 536 proteins categorized into three clusters. Among the biological processes and pathways of the highly expressed proteins in the HIN-AC sequence, proteins were predominantly enriched in response to gut microbiota, cell proliferation, leukocyte migration, and extracellular matrix (ECM) organization events. SERPINH1 and P3H1 were identified as the key proteins that promote the HIN-AC sequence. In the correlation analysis of infiltrating immune cells, both SERPINH1 and P3H1 expression correlated negatively with tumor purity, while correlating positively with abundance of CD8+ T cells, B cells, macrophage/monocytes, dendritic cells, cancer-associated fibroblasts, endothelial cells, neutrophils, and natural killer cells. Furthermore, both SERPINH1 and P3H1 expression positively correlated with common immune checkpoints and mesenchymal molecular subtype. High P3H1 expression was associated with poor disease-free survival and overall survival. Conclusions ECM-related biological processes and pathways are typical features of the HIN-AC sequence. SERPINH1 and P3H1 might be the key proteins in this sequence and be related to ECM remodeling and immune suppression status in CRC.

Exploring polyps to colon carcinoma voyage: can blocking the crossroad halt the sequence?

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.

Describing the heterotopic gastric mucosa (inlet patch) located in the esophagus with cases

Aim: The inlet patch, also called as the heterotopic gastric mucosa, is often located in proximal esophagus and is generally asymptomatic. These lesions are rarely polypoid and mostly have a patchy pattern. In the literature, there are only few cases of inlet patches that show a malignant progression following a metaplasia- dysplasia- adenocarcinoma sequence. In our study, we aimed to present the endoscopic and morphological features of our case series. Methods: The study, which was conducted in two clinics, included the inlet patch cases diagnosed in esophagus biopsy materials between 2016 and 2019. The slides and the demographic data of the cases were re-analyzed. Results: Among 4190 cases whose esophageal biopsies were examined, 63 inlet patches (1.5%) were diagnosed. Thirty four cases were male and 29 were female. Age range was 16-82 years. The cases were mostly located in proximal esophagus and the size of the lesions ranged between 0.2-3.5 cm. One of the four cases with polypoid appearance was microscopically diagnosed as a hyperplastic polyp. The most common gastric type epithelium was the oxyntic type. Helicobacter pylori was observed in four cases, and intestinal metaplasia and low-grade dysplasia were observed in one. No malignancy was diagnosed in our series. Conclusion: Although benign, the inlet patch is significant due to its risk of progression to malignancy. Thus, obtaining biopsies from each lesion endoscopically considered as inlet patch is recommended. This will help determine the precise incidence of the inlet patch and more importantly, identify neoplasia earlier.

Dysregulation of microRNA expression during the progression of colorectal tumors.

MicroRNAs (miRNAs) are potential biomarkers of neoplastic lesions, but additional information on dysregulated miRNA expression during progression of the adenoma–adenocarcinoma sequence may be helpful to identify the role of miRNAs in this sequence. We examined the expression levels of 13 miRNAs (hsa‐miRNA‐19a‐3p, hsa‐miRNA‐21‐5p, hsa‐miRNA‐27a‐3p, hsa‐miRNA‐27b‐3p, hsa‐miRNA‐31‐5p, hsa‐miRNA‐34b‐3p, hsa‐miRNA‐125b‐5p, hsa‐miRNA‐143‐3p, miRNA‐191‐5p, hsa‐miRNA‐193b‐3p, hsa‐miRNA‐195‐5p, hsa‐miRNA‐206 and hsa‐let‐7a‐5p) that are closely associated with colorectal carcinogenesis in 40 conventional adenomas (tubular and tubulovillous adenomas), 20 intramucosal carcinomas (IMCs) and 60 invasive colorectal cancers (iCRCs) using reverse‐transcription polymerase chain reaction. These 120 tumors were divided into two cohorts, that is, cohort 1 (60 cases) and cohort 2 (for validation; 60 cases). We analyzed the expression levels of these miRNAs in the first step (adenoma→IMC) and second step IMC→iCRC) of the adenoma–carcinoma sequence in both cohorts. Although no significant differences in the expression of any of the 13 miRNAs were found between adenomas and IMCs consistently in both cohorts, the expression levels of hsa‐miRNA‐125b‐5p, hsa‐miRNA‐143‐3p, and hsa‐miRNA‐206 were significantly upregulated in iCRC in both cohorts compared with those in IMC. The current results suggest that certain miRNAs, including hsa‐miRNA‐125b‐5p, hsa‐miRNA‐143‐3p and hsa‐miRNA‐206, are candidate markers that play critical roles in the progression of IMC to iCRC.

(Pro)renin Receptor Expression Increases throughout the Colorectal Adenoma-Adenocarcinoma Sequence and It Is Associated with Worse Colorectal Cancer Prognosis.

(Pro)renin receptor (PRR) is a protein that takes part in several signaling pathways such as Renin Angiotensin System and Wnt signalling. Its biological role has recently been related to cancer progression and in this study, we investigated its relevance in colorectal cancer (CRC). To that end, we analysed the immunohistochemical expression of PRR in adenomatous polyps and CRCs from the same patients (n = 42), and in primary tumours and nodal and liver metastases from advanced CRC patients (n = 294). In addition, the soluble fraction of PRR was measured by ELISA in plasma samples from 161 CRC patients. The results showed that PRR expression was gradually augmented along the uninvolved mucosa–adenoma–adenocarcinoma sequence. Besides, the stronger expression of PRR in primary tumours was markedly associated with local tumour extent and the onset of metastases. Moreover, PRR expression in both primary and distant metastases was associated with worse 5- and 10-year survival of CRC patients. Plasmatic PRR levels did not change with respect to controls and were not associated with CRC aggressiveness. These results suggest a key role of PRR in the development and progression of CRC and a potential use of this protein as a new prognostic biomarker and/or therapeutic target for this disease.

Transforming human papillomavirus infection and the esophageal transformation zone: prime time for total excision/ablative therapy?

High-risk human papillomavirus (hr-HPV) infection is causal for almost all cervical malignancy (both squamous and adenocarcinoma), 90% of anal neoplasia, 70% of penile tumors, and 25% of head and neck cancers. The shared immunogenetics of cervical and esophageal malignancy suggests that HPV infection could well be a common denominator in the etiology of both cancers. In this regard, we have demonstrated that transcriptionally active hr-HPV (genotypes 16 and 18) is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma. Increasing hr-HPV viral load and integration status has been linked with greater disease severity along the Barrett metaplasia-dysplasia-adenocarcinoma sequence as has been demonstrated in cervical intraepithelial neoplasia and cancer. HPV infections in both the cervix and esophagus are both focal, i.e., present in greater quantities at the squamocolumnar junction (SCJ). HPV affinity is to junctional tissue, as basal cells are particularly accessible at the squamocolumnar transformation zone and especially susceptible to this viral infection. We have postulated that progressive acid damage to the esophagus increases the likelihood of mucosal breaks enabling the virus to enter the basal layer of the transformation zone. The SCJ is the transformation zone of the esophagus and is strikingly similar to the transition zone (ectoendocervical SCJ) of the uterine cervix where almost all high-grade cervical lesions and cancers arise including 80% of adenocarcinomas. These transition zone cells exhibit features of squamous epithelium as well as glandular cells, which have been described in both Barrett's esophagus and cervical mucosa. Barrett's esophagus (BE) is derived from a discrete population of embryonic cells residing at the SCJ. There is loss of SCJ immune-phenotype following excision without regeneration at other junctional sites. Prevention of cervical cancer in up to 80-95% of patients with screen-detected CIN is dependent on the excision/ablation of the entire transformation zone. The persistence of hr-HPV 16/18 following eradication of CIN is a significant risk factor for recurrence. Similarly, we have demonstrated that persistent hr-HPV infection 16/18 and p53 overexpression are associated with treatment failure after endoscopic ablation of BD/EAC. Thus, we believe that excision/ablation of the SCJ in patients with BD/intramucosal EAC should be performed to reduce the potential malignant risk. We propose to test this hypothesis by a multicenter randomized controlled trial whereby patients (both HPV positive and those which are virus negative) will be allocated into two arms: complete excision of the SCJ via endoscopic mucosal resection (EMR) in addition to radiofrequency ablation (RFA)± EMR of BD/intramucosal EAC (experimental arm) versus current standard of care (RFA ± EMR) of said lesions. Treatment efficacy in both groups will be evaluated by comparing disease elimination, regression/progression, and recurrence (if any). All patients would be entered into an intensive endoscopic surveillance protocol (biannually) for at least 2 years with lesional/neosquamous biopsies to compare the recurrence rate of both dysplasia/neoplasia in both arms. Viral (HPV DNA/p16INK4A/E6/E7 mRNA) and host biomarkers (e.g., p53) will be analyzed both at baseline and posttreatment intervals. A positive study would initiate development of tools best suited for SCJ destruction.

Economic value of narrow-band imaging versus white light endoscopy for the diagnosis and surveillance of Barrett's esophagus: Cost-consequence model.

Barrett’s esophagus (BE) is an abnormality arising from gastroesophageal reflux disease that can progressively evolve into a sequence of dysplasia and adenocarcinoma. Progression of Barrett’s esophagus into dysplasia is monitored with endoscopic surveillance. The current surveillance standard requests random biopsies plus targeted biopsies of suspicious lesions under white-light endoscopy, known as the Seattle protocol. Recently, published evidence has shown that narrow-band imaging (NBI) can guide targeted biopsies to identify dysplasia and reduce the need for random biopsies. We aimed to assess the health economic implications of adopting NBI-guided targeted biopsy vs. the Seattle protocol from a National Health Service England perspective. A decision tree model was developed to undertake a cost-consequence analysis. The model estimated total costs (i.e. staff and overheads; histopathology; adverse events; capital equipment) and clinical implications of monitoring a cohort of patients with known/suspected BE, on an annual basis. In the simulation, BE patients (N = 161,657 at Year 1; estimated annual increase: +20%) entered the model every year and underwent esophageal endoscopy. After 7 years, the adoption of NBI with targeted biopsies resulted in cost reduction of £458.0 mln vs. HD-WLE with random biopsies (overall costs: £1,966.2 mln and £2,424.2 mln, respectively). The incremental investment on capital equipment to upgrade hospitals with NBI (+£68.3 mln) was offset by savings due to the reduction of histological examinations (-£505.2 mln). Reduction of biopsies also determined savings for avoided adverse events (-£21.1 mln). In the base-case analysis, the two techniques had the same accuracy (number of correctly identified cases: 1.934 mln), but NBI was safer than HD-WLE. Budget impact analysis and cost-effectiveness analyses confirmed the findings of the cost-consequence analysis. In conclusion, NBI-guided targeted biopsies was a cost-saving strategy for NHS England, compared to current practice for detection of dysplasia in patients with BE, whilst maintaining at least comparable health outcomes for patients.

Significance of Expression of Cancer Stem Cell Markers CD133 and Nestin in Pancreatic Intraepithelial Carcinoma-invasive Adenocarcinoma Sequence.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and one of the most leading causes of cancer related deaths. It has a very poor prognosis with high recurrence rate. We investigated the expression of CSC markers (CD133 and nestin) in 100 patients [30 pancreatic intraepithelial tumor cases (PanIN) and 70 PDAC cases] and correlate the expression levels of these markers with clinicopathological data with the aid of Ki67 expression. Our findings showed that both cancer stem markers are related to the grade, stage, metastasis of PDAC and to the grade of PanIN cases and revealed that both markers are associated with PanIN-PDAC sequence with inverse relation between them. Both markers may contribute to proliferation, differentiation, invasiveness, and histologic types of PDAC. Sothey may also be useful for developing new therapeutic modalities for PDAC.

The Mitochondrial Genes BAK1, FIS1 and SFN are Linked with Alterations in Mitochondrial Membrane Potential in Barrett's Esophagus.

Barrett’s esophagus and esophageal cancer lack prognostic markers that allow the tailoring of personalized medicine and biomarkers with potential to provide insight into treatment response. This study aims to characterize mitochondrial function across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett’s esophagus and examines the functional effect of manipulating mitochondrial genes. Mitochondrial genes of interest were validated in in vitro cell lines across the metaplasia (QH), dysplasia (GO) and adenocarcinoma (OE33) sequence and in in vivo patient tissue samples. These genes were subsequently knocked down in QH and OE33 cells and the functional effect of siRNA-induced knockdown on reactive oxygen species production, mitochondrial mass, mitochondrial membrane potential and cellular metabolism was investigated. Three global mitochondrial genes (BAK1, FIS1 and SFN) were differentially altered across the in vivo Barrett’s disease sequence. We also demonstrate that knockdown of BAK1, FIS1 and SFN in vitro resulted in significant alterations in mitochondrial membrane potential; however, no differences in reactive oxygen species or mitochondrial mass were observed. Furthermore, knockdown of these genes in esophageal adenocarcinoma cells significantly altered cellular metabolism. In conclusion, we found that differential expression of BAK1, FIS1, and SFN were altered across the Barrett’s disease sequence and manipulation of these genes elicited significant effects on mitochondrial membrane potential.

DWI in Assessing Aggressiveness of Rectal Cancer

Background: diffusion-weighted magnetic resonance imaging (DW-MRI) permits non-invasive assessment of tumor characteristics. Aim of the work: this study was aimed to emphasize the role of DWI in assessing aggressiveness of rectal cancer with the histopathological correlation. Patients and methods: this was a prospective study that included thirty patients with histopathological proved rectal carcinoma referred from the Surgical Department, Ain Shams University Hospitals to the MRI Radiology Unit for Rectal Cancer Staging. Pelvic MRI study with conventional sequences and DWI were performed. Results: 81% of moderately differentiated adenocarcinoma (ADC) (grade II) showed restricted diffusion with low signals in ADC sequence, while none of the poorly differentiated adenocarcinoma (grade III) showed restricted diffusion with high signals in ADC sequence (T2 shin-through). There was a high statistically significant difference in characterization of poorly (grade III) and moderately differentiated adenocarcinomas (grade II). Conclusion: significant correlations were detected between mean ADC values and differentiation grade. ADC may be useful as an imaging tool for re-staging of tumor aggressiveness, but it cannot serve as an independent tool for primary staging of rectal cancer.

Epigenetics: DNA Methylation Analysis in Esophageal Adenocarcinoma.

The aberrant DNA methylation has been noted to occur at promoter of tumor suppressor, cell adhesion, DNA repair, and other growth regulating genes during the progression of nonneoplastic esophageal mucosa to Barrett esophagus to esophageal adenocarcinoma. Methylation-mediated silencing of individual gene or concurrent loss of a number of genes plays crucial roles in dysplasia-metaplasia-neoplasia sequence of esophageal adenocarcinoma. In addition, promoter methylation of genes had shown significant prognostic potential in patients with esophageal adenocarcinoma. Thus, determination of methylation status of genes of interest can be used as a molecular marker for risk stratification and/or better prognosis of patients with esophageal adenocarcinoma. There are a number of methods including bead array, PCR and sequencing, pyrosequencing, methylation-specific PCR, and PCR with high-resolution melt curve available to determine the methylation status of particular gene of interest. Herein, we describe the polymerase chain reaction followed by sequencing-based protocol for identifying DNA methylation status in esophageal adenocarcinoma.

Intraductal papillary mucinous neoplasm to pancreas ductal adenocarcinoma sequence and pancreas cancer screening.

Intraductal papillary mucinous neoplasm to pancreas ductal adenocarcinoma sequence and pancreas cancer screening.

Sa1141 - Identification of Myeloid Derived Suppressor Cells in the Barrett’s Metaplasia to Esophageal Adenocarcinoma Sequence

Sa1141 - Identification of Myeloid Derived Suppressor Cells in the Barrett’s Metaplasia to Esophageal Adenocarcinoma Sequence

P16ink4a Subcellular Expression Patterns in Colorectal Adenocarcinoma, Adenoma and Non-Neoplastic Tissue Samples

Background:Colorectal cancer (CRC) is one of the most common neoplasms with high mortality at advanced stages worldwide. Thus diagnosis of CRC at an early stage with sensitive molecular methods is a high priority. The aim of this study was to evaluate P16ink4a subcellular expression patterns in colorectal adenocarcinoma, adenoma and non-neoplastic tissue samples.Methods:A total of 137 colorectal formalin fixed paraffin-embedded tissue blocks from the pathology archives of Ali-Ebne-Abitaleb central hospital, Zahedan, Iran, were examined in three groups: adenocarcinoma (n= 63), adenoma (n= 38) and non-neoplastic (n= 36). The subcellular expression pattern was determined by immunocytochemistry. Data analysis was performed using Kruskal-Wallis and Fisher exact tests with the significance level set as p<0.05.Results:P16ink4a subcellular localization was observed in three different patterns, nuclear+cytoplasmic (73.33%), cytoplasmic (13.33%) and nuclear (13.33%). In most samples, nuclear+cytoplasmic was the predominant subcellular pattern. However, a significant difference in P16ink4a subcellular expression patterns was observed along the non-neoplastic, adenoma, adenocarcinoma sequence (p<0.001). An association with the histological tumor type was also noted (p=0.021).Conclusion:Considering variation in localization of P16ink4a under different pathological conditions, P16ink4a night be sensitive prognostic biomarker for benign colon lesions. Its use may improve strategies for screening, prognostic assessment and management of patients with CRC. Further studies are recommended in this field.

Expression profiles of cancer stem cell markers: CD133, CD44, Musashi-1 and EpCAM in the cardiac mucosa—Barrett’s esophagus—early esophageal adenocarcinoma—advanced esophageal adenocarcinoma sequence

IntroductionBarrett's esophagus (BE), which develops as a result of gastroesophageal reflux disease, is a preneoplastic condition for esophageal adenocarcinoma (EAC). A new hypothesis suggests that cancer is a disease of stem cells, however, their expression and pathways in BE − EAC sequence are not fully elucidated yet. AimsWe used a panel of putative cancer stem cells markers to identify stem cells in consecutive steps of BE-related cancer progression. MethodsImmunohistochemistry was performed on formalin-fixed, paraffin-embedded blocks from 58 patients with normal cardiac mucosa (n=5), BE (n=14), early EAC (pT1) from mucosal resection (n=17) and advanced EAC (pT1-T4) from postoperative specimens (n=22). Expression of the CD133, CD44, Musashi-1 and EpCAM was analyzed using respective monoclonal antibodies. ResultsAll markers showed a heterogeneous expression pattern, mainly at the base of the crypts of Barrett’s epithelium and EAC, with positive stromal cells in metaplastic and dysplastic lesions. Immuno-expression of EpCAM, CD44 and CD133 in cardiac mucosa was significantly lower (mean immunoreactivity score (IRS)=1.2; 0.0; 0.4; respectively) compared to their expression in Barrett’s metaplasia (mean IRS=4.3; 0.14; 0.7; respectively), in early adenocarcinoma (mean IRS=4.4; 0.29; 1.3; respectively) and in advanced adenocarcinoma (mean IRS=6.6; 0.7; 2.7; respectively) (p<0.05). On the contrary, Musashi-1 expression was higher in BE and early ADC compared to GM and advanced ADC (NS). ConclusionOur results suggest that the stem cells could be present in premalignant lesions. EpCAM, CD44 and CD133 expression could be candidate markers for BE progression, whereas Musashi-1 may be a marker of the small intestinal features of Barrett's mucosa.

Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence.

BackgroundBarrett’s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s disease progression is under studied.MethodsUsing an in-vitro model representing the Barrett’s esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles.ResultsBarrett’s metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett’s disease sequence in-vitro. Using patient in-vivo samples, Barrett’s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett’s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett’s metaplastic tissue compared with matched normal squamous epithelium.ConclusionsWe have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s disease sequence.

Distribution of CDH13, CDH1, MGMT and PTEN promoter methylation and KRAS, BRAF and EGFR mutation in colorectal cancer.

e15073Background: The adenocarcinoma sequence is associated with the accumulation of epigenetic and genetic changes as normal tissue becomes cancerous. We have been interested in variants in the me...

Assessment of murine colorectal cancer by micro-ultrasound using three dimensional reconstruction and non-linear contrast imaging

The relatively low success rates of current colorectal cancer (CRC) therapies have led investigators to search for more specific treatments. Vertebrate models of colorectal cancer are essential tools for the verification of new therapeutic avenues such as gene therapy. The evaluation of colorectal cancer in mouse models has been limited due to the lack of an accurate quantitative and longitudinal noninvasive method. This work introduces a method of three-dimensional micro-ultrasound reconstruction and microbubble administration for the comprehensive and longitudinal evaluation of CRC progression. This approach enabled quantification of both tumor volume and relative vascularity using a well-established inducible murine model of colon carcinogenesis. This inducible model recapitulated the adenocarcinoma sequence that occurs in human CRC allowing systematic in situ evaluation of the ultrasound technique. The administration of intravenous microbubbles facilitated enhancement of colon vascular contrast and quantification of relative vascularity of the mid and distal colon of the mouse in three dimensions. In addition, two-dimensional imaging in the sagittal orientation of the colon using Non-Linear Contrast Mode enabled calculation of relative blood volume and perfusion as the microbubbles entered the colon microvasculature. Quantitative results provided by the outlined protocol represent a noninvasive tool that can more accurately define CRC development and progression. This ultrasound technique will allow the practical and economical longitudinal study of murine CRC in both basic and preclinical studies.