Mucins and associated glycan signatures in colon adenoma-carcinoma sequence: Prospective pathological implication(s) for early diagnosis of colon cancer.
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ABSTRACT:
SUBMITTER: Krishn SR
PROVIDER: S-EPMC4881851 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
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Project description:The colon adenoma-carcinoma sequence is a multistep genomic-altering process that occurs during colorectal cancer (CRC) carcinogenesis. Organoids are now commonly used to model both non-cancerous and cancerous tissue. This study aims to investigate how well organoids mimic tissues in the adenoma-carcinoma sequence by comparing their transcriptomes. A total of 234 tissue samples (48 adenomas and 186 CRC) and 60 organoid samples (15 adenomas and 45 CRC) were analyzed. We found that cell-proliferation-related gene sets were consistently enriched in both CRC tissues and organoids compared to adenoma tissues and organoids by gene set enrichment analysis (GSEA). None of the known pathways in the colon adenoma-carcinoma sequence were consistently enriched in CRC organoids. There was no enrichment of the tumor microenvironment-related gene sets in CRC organoids. CRC tissues enriched immune-response-related gene sets, whereas CRC organoids did not. The proportions of infiltrating immune cells were different between tissues and organoids, whereas there was no difference between cancer and adenoma organoids. The amounts of cancer stem cells and progenitor cells were not different between CRC and adenoma organoids, whereas a difference was noted between CRC and adenoma tissues. In conclusion, we demonstrated that organoids model only part of the adenoma-carcinoma sequence and should be used with caution after considering their limitations.
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Project description:Sessile serrated adenoma/polyps (SSA/P) are premalignant lesions of colorectal cancer that are difficult to distinguish histologically from hyperplastic polyps (HP) of minimal to no malignant potential. Specific markers for differentiating SSA/P from HP can aid clinicians for optimizing colon surveillance intervals. The present study investigates the potential of mucins and associated O-glycans to distinguish SSA/P from HP. Expression of colonic mucins (MUC1, MUC4, MUC17, MUC2, and MUC5AC) and O-glycans [Sialyl LewisA (CA19-9) and Tn/Sialyl-Tn on MUC1] were analyzed in HP (n=33), SSA/P (n=39), and tubular adenoma (TA) (n=36) samples by immunohistochemistry. A significantly reduced expression of MUC4 (p=0.0066), elevated expression of MUC17 (p=0.0002), and MUC5AC (p<0.0001) was observed in SSA/P cases in comparison to HP cases. Interestingly, significantly higher number of SSA/P cases (p<0.0001) exhibited MUC5AC expression in the goblet cells as well as filled the crypt lumen compared to only goblet cells in majority of the HP cases. Improved diagnostic potential was revealed by multivariate logistic regression analysis where combinatorial panel of MUC5AC/MUC17 discriminated SSA/P from HP (SN/SP=85/82%). Finally, the decision tree model based marker panel (CA19-9/MUC17/MUC5AC) predicted HP, SSA/P and TA with SN/SP of 58%/95%, 79%/90% and 97%/83%, respectively. Overall, the mucin and associated O-glycan based panel defined in the present study could aid in discriminating SSA/P from HP to devise better colon surveillance strategies.
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Project description:Early diagnosis of urological diseases is often difficult due to the lack of specific biomarkers. More powerful and less invasive biomarkers that can be used simultaneously to identify urological diseases could improve patient outcomes. The aim of this study was to evaluate a urological disease-specific scoring system established with a machine learning (ML) approach using Ig N-glycan signatures. Immunoglobulin N-glycan signatures were analyzed by capillary electrophoresis from 1312 serum subjects with hormone-sensitive prostate cancer (n = 234), castration-resistant prostate cancer (n = 94), renal cell carcinoma (n = 100), upper urinary tract urothelial cancer (n = 105), bladder cancer (n = 176), germ cell tumors (n = 73), benign prostatic hyperplasia (n = 95), urosepsis (n = 145), and urinary tract infection (n = 21) as well as healthy volunteers (n = 269). Immunoglobulin N-glycan signature data were used in a supervised-ML model to establish a scoring system that gave the probability of the presence of a urological disease. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). The supervised-ML urologic disease-specific scores clearly discriminated the urological diseases (AUC 0.78-1.00) and found a distinct N-glycan pattern that contributed to detect each disease. Limitations included the retrospective and limited pathological information regarding urological diseases. The supervised-ML urological disease-specific scoring system based on Ig N-glycan signatures showed excellent diagnostic ability for nine urological diseases using a one-time serum collection and could be a promising approach for the diagnosis of urological diseases.
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Project description:Mucins are a diverse and heterogeneous family of glycoproteins that comprise the bulk of mucus and the epithelial glycocalyx. Mucins are intimately involved in viral transmission. Mucin and virus laden particles can be expelled from the mouth and nose to later infect others. Viruses must also penetrate the mucus layer before cell entry and replication. The role of mucins and their molecular structure have not been well-characterized in coronavirus transmission studies. Laboratory studies predicting high rates of fomite transmission have not translated to real-world infections, and mucins may be one culprit. Here, we probed both surface and direct contact transmission scenarios for their dependence on mucins and their structure. We utilized disease-causing, bovine-derived, human coronavirus OC43. We found that bovine mucins could inhibit the infection of live cells in a concentration- and glycan-dependent manner. The effects were observed in both mock fomite and direct contact transmission experiments and were not dependent upon surface material or time-on-surface. However, the effects were abrogated by removal of the glycans or in a cross-species infection scenario where bovine mucin could not inhibit the infection of a murine coronavirus. Together, our data indicate that the mucin molecular structure plays a complex and important role in host defense.
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Project description:Background and study aims?:Longer observation times are associated with increased adenoma detection rates (ADR) in the entire colon. However, adenomas in the proximal colon are at risk of being missed during colonoscopy. The aim of this study was to investigate the impact of observation time on detection of adenomatous polyps in the proximal colon. Patients and methods?:This was a prospective study at a university hospital in Germany. Colonoscopies were conducted using magnetic endoscope imaging (MEI) in order to determine the exact position of the scope. Exact observation times spent for the detection of polyps in the proximal and distal colon segments were assessed. The primary outcome was adenoma detection in the proximal colon. ROC curves were generated in order to test the correlation between observation time and adenoma detection. Logistic regression analysis was used to check for interfering factors. Results:?A total 480 procedures with 538 polyps were available for analysis. The overall adenoma detection rate was 38.5?%. ADR in the proximal colon was 28.0?%. There was a significant association between observation time in the proximal colon and the detection of proximal adenomas ( P ?<?0.001). The impact of the time factor on ADR was stronger in the proximal compared to the distal colon ( P ?=?0.030). A net period of 4?min 7 sec was found to be the minimum time span for sufficient adenoma detection in the proximal colon. Conclusion?:Observation time is significant in terms of adenoma detection in the proximal colon. The impact of observation time on ADR is stronger in the proximal compared to the distal colon. In the proximal colon a minimum time span of 4 minutes should be spent in order to ensure adequate adenoma detection.
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