Pathway Of Colorectal Carcinogenesis Research Articles

Detection of sessile serrated adenoma using artificial intelligence-enhanced endoscopy: an Asian perspective.

As the serrated pathway has gained prominence as an alternative colorectal carcinogenesis pathway, sessile serrated adenomas or polyps (SSA/P) have been highlighted as lesions to rule out during colonoscopy. These lesions are however morphologically difficult to detect on endoscopy and can be mistaken for hyperplastic polyps due to similar endoscopic features. With the underlying nature of rapid progression and malignant transformation, interval cancer is a likely consequence of undetected or overlooked SSA/P. Real-time artificial intelligence (AI)-assisted colonoscopy via the computer-assisted detection system (CADe) is an increasingly useful tool in improving adenoma detection rate by providing a second eye during the procedure. In this article, we describe a guide through a video to illustrate the detection of SSA/P during AI-assisted colonoscopy. Consultant-grade endoscopists utilized real-time AI-assisted colonoscopy device, as part of a larger prospective study, to detect suspicious lesions which were later histopathologically confirmed to be SSA/P. All lesions were picked up by the CADe where a real-time green box highlighted suspicious polyps to the clinician. Three SSA/P of varying morphology are described with reference to classical SSA/P features and with comparison to the features of the hyperplastic polyp found in our study. All three SSA/P observed are in keeping with the JNET Classification (Type 1). In conclusion, CADe is a most useful aid to clinicians during endoscopy in the detection of SSA/P but must be complemented with factors such as good endoscopy skill and bowel prep for effective detection, and biopsy coupled with subsequent accurate histological diagnosis.

A shift in focus towards precision oncology, driven by revolutionary nanodiagnostics; revealing mysterious pathways in colorectal carcinogenesis.

Multiple molecular mechanisms contribute to the development of colorectal cancer (CRC), with chromosomal instability (CIN) playing a significant role. CRC is influenced by mutations in several important genes, including APC, TP53, KRAS, PIK3CA, BRAF, and SMYD4. The three molecular subtypes of this disease are CIN, MSI-H, and CIMP (CpG-island phenotype). p53 dysfunction and aberrant Wnt signalling are common characteristics of CRC carcinogenesis. Despite advances in conventional therapy, metastatic CRC remains difficult to treat due to toxicity and resistance. Theranostics for cancer could significantly benefit from nanotechnology, as it would enable more targeted, individualised care with fewer side effects. Utilising functionalized nanoparticles has enabled MRI-guided gene therapy, magnetic hyperthermia, chemotherapy, immunotherapy, and photothermal/photodynamic therapy, thereby radically modifying the way cancer is treated. Active targeting using ligands or peptides on nanoparticles improves the delivery of drugs to cancer cells. Nanostructures such as drug peptide conjugates, chitosan nanoparticles, gold nanoparticles, carbon nanotubes, mesoporous silica-based nanoparticles, silver nanoparticles, hybrid lipid-polymer nanoparticles, iron oxide nanoparticles, and quantum dots may enable targeted drug delivery and enhanced therapeutic efficacy against CRC. Nanomedicines are presently being evaluated in clinical trials for the treatment of colorectal cancer, with the promise of more effective and individualised therapies. This article examines current nanomedicine patents for CRC, including the work of Delta-Fly, Merrimack, and Pfenning, Meaning & Partner, among others. In terms of future nanomedicine research and development, ligand production, particle size, and clearance are crucial factors. Lastly, the numerous nanostructures utilized in nanomedicine for targeted drug administration and diagnostics indicate optimistic prospects for enhancing CRC treatment. The successes of nanomedicine research and development for existing colon cancer treatments are also highlighted in this review.

Menin Maintains Cholesterol Content in Colorectal Cancer via Repression of LXR-Mediated Transcription.

Menin is a nuclear scaffold protein that regulates gene transcription in an oftentimes tissue-specific manner. Our previous work showed that menin is over-expressed in colorectal cancer (CRC); however, the full spectrum of menin function in colonic neoplasia remains unclear. Herein, we aimed to uncover novel menin-regulated pathways important for colorectal carcinogenesis. RNA-Seq analysis identified that menin regulates LXR-target gene expressions in CRC cell lines. Isolated colonic epithelium from Men1f/f;Vil1-Cre and Men1f/f mice was used to validate the results in vivo. Cholesterol content was quantified via an enzymatic assay. RNA-Seq analysis in the HT-29 CRC cell line identified that menin inhibition upregulated LXR-target genes, specifically ABCG1 and ABCA1, with protein products that promote cellular cholesterol efflux. Similar results were noted across other CRC cell lines and with different methods of menin inhibition. Consistent with ABCG1 and ABCA1 upregulation, and similarly to LXR agonists, menin inhibition reduced the total cellular cholesterol in both HT-29 and HCT-15 cells. To confirm the effects of menin inhibition in vivo, we assessed Men1f/f;Vil1-Cre mice lacking menin expression in the colonic epithelium. Men1f/f;Vil1-Cre mice were found to have no distinct baseline phenotype compared to control Men1f/f mice. However, similarly to CRC cell lines, Men1f/f;Vil1-Cre mice showed an upregulation of Abcg1 and a reduction in total cellular cholesterol. Promoting cholesterol efflux, either via menin inhibition or LXR activation, was found to synergistically suppress CRC cell growth under cholesterol-depleted conditions and when administered concomitantly with small molecule EGFR inhibitors. Menin represses the transcription of LXR-target genes, including ABCA1 and ABCG1 in the colonic epithelium and CRC. Menin inhibition conversely upregulates LXR-target genes and reduces total cellular cholesterol, demonstrating that menin inhibition may be an important mechanism for targeting cholesterol-dependent pathways in colorectal carcinogenesis.

The detection rate and yield of advanced relevant serrated polyps: one small step for the yield, one giant leap for the quality of colonoscopy.

Over the last two decades, it has been well clarified that the serrated/methylated pathway of colorectal carcinogenesis is responsible for about 20 %–30 % of all colorectal cancers (CRCs) and is distinct from the traditional adenoma–carcinoma sequence [1]. Three main subgroups of serrated polyps have been recognized, with different malignant potential [2]. Hyperplastic polyps (HPPs) are believed to have a benign course, unless larger than 10 mm, whereas sessile serrated lesions (SSLs), especially those with dysplasia, and traditional serrated adenomas (TSAs), regardless of their size, have the potential for malignant transformation. Therefore, there is no doubt that these precancerous lesions are clinically relevant and deserve all our attention, above all they are often flat in appearance with indistinct borders and difficult to detect.

Significance of Micromorphological Characteristics and Expression of Intermediate Filament Proteins CK7 and CK20 in the Differential Diagnosis of Serrated Lesions of the Colorectum

Serrated lesions in the colorectum include all epithelial neoplastic lesions, which show a sawtooth-like morphology in the epithelial crypts. Classification systems nosologically divide colon serrated polyps into three different categories, primarily emphasizing their micromorphological growth pattern and cytodifferentiation: (1) hyperplastic polyps, (2) sessile serrated adenomas/polyps and (3) traditional serrated adenomas. Overall, 109 patients with serrated lesions of the colon, who underwent endoscopic or surgical polypectomy/tumorectomy during one or multiple endoscopic or surgical interventions, over a four-year period, were analyzed. The average age of patients was 62.8 ± 11.6 years. The frequency of serrated lesions of the colon in male patients was 2.4 times higher than in females (70.6% vs. 29.4%). All sessile serrated lesions without dysplasia were positive for CK7 and statistically significant compared to other serrated lesions, if this positivity was present in the complete crypt (p = 0.005). CK20 positivity, which is limited to the upper half of the crypt, is a special feature of hyperplastic polyps compared to other serrated lesions, which is statistically significant (p = 0.0078). Whereas, CK20 positivity of complete crypts is a statistically significant feature of traditional serrated adenomas (p < 0.01). Differences in the expression pattern of cytokeratin 7 and 20 in different serrated lesions may indicate different pathways of colorectal carcinogenesis, and be diagnostically and prognostically useful.

Associations of dietary, lifestyle, and other participant characteristics with APC, β-catenin, E-cadherin, and MSH2 expression in the normal mucosa of sporadic colorectal adenoma patients

Abnormal expression of Wnt pathway and DNA mismatch repair proteins is common during colorectal carcinogenesis. To investigate cross-sectional associations of lifestyle, dietary, and other participant characteristics with the expression of such proteins, we measured APC, β-catenin, E-cadherin, and MSH2 colorectal crypt expression in biopsies of normal-appearing colorectal mucosa from 104 sporadic colorectal adenoma patients using automated immunohistochemistry and quantitative image analysis. We used multivariable general linear models to compare adjusted mean biomarker expression across categories of participant characteristics. Example findings include that among women relative to men, mean APC expression in whole crypts, the upper 40% of crypts (differentiation zone), and the lower 60% of crypts (proliferation zone) was 322.9% higher (p<0.01), 296.7% higher (p<0.01), and 399.1% higher (p<0.01), respectively. Among participants with higher alcohol consumption, APC expression in the crypt differentiation zone was estimated to be 15.9% lower (p=0.08). Among those with higher total meat consumption, β-catenin expression in whole crypts and the crypt proliferation zone was estimated to be 20.5% higher (p=0.07) and 19.6% higher (p=0.06), respectively, and MSH2 expression in the crypt differentiation zone was estimated to be 64.4% lower (p=0.10). Among those with a higher body mass index, MSH2 expression in the crypt differentiation zone was estimated to be 87.5% lower (p=0.15). These pilot study findings suggest that being male, higher adiposity, and higher alcohol and meat consumption may be unfavorably associated with biomarkers of colorectal carcinogenesis pathway proteins in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients and support further investigation in larger studies.

Prevalence of mismatch repair mutations in colorectal carcinoma patients in Mangalore

Colorectal cancer (CRC) is highly prevalent throughout the world and represents the 3rd most common cancer in men and the 2nd in women worldwide. Microsatellite instability (MSI) is a term used to denote a hypermutable phenotype caused by the loss of DNA mismatch repair (MMR) activity, and is a phenomenon now linked to the pathways of colorectal carcinogenesis. Compounding its importance is its integral association with Lynch syndrome, the most common cause for CRCs in young individuals. In the present study, we aimed to analyse the proportion of patients with risk of microsatellite instability by checking for loss of immunostaining for mismatch repair (MMR) proteins.From January 2016 to December 2016 and May 2017 to October 2017, 40 consecutive newly diagnosed cases of colorectal cancer were included in the study. The expression of MMR proteins in the tumour tissue using IHC for MSH2, MSH6, MLH1 and PMS2 was studied.Among the 40 cases, 3 (7.5%) demonstrated loss of MMR proteins and 37 (92.5%) cases had intact nuclear expression. Out of the three cases with MMR loss, one showed concurrent loss of MLH1 and PMS2, the second showed concurrent loss of MSH2 and MSH6 and the third showed an isolated loss of MSH6.Colorectal carcinomas showing MMR mutations are seen in the Mangalorean population. However, the incidence in our study was relatively low compared to most other studies, probably due to a variation in ethnicity.

Genomic landscape of colorectal carcinogenesis.

The molecular pathogenesis of solid tumour was first assessed in colorectal cancer (CRC). To date, ≤ 100 genes with somatic alterations have been found to inter-connectively promote neoplastic transformation through specific pathways. The process of colorectal carcinogenesis via genome landscape is reviewed on the basis of an adenoma-to-carcinoma sequence, as shown by serial histological and epidemiological observations. The relevant literatures from PubMed (1980-2021) have been reviewed for this article. The major routes of CRC development, chromosomal instability (CIN), microsatellite instability (MSI), and the serrated route either via CIN or MSI, proceed through the respective molecular pathway of colorectal carcinogenesis. Particular aspects of CRC carcinogenesis can also be determined by evaluating familial CRCs (FCRC) and genotype-phenotype correlations. Specific causative gene alterations still leave to be identified in several FCRCs. Otherwise, recently verified FCRC can be particularly notable, for example, EPCAM-associated Lynch syndrome, polymerase proofreading-associated polyposis, RNF43-associated polyposis syndrome or NTHL1 tumour syndrome, and hereditary mixed polyposis syndrome. The oncogenic landscape is described, including representative pathway genes, the three routes of carcinogenesis, familial CRCs, genotype-phenotype correlations, the identification of causative genes, and consensus molecular subtypes (CMS). Whole genome research using multi-gene panels (MGPs) has facilitated high through-put detection of previously unidentified genes involved in colorectal carcinogenesis. New approaches designed to identify rare variants are recommended to consider their alterations implicated in the molecular pathogenesis.

A Case of Microsatellite Instability–High Colon Cancer in a Young Woman With Familial Adenomatous Polyposis

Two major molecular pathways of colorectal carcinogenesis, chromosomal instability (CIN) and microsatellite instability (MSI), are considered to be mutually exclusive. Distinguishing CIN from MSI-high tumors has considerable therapeutic implications, because patients with MSI-high tumors can derive considerable benefit from immune checkpoint inhibitors, and tumors that evolved through the CIN pathway do not respond to these agents. Familial adenomatous polyposis (FAP) is a genetic syndrome that is defined by a mutation in the APC gene and is thought to lead to carcinogenesis through the CIN pathway. Here, we report a case of a young woman with FAP who was treated for medulloblastoma as a child and developed advanced MSI-high colon cancer as a young adult. Her response to second-line immunotherapy enabled resection of her colon cancer, and she is free of disease >10 months after surgery. This case highlights the potential for overlap between the CIN and MSI carcinogenic pathways and associated therapeutic implications.

Effects of YAP1 and SFRP2 overexpression on the biological behavior of colorectal cancer cells and their molecular mechanisms.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and has a high mortality rate. With the development of tumor molecular biology, more and more attention is being paid to the mechanisms of cell pathways in colorectal carcinogenesis, such as the Hippo/Yes-associated protein 1 (YAP1) and Wnt/β-catenin signaling pathways. The abnormal expression of YAP1 and β-catenin have been reported in CRC, and can lead to excessive cell proliferation, and eventually, tumor formation. Secreted frizzled-related protein 2 (SFRP2) levels have been found to be decreased in a variety of cancers, and SFRP2 is an antagonist that binds directly to Wnt signal. At present, the molecular basis of colorectal tumors is still not fully understood. In the present study, we sought to identify the molecular mechanisms underlying YAP1 and SFRP2 in the development of CRC. We constructed CRC cell lines that stably overexpressed YAP1 and SFRP2 using lentivirus packaging and cell infection. The levels of expression of the proteins were evaluated by western blot and immunofluorescence assays. Protein complex immunoprecipitation (Co-IP) was used to detect the interaction between YAP1, SFRP2, and β-catenin. The functional roles of YAP1 and SFRP2 in CRC was determined by a Cell Counting Kit-8 (CCK8) proliferation assay and flow cytometric apoptosis assay. The data of the present study showed that the overexpression of SFRP2 promoted the expression of YAP1 and β-catenin protein, and the overexpression of YAP1 promoted the expression of β-catenin protein. YAP1 overexpression promoted cell proliferation, while SFRP2 overexpression inhibited cell proliferation and promoted cell apoptosis. Our findings showed that the expression of YAP1, SFRP2, and β-catenin is correlated in CRC cells. The Hippo pathway and Wnt pathway interact with each other in the pathogenesis of CRC, and YAP1 and SFRP2 are involved in the formation and development of CRC.

Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure.

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer.

Colorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5–10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the SRC gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of SRCV177M resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of paxillin, β-Catenin, and STAT3 mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the SRCV177M variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis.

Molecular Pathogenesis and Classification of Colorectal Carcinoma.

Molecular pathways in colorectal carcinogenesis involve several complex genetic and epigenetic modulations that cause normal colonic mucosa to metamorphose into a benign polyp and subsequently into a malignant tumor. Our purpose is to recapitulate historical and recent genomic research in order to augment the understanding of colorectal cancer pathogenesis. In 2015, the molecular classification for colorectal cancers was unified into one system with four distinct groups, also called as consensus molecular subtypes. This led to an enhanced understanding of molecular and immune signatures which has implications on predicting the clinical behavior as well as response to different therapeutic agents. In this review, we expound on the current literature as well as draw on our own experience to present the important molecular pathogenesis pathways, key genetic mutations, differences in pathogenesis of left versus right sided tumors as well as the molecular classification of colorectal cancers.

MiR-181a-2* expression is different amongst carcinomas from the colorectal serrated route.

Serrated adenocarcinoma (SAC) and colorectal carcinomas showing histological and molecular features of high-level of microsatellite instability (hmMSI-H) are both end points of the serrated pathway of colorectal carcinogenesis. Despite common features (right-sided location, CpG island methylation phenotype and BRAF mutation) there are no studies comparing the microRNA (miRNA) expression profiles in SACs and hmMSI-H. The microtranscriptome from 12 SACs and 8 hmMSI-H were analysed using Affymetrix GeneChip miRNA 3.0 arrays and differentially enriched functions involving immune response were observed from this comparison. miR-181a-2* was found significantly more expressed in hmMSI-H than in SAC and higher expression of this miRNA in microsatellite unstable colorectal cancer were corroborated by Real-Time PCR in an extended series (61 SAC, 21 hmMSI-H). An analysis of genes possibly regulated by miR-181a-2* was carried out and, amongst these, an inverse correlation of NAMPT with miR-181a-2* expression was observed, whereas, for TRAF1 and SALL1, additional regulation mechanisms involving CpG island methylation were observed. miR-181a-2* is associated with particular histological and molecular features of colorectal carcinomas within the serrated pathological pathway and might play a role in the immune responses of microsatellite instability carcinomas.

Pathways of Colorectal Carcinogenesis

Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.

Pathways of colorectal carcinogenesis

Колоректалният карцином (КРК) възниква в резултат на акумулиране на различни типове на увреждане на генома: нарушения в транскрипцията на гени и епигенетични нарушения. Сред генетичните нарушения най-голямо значение имат хромозомнатa (CIN) и микросателитна нестабилност (MSI). Мутациите в тумор-супресорните гени и протоонкогени: APC, TP53, SMAD2, SMAD4, DCC, KRAS, PIK3CA, и загубата на хетерозиготност (LOH) в хромозоми 1, 5, 8, 17 и 18 са най-честите причини за CIN. Инактивиращи мутации на гени, участващи в репарацията на ДНК - MMR (mismatch repair) - MLH1, MSH2, MSH6, обуславят възникването на мултиплени мутации и делеции. Епигенетичните нарушения са породени от хиперметилация на промоторните зони на множество гени, известни като CpG острови, и придобитият метилаторен фенотип заглушава множество гени, включително гените, участващи в репарацията на ДНК. Изясняването на геномните и епигеномни нарушения и ролята им в колоректалната карциногенеза е от съществено значение за изработване на ефективни стратегии за превенция и терапия на пациентите с КРК.

A Changing Spectrum of Colorectal Cancer Biology With Age: Implications for the Young Patient.

The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ≈25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers OBJECTIVE:: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups. This was a retrospective cohort study. The study was conducted at a high-volume tertiary referral center. Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens. Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (≤50, 51-60, 61-70, 71-80, and >81 y). Patients with IBD or hereditary syndromes were excluded. A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were ≤50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers. This study was limited by its retrospective design. The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at http://links.lww.com/DCR/A709.

Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review

Colorectal carcinogenesis (CRC) imposes a major health burden in developing countries. It is the third major cause of cancer deaths. Despite several treatment strategies, novel drugs are warranted to reduce the severity of this disease. Adenomatous polyps in the colon are the major culprits in CRC and found in 45% of cancers, especially in patients 60 years of age. Inflammatory polyps are currently gaining attention in CRC, and a growing body of evidence denotes the role of inflammation in CRC. Several experimental models are being employed to investigate CRC in animals, which include the APCmin/+ mouse model, Azoxymethane, Dimethyl hydrazine, and a combination of Dextran sodium sulphate and dimethyl hydrazine. During CRC progression, several signal transduction pathways are activated. Among the major signal transduction pathways are p53, Transforming growth factor beta, Wnt/β-catenin, Delta Notch, Hippo signalling, nuclear factor erythroid 2-related factor 2 and Kelch-like ECH-associated protein 1 pathways. These signalling pathways collaborate with cell death mechanisms, which include apoptosis, necroptosis and autophagy, to determine cell fate. Extensive research has been carried out in our laboratory to investigate these signal transduction and cell death mechanistic pathways in CRC. This review summarizes CRC pathogenesis and the related cell death and signal transduction pathways.

RNF6 Promotes Colorectal Cancer by Activating the Wnt/β-Catenin Pathway via Ubiquitination of TLE3.

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958-71. ©2018 AACR.

Investigating Prevalence and Progression of Serrated Polyps: Tampa VA Experience

Introduction: Adenomas have historically been considered the sole precursor lesions that lead to colorectal cancer (CRC) via the adenoma-carcinoma sequence. A recently recognized pathway in colorectal carcinogenesis involves “serrated polyps”, which until recently were considered to be innocuous lesions. Serrated polyps are classified into sessile serrated adenomas (SSA), traditional serrated adenomas (TSA) and serrated adenomas (SA). Despite the serrated neoplastic pathway accounting for up to 10-20% of all sporadic colorectal cancers, these polyps remain under diagnosed and poorly understood. We aim to identify the prevalence and potential progression of serrated polyps in our veteran population. Methods: Retrospective analysis was performed on all patients who underwent all cause colonoscopies over a 10-year period from 1/1/2005-12/31/2015. Our primary aim was to analyze the trend in prevalence of serrated polyps. Secondary outcomes were to correlate prevalence of serrated polyps with modifiable lifestyle factors. Low risk adenomas were categorized as tubular adenoma and high-risk adenomas were categorized as tubulo-villous adenomas.Table: Table. Risk factors affecting TA vs. SA and TA vs.TSATable: Table. Risk factors affecting TA vs. SSAFigure: Prevalence of serrated polyps over 10 years.Results: An electronic databank was created after analyzing 14,593 pathology reports from a 10-year period. The individual cases were categorized as SSA, TSA, SA, SSA+high-risk adenoma, SSA+low risk adenoma, SA+high-risk adenoma, SA+low risk adenoma, TSA+high risk adenoma, TSA+low risk adenoma and TA (control). There was a progressive increase in the percentage of serrated polyps per all lesions identified on colonoscopy over the 10-year period. There was no significant correlation between HgA1c, total cholesterol, HLD, LDL and triglycerides between TA vs. TSA and SA. There was a statistical significance between TA vs. SSA in regards to LDL (P<0.03).Figure: Categories of polyps in the study.Conclusion: A database of serrated polyps detected undergoing colonoscopy was generated. Temporal trends in the detection of these lesions and variables that might affect their prevalence were identified and analyzed. Further data is being collected including correlation with Vitamin D and ASA use. Serrated polyps are increasingly being recognized as lesions that can progress into cancer. Therefore, it is imperative that gastroenterologists and pathologists are aware to remove and properly classify these serrated lesions. To our knowledge, this is the first study to date investigating the prevalence of serrated polyps in the veteran population.