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Abstract Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan–Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan–Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC. [ABSTRACT FROM AUTHOR]

Abstract Background Lipid metabolism-related genes (LMRGs) have been reported to be correlated with the immune infiltration of colorectal cancer (CRC). This study aimed to investigate the immune infiltration characteristics along the colorectal adenoma-carcinoma sequence (ACS) based on LMRGs. Methods Gene expression data of colorectal adenoma and carcinoma samples were obtained from the public databases. The “limma” package was applied to determine the differentially expressed LMRGs. Unsupervised consensus clustering was used to cluster colorectal samples. The features of the tumor microenvironment were analyzed by the “ESTIMATE”, “GSVA”, and “TIDE” algorithms. Results The expression of 149 differentially expressed LMRGs was defined as the LMRG signature. Based on this signature, the adenoma and carcinoma samples were divided into three clusters. Unexpectedly, these sequential clusters showed a directional relationship and collectively constituted the progressive course of colorectal ACS. Interestingly, the LMRG signature revealed that adenoma progression was accompanied by a progressive loss of immune infiltration and a stepwise establishment of a cold microenvironment, but carcinoma progression was characterized by a progressive gain of immune infiltration and a gradual establishment of a hot microenvironment. Conclusions The LMRG signature reveals dynamic immune infiltration along the colorectal ACS, which substantially changes the understanding of the tumor microenvironment of CRC carcinogenesis and provides novel insight into the role of lipid metabolism in this process.

Background: Lipid metabolism-related genes (LMRGs) have been reported to be correlated with the immune infiltration of colorectal cancer (CRC). This study aimed to investigate the immune infiltration characteristics along the colorectal adenoma-carcinoma sequence (ACS) based on LMRGs. Methods: Gene expression data of colorectal adenoma and carcinoma samples were obtained from the public databases. The "limma" package was applied to determine the differentially expressed LMRGs. Unsupervised consensus clustering was used to cluster colorectal samples. The features of the tumor microenvironment were analyzed by the "ESTIMATE", "GSVA", and "TIDE" algorithms. Results: The expression of 149 differentially expressed LMRGs was defined as the LMRG signature. Based on this signature, the adenoma and carcinoma samples were divided into three clusters. Unexpectedly, these sequential clusters showed a directional relationship and collectively constituted the progressive course of colorectal ACS. Interestingly, the LMRG signature revealed that adenoma progression was accompanied by a progressive loss of immune infiltration and a stepwise establishment of a cold microenvironment, but carcinoma progression was characterized by a progressive gain of immune infiltration and a gradual establishment of a hot microenvironment. Conclusions: The LMRG signature reveals dynamic immune infiltration along the colorectal ACS, which substantially changes the understanding of the tumor microenvironment of CRC carcinogenesis and provides novel insight into the role of lipid metabolism in this process. [ABSTRACT FROM AUTHOR]

Background: No effective early diagnostic biomarkers are available for colorectal cancer (CRC). Therefore, we sought to identify new biomarkers that could identify CRC from progression as a pre-cancerous lesion to its invasive form. Recent studies have shown that microRNAs (miRs) are associated with the onset of cancer invasion and progression. Aims: We hypothesized that the identification of miRs associated with CRC might be useful to detect this disease at early stages. Methods: We conducted an integrated analysis of 79 isolated colorectal tumor glands, including adenomas, intramucosal cancers, and invasive CRCs that showed a microsatellite stable phenotype using GeneChip miRNA 4.0 microarray assays. The colorectal tumors we examined were divided into 2 cohorts (42 in the first cohort and 37 in the second cohort). Results: First, cluster analysis was performed to stratify expression patterns of multiple miRs that were pooled according to the following criteria: fold change in expression (< −2.0 or > 2.0), p < 0.05, and mature miRs. As a result, the expression patterns of pooled miRs were subdivided into 3 subgroups that were correlated with tumor grade. Each subgroup was characterized by specific miRs. In addition, we found that specific miRs, including miR-140-3p and miR-378i, were closely associated with cancer invasion. Finally, we analyzed paired dysregulated miRs between adenomatous and cancerous components present within the same tumor. Discussion: We showed that several miRs were dysregulated during progression from adenoma to intramucosal cancer. Specific miRs may have key roles in progression from intramucosal tumor to invasive CRC. [ABSTRACT FROM AUTHOR]

Background: Although MicroRNAs (mIRNAs) play Important roles In various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors. Methods: We examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of "adenoma in/with carcinoma" to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA-mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs. Results: Specific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression. Conclusions: We found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors. [ABSTRACT FROM AUTHOR]

Background: To optimize colorectal cancer (CRC) screening and surveillance, information regarding the time-dependent risk of advanced adenomas (AA) to develop into CRC is crucial. However, since AA are removed after diagnosis, the time from AA to CRC cannot be observed in an ethically acceptable manner. We propose a statistical method to indirectly infer this time in a progressive three-state disease model using surveillance data.Methods: Sixteen models were specified, with and without covariates. Parameters of the parametric time-to-event distributions from the adenoma-free state (AF) to AA and from AA to CRC were estimated simultaneously, by maximizing the likelihood function. Model performance was assessed via simulation. The methodology was applied to a random sample of 878 individuals from a Norwegian adenoma cohort.Results: Estimates of the parameters of the time distributions are consistent and the 95% confidence intervals (CIs) have good coverage. For the Norwegian sample (AF: 78%, AA: 20%, CRC: 2%), a Weibull model for both transition times was selected as the final model based on information criteria. The mean time among those who have made the transition to CRC since AA onset within 50 years was estimated to be 4.80 years (95% CI: 0; 7.61). The 5-year and 10-year cumulative incidence of CRC from AA was 13.8% (95% CI: 7.8%;23.8%) and 15.4% (95% CI: 8.2%;34.0%), respectively.Conclusions: The time-dependent risk from AA to CRC is crucial to explain differences in the outcomes of microsimulation models used for the optimization of CRC prevention. Our method allows for improving models by the inclusion of data-driven time distributions. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of mast cells in the tumor microenvironment (TME) remains controversial but has become increasingly evident and explored as a possible therapeutic target. In this study, we investigated the underexplored mast cell heterogeneity of intestinal cancer by applying standardized mast cell subtyping during adenoma-carcinoma progression. We immunohistochemically evaluated and scored the occurrence of interepithelial mucosal mast cells (ieMMCs) in tumors of frequently employed genetically engineered mouse models and in human colonic adenomas and carcinomas. We found a decrease of ieMMCs from colonic low-grade adenomas to carcinomas. Moreover, mouse models based on altered Wnt signaling showed higher ieMMC scores than models based on altered MAPK signaling. Our descriptive study indicates that ieMMCs play a special role in the molecular TME related to adenoma-carcinoma progression. Furthermore, it emphasizes the need for adequate immunohistochemical methodology and experimental setup when investigating the functional role of mast cell populations of the TME. Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active β-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME. [ABSTRACT FROM AUTHOR]

BackgroundMost colorectal cancer (CRC) cases are sporadic and develop along the adenoma-carcinoma sequence. Intestinal microbial dysbiosis is involved in the development of colorectal cancer. However, there are still no absolute markers predicting the progression from adenoma to carcinoma. This study aimed to investigate the characteristics of intestinal microbiota in patients with colorectal adenoma and carcinoma and its correlations with clinical characteristics.MethodsFecal samples were collected from 154 patients with CRC, 20 patients with colorectal adenoma (AD) and 199 healthy controls. To analyze the differences in the intestinal microbiota, 16S rRNA gene sequencing was conducted.ResultsAt the genus level, there were four significantly different genera among the three groups, namely Acidaminococcus, Alloprevotella, Mycoplasma, and Sphingobacterium, while Acidaminococcus significantly decreased with the order of Control-AD-CRC (P < 0.05). In addition, Parvimonas, Peptostreptococcus, Prevotella, Butyricimonas, Alistipes, and Odoribacter were the key genera in the network of colorectal adenoma/carcinoma-associated bacteria. The top 10 most important species, including Butyricimonas synergistica, Agrobacterium larrymoorei, Bacteroides plebeius, Lachnospiraceae bacterium feline oral taxon 001, Clostridium scindens, Prevotella heparinolytica, bacterium LD2013, Streptococcus mutans, Lachnospiraceae bacterium 19gly4, and Eubacterium hallii, showed the best performance in distinguishing AD from CRC (AUC = 85.54%, 95% CI: 78.83–92.25%). The clinicopathologic features, including age, gender, tumor location, differentiation degree, and TNM stage, were identified to be closely linked to the intestinal microbiome in CRC.ConclusionSeveral intestinal bacteria changed along the adenoma-carcinoma sequence and might be the potential markers for the diagnosis and treatment of colorectal adenoma/carcinoma. Intestinal microbiota characteristics in CRC should account for the host factors.

Duodenal tumors with a sporadic adenoma-carcinoma sequence are extremely rare. For such clinically suspected cases without a specific family history, performing a comprehensive gene search is important to understand the germline mutation background. We present a 68-year-old woman without a genetic or familial history of familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, or Lynch syndrome who presented to Kosei Hospital, Japan, with exertional dyspnea induced by abdominal pain lasting 3 weeks. A duodenal tumor was suspected by contrast-enhanced computed tomography. Esophagogastroduodenoscopy showed a lesion accompanied by a white microprotuberance on the descending part of the duodenum opposite the papilla, with a giant ulcerative lesion at the center of the white lesion. Biopsy revealed a low-grade adenoma, high-grade adenoma, and adenocarcinoma. Immunohistochemical analysis of the adenoma and adenocarcinoma showed Ki-67, p53, cytokeratin 20, caudal-type homeobox 2, and carcinoembryonic antigen positivity and cytokeratin 7 negativity. The findings suggested the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma. However, in the mutational analysis using next-generation sequencing, c.4348C>T (p.Arg1450Ter) mutation in APC was detected in all normal mucosal, adenoma, and carcinoma tissues. This mutation is common in FAP patients. Even if the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma is suggested in cases without a familial FAP history, as in this case, genetic analysis may reveal FAP. Thus, performing a comprehensive genetic analysis of duodenal carcinoma patients with a possible adenoma-carcinoma sequence is necessary to explore their genetic background.

Abstract Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder of the colon. Patients with UC have an increased risk of developing colorectal cancer. However, appendix adenocarcinoma associated with UC is extremely rare.

The concept of the adenoma-carcinoma sequence in colorectal cancer (CRC) is widely accepted. However, the relationship between the characteristics of the transcriptome and the adenoma-carcinoma sequence in CRC remains unclear. Here, the transcriptome profiles of 15 tissue samples from five CRC patients were generated by RNAseq. Six specific dynamic expression patterns of differentially expressed genes (DEGs) were generated by mFuzz. Weighted correlation network analysis showed that DEGs in cluster 4 were associated with carcinoma tissues, and those in cluster 6 were associated with non-normal tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified metabolic dysregulation as a consistent finding throughout the transition process, whereas downregulation of the immune response occurred during normal to adenoma transition, and the upregulation of canonical pathways was associated with adenoma to carcinoma transition. Overall survival analysis of patients in cluster 6 identified TPD52L1 as a marker of poor prognosis, and cell proliferation, colony formation, wound healing, and Transwell invasion assays showed that high expression levels of TPD52L1 promoted malignant behaviors. In total, 70 proteins were identified as potential partners of hD53 by mass spectrometry. CRC formation was associated with three cancer hallmarks: dysregulation of metabolism, inactivation of the immune response, and activation of canonical cancer pathways. The TPD52L1 gene was identified as a potential marker to track tumor formation in CRC and as an indicator of poor patient prognosis.

Introduction: Exosomes are membrane-enclosed nanovesicles, which are increasingly being recognized as important cell communication components for their role in transmitting microRNAs (miRNAs). No previous study has addressed the exosomal miRNA profile in colorectal adenomas (CRAs) because the long-term culture of CRA is challenging. This study aimed to identify the miRNA signature in organoid exosomes derived from human CRA and colorectal cancer (CRC) samples. Methods: Organoid cultures were developed from resected colorectal tissues of patients with CRA or CRC undergoing surgery or endoscopic mucosal resection. Exosomes were prepared from the conditioned medium of the organoids. miRNAs were prepared from the exosomes and their source organoids. The miRNA expression profiles were compared using microarray analysis. The impact of alteration of miRNA expression on cell proliferation was examined using miRNA mimics or inhibitors in HT-29 human CRC cells. Results: We established 6 organoid lines from CRC and 8 organoid lines from CRA. Exosomal miRNA signatures were different between the organoids derived from CRA and CRC. Both exosomal and cellular miR-1246 expressions were upregulated in CRC-derived organoids compared to their expression in CRA-derived organoids. Alteration of miR-1246 expression by the miR-1246 mimic or inhibitor increased or decreased cell proliferation in HT-29 cells, respectively. Conclusions: We report for the first time the miRNA profiles of exosomes in CRA- and CRC-derived organoids. The upregulation of miR-1246 might play a role in increased cell proliferation in the process of CRA-carcinoma transition. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder of the colon. Patients with UC have an increased risk of developing colorectal cancer. However, appendix adenocarcinoma associated with UC is extremely rare. [ABSTRACT FROM AUTHOR]

The concept of the adenoma-carcinoma sequence in colorectal cancer (CRC) is widely accepted. However, the relationship between the characteristics of the transcriptome and the adenoma-carcinoma sequence in CRC remains unclear. Here, the transcriptome profiles of 15 tissue samples from five CRC patients were generated by RNAseq. Six specific dynamic expression patterns of differentially expressed genes (DEGs) were generated by mFuzz. Weighted correlation network analysis showed that DEGs in cluster 4 were associated with carcinoma tissues, and those in cluster 6 were associated with non-normal tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified metabolic dysregulation as a consistent finding throughout the transition process, whereas downregulation of the immune response occurred during normal to adenoma transition, and the upregulation of canonical pathways was associated with adenoma to carcinoma transition. Overall survival analysis of patients in cluster 6 identified TPD52L1 as a marker of poor prognosis, and cell proliferation, colony formation, wound healing, and Transwell invasion assays showed that high expression levels of TPD52L1 promoted malignant behaviors. In total, 70 proteins were identified as potential partners of hD53 by mass spectrometry. CRC formation was associated with three cancer hallmarks: dysregulation of metabolism, inactivation of the immune response, and activation of canonical cancer pathways. The TPD52L1 gene was identified as a potential marker to track tumor formation in CRC and as an indicator of poor patient prognosis. [ABSTRACT FROM AUTHOR]

Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra‐GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz–Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra‐GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis‐associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS‐associated GI malignancies. [ABSTRACT FROM AUTHOR]

Duodenal tumors with a sporadic adenoma-carcinoma sequence are extremely rare. For such clinically suspected cases without a specific family history, performing a comprehensive gene search is important to understand the germline mutation background. We present a 68-year-old woman without a genetic or familial history of familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, or Lynch syndrome who presented to Kosei Hospital, Japan, with exertional dyspnea induced by abdominal pain lasting 3 weeks. A duodenal tumor was suspected by contrast-enhanced computed tomography. Esophagogastroduodenoscopy showed a lesion accompanied by a white microprotuberance on the descending part of the duodenum opposite the papilla, with a giant ulcerative lesion at the center of the white lesion. Biopsy revealed a low-grade adenoma, high-grade adenoma, and adenocarcinoma. Immunohistochemical analysis of the adenoma and adenocarcinoma showed Ki-67, p53, cytokeratin 20, caudal-type homeobox 2, and carcinoembryonic antigen positivity and cytokeratin 7 negativity. The findings suggested the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma. However, in the mutational analysis using next-generation sequencing, c.4348C>T (p.Arg1450Ter) mutation in APC was detected in all normal mucosal, adenoma, and carcinoma tissues. This mutation is common in FAP patients. Even if the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma is suggested in cases without a familial FAP history, as in this case, genetic analysis may reveal FAP. Thus, performing a comprehensive genetic analysis of duodenal carcinoma patients with a possible adenoma-carcinoma sequence is necessary to explore their genetic background. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is highly prevalent worldwide. In 2018, there were over 1.8 million new cases. Most sporadic CRC develop from polypoid adenomas and are preceded by intramucosal carcinoma (stage 0), which can progress into more malignant forms. This developmental process is known as the adenoma‐carcinoma sequence. Early detection and endoscopic removal are crucial for CRC management. Accumulating evidence suggests that the gut microbiota is associated with CRC development in humans. Comprehensive characterization of this microbiota is of great importance to assess its potential as a diagnostic marker in the very early stages of CRC. In this review, we summarized recent studies on CRC‐associated bacteria and their carcinogenic mechanisms in animal models, human cell lines and human cohorts. High‐throughput technologies have facilitated the identification of CRC‐associated bacteria in human samples. We have presented our metagenome and metabolome studies on fecal samples collected from a large Japanese cohort that revealed stage‐specific phenotypes of the microbiota in CRC. Furthermore, we have discussed the potential carcinogenic mechanisms of the gut microbiota, from which we can infer whether changes in the gut microbiota are a cause or effect in the multi‐step process of CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

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.

The adenoma‑carcinoma sequence, the sequential mutation and deletion of various genes by which colorectal cancer progresses, is a well‑established and accepted concept of colorectal cancer carcinogenesis. Proteins of the polycomb repressive complex 2 (PRC2) function as transcriptional repressors by trimethylating histone H3 at lysine 27; the activity of this complex is essential for cell proliferation and differentiation. The histone methyltransferase enhancer of zeste homolog 2 (EZH2), an essential component of PRC2, is associated with the transcriptional repression of tumor suppressor genes. EZH2 expression has previously been reported to increase with the progression of pancreatic intraductal papillary mucinous neoplasm. Thus, we hypothesized that EZH2 expression also increases during the adenoma‑carcinoma sequence of colorectal cancer. The present study investigated changes in EZH2 expression during the colorectal adenoma‑carcinoma sequence. A total of 47 patients with colorectal adenoma, 20 patients with carcinoma in adenoma and 43 patients with colorectal carcinoma who underwent surgical or endoscopic resection were enrolled in this study. Non‑cancerous tissue from the clinical specimens was also examined. The association between EZH2 expression, pathology and expression of tumor suppressor genes during colorectal carcinogenesis were analyzed. Each specimen was immunohistochemically stained for EZH2, proliferation marker protein Ki‑67 (Ki‑67), cyclin‑dependent kinase inhibitor (CDKN) 1A (p21), CDKN1B (p27) and CDKN2A (p16). Total RNA was extracted from formalin‑fixed paraffin‑embedded blocks and reverse transcription‑quantitative polymerase chain reaction analysis of these genes was performed. Ki‑67 and EZH2 expression scores increased significantly during the progression of normal mucosa to adenoma and carcinoma (P=0.009), and EZH2 expression score was positively associated with Ki‑67 expression score (P=0.02). Conversely, p21 mRNA and protein expression decreased significantly, whereas expression of p27 and p16 did not change significantly. During the carcinogenesis sequence from normal mucosa to adenoma and carcinoma, EZH2 expression increased and p21 expression decreased significantly. EZH2 may therefore contribute to the development of colorectal cancer from adenoma via suppression of p21. [ABSTRACT FROM AUTHOR]

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We previously reported to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. In this report, we focused on colorectal adenoma (tubular or tubulovillous adenoma), or tubular early carcinoma or type 2 adenocarcinoma, familial adenomatous polyposis (FAP), ulcerative colitis-associated tumor (UCAT), and sessile serrated adenoma/polyp (SSA/P). We tried to clarify the relationship between the expression of the miRNAs and the colorectal tumor development. The expression levels of miR-143, -145, and -34a were reduced in most of the polypoid and FAP tumors compared with those in the flat elevated, UCAT, SSA/P ones. In type 2 adenocarcinomas, the expression profile of these miRNAs was similar to those of the polypoid and FAP tumors. The expression levels of miR-7 and -21 were up-regulated in non-granular type of laterally spreading tumor, UCAT, and SSA/P compared with those in polypoid and FAP tumors. These findings indicated that the expression of onco-related miRNAs was closely associated with the development and endoscopic appearance of colorectal tumors. [ABSTRACT FROM AUTHOR]

Background: Some gastric adenomas may progress to adenocarcinoma in a short time, but others remain as adenoma for a long time. Methods: Among 1138 cases diagnosed as adenoma by biopsy at Kure Medical Association Hospital between 1990 and 2010, 51 adenomas were enrolled. Of these, 28 adenomas (group A) were followed for 60 months or longer with no progression to adenocarcinoma within 60 months, and the other 23 adenomas (group B) were upgraded to carcinoma by consecutive biopsies performed within 1 year after the first biopsy. These adenomas were compared clinicopathologically and immunohistochemically. Results: Macroscopically, the mean size of group B adenomas was significantly larger than that of group A adenomas (18.6 vs. 9.9 mm) at the first biopsy. The frequency of a depressed area in the adenoma was significantly higher in group B than group A. Microscopically none of group A but 7 (30.4%) of 23 group B adenomas showed severe atypia. Each of a highly proliferative gland measured by Ki-67 labeling, cellular atypical grade, gastric phenotype defined by MUC5AC and MUC6 and CD204-positive tumor-associated macrophage (TAM) was a significant risk factor for adenocarcinoma development in gastric adenoma by univariate analysis. Only moderate or severe atypia of adenoma cells and the TAM number in the stroma of adenomas were independent risk factors by multivariate analysis. Conclusions: As independent risk factors, cellular atypia may reconfirm the importance of morphological analysis, and the TAM number may indicate the significance of TAM function in gastric adenoma. [ABSTRACT FROM AUTHOR]

Mechanisms underlying tumor progression remain a main problem in the diagnosis and treatment of patients with tumors. The present study compared the expression of full-length neurokinin-1 receptors (fl-NK-1R) and truncated neurokinin-1 receptors (tr-NK-1R) in adenoma and carcinoma from patients with colorectal carcinoma, to explore their possible contributions in adenoma-carcinoma progression. Samples were collected immediately following colorectal carcinoma surgery. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining, the relative mRNA and protein levels of tr-NK-1R and fl-NK-1R were compared in adenoma and carcinoma. tr-NK-1R mRNA was significantly upregulated (1.7 fold; P=0.026) in carcinoma tissues compared with adenoma tissues, while the fl-NK-1R transcription level showed no difference (P=0.438). No significant change was observed in the fl-NK-1R protein level in adenoma, carcinoma and peri-carcinoma tissues (P=0.244). However, total neurokinin-1 receptor (NK-1R) protein levels in adenoma and carcinoma tissues were significantly increased compared to peri-carcinoma tissue (P=0.026 and P=0.007, respectively). The outcomes suggested that the increase in total NK-1R protein in adenoma and carcinoma tissues is the result of the increase in tr-NK-1R levels. The present findings indicate that tr-NK-1R serves an important role in colorectal adenoma progression, with a possible role in adenoma-carcinoma progression. Thus, tr-NK-1R may be used as a marker for diagnosing and treating patients with colorectal adenomas. [ABSTRACT FROM AUTHOR]

In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of definedmutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize--i.e., to colonize distant sites--is the direct consequence of the loss of dependency on specific niche signals. [ABSTRACT FROM AUTHOR]

Background: Screening for colon cancer (CC) may not only reduce its occurrence but has also the potential to reduce the overall mortality. So far, there has been little evidence that detection of colon cancer by screening colonoscopy results in different survival rates compared to symptomatic patients. Patients and methods: Clinical, histological, diagnostic, and survival data of 1016 consecutive patients with CC from a prospectively expanded single-institutional database were analyzed for diagnostic, treatment, and prognostic factors. Findings were then stratified according to detection by screening colonoscopy vs. patients who became symptomatic prior to further diagnostic work-up. Results: 7.1 % of all patients were identified by screening colonoscopy for colon cancer. Screened patients were younger (68.2 vs. 64.8 years), had smaller T stage ( p = 0.032), lower tumor stage ( p = 0.009), and a tendency to less lymph node metastasis. Overall survival was superior in screened patients, and stage-specific survival showed a tendency to improved survival, which was not statistically significant. Furthermore, a higher percentage of screened patients underwent adjuvant chemotherapy (84.6 vs. 55.0 %, p = 0.032). Conclusion: Survival outcome and enrollment in a multimodal treatment was higher in screening-detected patients compared to patients diagnosed after the onset of clinical symptoms. Besides a potential occurrence of lead time bias, these findings strongly support the need for continued improvement of screening programs and the recruitment of more patients for colorectal cancer screening. [ABSTRACT FROM AUTHOR]

Aims Dickkopf-1 (Dkk1), an antagonist of the Wnt-β-catenin signalling pathway, has been reported to play a role in cancer progression. However, little is known about the role of Dkk1 during the colorectal adenoma-carcinoma sequence. This study aimed to elucidate the role of Dkk1 in tumorigenesis and angiogenesis in colorectal cancer. Methods and results We examined Dkk1 expression immunohistochemically in 476 colorectal tissue samples, including 46 sets of matched specimens. Dkk1 expression was down-regulated during the colorectal adenoma-carcinoma sequence, both among the 476 samples and in the 46 sets of matched specimens. Dkk1 expression was correlated with decreased microvessel density ( P < 0.05) and VEGF expression. In-vitro 3D coculture experiments showed that Dkk1 overexpression in HCT116 cells inhibited tube-like structure formation and down-regulated VEGF expression in human umbilical vein endothelial cells. Xenografts of Dkk1-overexpressing colorectal cancer cells were smaller, and showed lower microvessel density and VEGF expression levels, than those of control cells. Conclusions This study is the first to show the roles of Dkk1 during the colorectal adenoma-carcinoma sequence, which may involve suppression of the tumorigenesis and angiogenesis of CRC. Dkk1 could therefore serve as a potential target for tumour therapy. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is associated with germline mutations in DNA mismatch repair (MMR) genes. The first "hit" to inactivate one allele of the predisposing MMR gene is present in every cell, contributing to accelerated tumorigenesis. Less information is available of the nature, timing, and order of other molecular "hits" required for tumor development. To this end, MMR protein expression and coordinated promoter methylation were examined in colorectal specimens prospectively collected from LS mutation carriers (n = 55) during colonoscopy surveillance (10/2011-5/2013), supplemented with retrospective specimens. Results: Loss of MMR protein corresponding to the gene mutated in the germline increased with dysplasia, with frequency of 0 % in normal mucosa, 50-68 % in low-grade dysplasia adenomas, and 100 % in high-grade dysplasia adenomas and carcinomas. Promoter methylation as a putative "second hit" occurred in 1/56 (2 %) of tumors with silenced MMR protein. A general hypermethylation tendency was evaluated by two gene sets, eight CpG island methylator phenotype (CIMP) genes, and seven candidate tumor suppressor genes linked to colorectal carcinoma (CRC). Hypermethylation followed the same trend as MMR protein loss and was present in some low-grade dysplasia adenomas that still expressed MMR protein suggesting the absence of a "second hit." To assess prospectively collected normal mucosa for carcinogenic "fields," the specimen donors were stratified according to age at biopsy (50 years or below vs. above 50 years) and further according to the absence vs. presence of a (previous or concurrent) diagnosis of CRC. In mutation carriers over 50 years old, two markers from the candidate gene panel (SFRP1 and SLC5A8) revealed a significantly elevated average degree of methylation in individuals with CRC diagnosis vs. those without. Conclusions: Our findings emphasize the importance and early appearance of epigenetic alterations in LS-associated tumorigenesis. The results serve early detection and assessment of progression of CRC. [ABSTRACT FROM AUTHOR]

The majority of rectal carcinomas are sporadic in nature, and relevant testing for driver mutations to guide therapy is important. A thorough family history is necessary and helpful in elucidating a potential hereditary predilection for a patient's carcinoma. The adequate diagnosis of a heritable tendency toward colorectal carcinoma alters the management of a patient disease and permits the implementation of various surveillance algorithms as preventive measures. [ABSTRACT FROM AUTHOR]

Mono-allelic germline mutations in DNA mismatch repair (MMR) genes lead to Lynch syndrome (LS). Questions remain as to the timing of the inactivation of the wild-type allele in LS-associated tumorigenesis. Speculation exists that it happens after the neoplasia has been initiated. However, a recent study reported the presence of MMR-deficiency in non-neoplastic colonic crypts in LS; thus the possibility can be raised that these crypts may be tumor precursors, and as such, biallelic loss of MMR may occur prior to neoplasia. Here we report a unique case that showed findings supporting both of the two seemingly conflicting notions. The patient was a 40-year-old female with LS, MSH2 type, who underwent a segmental colectomy for an adenocarcinoma. By immunohistochemistry, the carcinoma lost MSH2/MSH6. Interestingly, there was also complete loss of MSH2/MSH6 in a distinct focus of 20 colonic crypts that were morphologically non-neoplastic, thus supporting the possibility of biallelic loss of MMR before initiation of neoplasia. However, in a separate adenoma, MMR was preserved in neoplastic glands with low grade dysplasia and lost only in glands with high grade dysplasia, i.e., MMR loss after tumor initiation. These are relevant findings with regard to the timing of MMR deficiency in LS tumorigenesis, and bring forth the possibility that varied tumorigenic pathways may exist. Additionally, we observed that the MMR-deficient non-neoplastic crypts harbored increased intraepithelial CD8-positive T-lymphocytes similar to the patient's carcinoma, providing a potential new venue for the study of the natural antitumor immune responses in LS individuals. [ABSTRACT FROM AUTHOR]

Introduction. Chromosomal changes are widespread in the vast majority of colon carcinomas and aneuploidy is an established prognostic factor. However, this knowledge so far has no influence on tumor classification. We reported a morphology-based classification scheme, the core classification, that correlates with DNA ploidy. In particular, tripolar mitoses were identified as surrogate markers of a near triploid DNA content. In addition, a survey on chromosome numbers and survival rates in carcinomas suggested that triploidy as a particular state of aneuploidy may be correlated with a more aggressive tumor phenotype. We therefore aimed to analyse DNA ploidy in the colorectal adenoma-carcinoma sequence. Material and methods. The study collection consisted of 15 adenomas and 15 adenocarcinomas of 10 patients. Some of them showed a morphological transition between benign and malignant tumor components which were selectively analysed by DNA measurements. In addition, we assessed the morphological parameters of the core classification. Results. The main findings of the study may be summarized as follows. 1) DNA ploidy changes are already consistently detectable in colon adenomas. They are usually associated with hyperdiploidy. 2) Adenoma tissue adjacent to carcinomas, however, may carry a hypodiploid DNA content while the nearby carcinoma samples were hyperdiploid. Hypodiploidy may thus represent a transition state to near triploid carcinomas. 3) The size of tumor nuclei and mitoses usually reflects the ploidy level of colon tumors. Specifically, triploid mitoses may point to a near triploid DNA content. 4) Triploidy per se cannot be equated with tumor aggressiveness as it may already be found in adenocarcinoma in situ. 5) Tripolar and tetrapolar mitoses in invasive colon cancer, however, are potential indicators of an advanced chromosomal instability and seemed to be associated with advanced tumor stages. Conclusions. We present data that hypodiploidy may represent a transition state from adenoma to carcinoma in a subset of colorectal tumors and that near-triploidy may be associated with a more aggressive course of the disease. However, the interpretation of tripolar mitoses and triploidy is largely dependent on the cell type (benign vs. malignant) and tissue context (invasive vs. non-invasive cancer). Furthermore, its interpretation may be distinct for different tumor stages and histotypes. Aneuploidy and multipolar mitoses are frequent findings in cancer cells. Their relevance for tumor biology deserves further studies. [ABSTRACT FROM AUTHOR]

The inhibitor of apoptosis family member livin is expressed in several types of cancer but not in most benign tissues, and it has been considered to be a poor prognostic mark in various malignancies. However, livin expression and its prognostic relevance have not been evaluated in colorectal adenoma-carcinoma sequence. In this study, we analyzed the difference of livin expression among normal mucosa, adenoma, and adenocarcinoma and investigated the relationship of livin expression in carcinomas with clinicopathological variables using immunohistochemistry and real-time reverse transcription-PCR. We observed that the expression of livin protein was mainly present on base of colorectal crypts in adenoma and throughout the epithelium in carcinoma, whereas did not present in accompanying normal mucosa, and the expression of livin messenger RNA (mRNA) in adenocarcinomas was significantly higher than in adenomas and in normal mucosa ( P = 0.001, respectively), whereas, compared with normal mucosa, the expression level of livin mRNA was up-regulated in adenomas but no significant difference ( P = 0.196). We also found that the expression levels of livin mRNA in rectal cancer was significantly higher than those in colonic cancer, and livin mRNA expression was strongly related to colorectal cancer invasive depth but not to clinical tumor stage, differentiation, lymph node metastasis, tumor morphological category and pathological type, and patient's age and gender. These findings support the possibility that the livin gene may play a role in colorectal tumorigenesis, and increased expression of livin mRNA may serve as a new target for colorectal cancer treatment. [ABSTRACT FROM AUTHOR]

Most colorectal carcinomas (CRCs) are considered to arise from conventional adenoma based on the concept of the adenoma-carcinoma sequence. Matrix metalloproteinases (MMPs) are known to be overexpressed as normal mucosa progresses to adenomas and carcinomas. There has been little previous investigation about MMP-13 expression in adenoma-carcinoma sequence. In this study, we aimed to investigate the immunohistochemical expression of MMP-13 in colorectal adenoma and CRC specimens using tissue microarray (TMA) technique. A total of 40 cases of CRC associated with adenoma were collected from files of the Pathology laboratory at Mansoura Gastroenterology Center between January 2007 and January 2012. Sections from TMA blocks were prepared and stained for MMP-13. Immunoreactivity to MMP-13 staining was localized to the cytoplasm of mildly, moderately, and severely dysplatic cells of adenomas and CRC tumor cells that were either homogenous or heterogeneous. There was no significant difference in MMP-13 expression between adenomas and CRCs either non-mucinous or mucinous. Adenomas with high MMP-13 expression were significantly associated with moderate to marked degree of inflammatory cellular infiltrate and presence of familial adenomatous polyps. In conclusion, MMP-13 may be a potential biological marker of early tumorigenesis in the adenoma-carcinoma sequence. [ABSTRACT FROM AUTHOR]

We present a case of a 64-year-old woman showing multistep progression from adenoma to adenocarcinoma in the bladder 46 years after augmentation ileocystoplasty. She underwent augmentation ileocystoplasty for tuberculous contracted bladder at 18 years. After 44 years, tubulovillous adenomas were found and resected at the ileovesical anastomosis site. After 2 more years, bladder tumors recurred and revealed adenocarcinomas. Finally, radical cystectomy was required because of frequent recurrence and tumor extensiveness. To our knowledge, this is the first case demonstrating adenoma-carcinoma sequence histopathologically in the bladder after augmentation cystoplasty, indicating multistep carcinogenesis similar to intestinal carcinogenesis.

Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy arising in mature cystic teratoma. In the present report we describe a 13-year-old girl who developed a large mass in her ovary. Fine needle biopsy identified intestinal type mucinous adenocarcinoma, which was also identified in the full surgical specimen. Extensive sampling of the surgical specimen also identified areas of mature cystic teratoma. Interestingly, molecular analysis of DNA extracted from various components of the lesion identified KRAS mutation in the carcinoma, borderline mucinous tumor and benign intestinal-type epithelium but not in the epidermal component of the teratoma. To the best of our knowledge this is the first report of KRAS mutation in mucinous carcinoma originating in mature cystic teratoma. We discuss the importance of extensive tissue sampling to differentiate between carcinoma originating in teratoma and metastatic colorectal carcinoma to the ovary. Additionally, the identification of KRAS mutation in the morphologically benign intestinal-type epithelium indicated that it is an early event in the carcinogenic sequence and that the molecular pathway of carcinogenesis in teratoma is similar to that in the carcinogenic process of somatic tissue. [ABSTRACT FROM AUTHOR]

Aims To clarify the lineage-specific carcinogenesis of gland-forming gastric neoplasms, by characterizing mucin phenotypes and proliferation patterns immunohistochemically using monoclonal antibodies against MUC2, MUC5 AC, MUC6, CD10 and Ki67. Methods and results We analysed 49 gland-forming intramucosal neoplasms, including 15 non-invasive low-grade neoplasms (group A), 10 non-invasive high-grade neoplasms (group B) and 24 intramucosal adenocarcinomas (group C). The mode of gland-forming gastric carcinoma development was different between the intestinal and gastric lineages. The pure intestinal-type accounted for 93% of group A, 50% of group B and 4.2% of group C tumours. A zonal pattern of cell proliferation was well retained in group A tumours and was lost size-dependently in group B tumours. These findings suggest that non-invasive low-grade neoplasms of the intestinal lineage progress to non-invasive high-grade neoplasms, but rarely to intramucosal adenocarcinomas. In tumours of the gastric lineage, which exhibited pure gastric or mixed phenotypes, the polarity of cell proliferation and differentiation was well retained in small (≦5 mm) tumours but was lost in larger tumours in groups B and C. Conclusions Intramucosal adenocarcinomas of the gastric lineage may often arise de novo, develop in the proper gastric mucosa, and are partially derived from non-invasive high-grade neoplasms. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims Neuropilin-1 ( NRP1) and neuropilin-2 ( NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor ( VEGF) to prevent tumour cell apoptosis and regulate angiogenesis. However, the precise role of NRP1 and NRP2 in the adenoma-carcinoma sequence ( ACS) of colorectal cancer remains unclear, and we aimed to determine this in surgical specimens comprising the ACS. Methods and results Histological analysis demonstrated that epithelial NRP1 expression increased significantly across the ACS ( P = 0.0007), and correlated with microvessel density ( MVD; r = 0.505, P = 0.0003) and weakly with VEGF ( r = 0.251, P = 0.001). In contrast, although NRP2 epithelial expression was increased significantly in all carcinomas ( P < 0.002), there was no correlation with MVD, VEGF or NRP1. Furthermore, patients showing coexpression of NRP1 and NRP2 had a potentially worse prognosis than those expressing a single neuropilin or neither one. Although vascular expression of NRP1 increased significantly across the ACS ( P = 0.0004) and correlated with MVD ( r = 0.361, P = 0.0006), NRP2 vascular expression decreased significantly ( P = 0.0001) and showed an inverse correlation with MVD ( r=−0.506, P = 0.0001), suggesting differential roles for neuropilins in the angiogenic process during colorectal cancer development. Conclusions These data suggest that an increase in NRP1 and NRP2 epithelial/tumour expression, as well as in NRP1 vascular expression, may be associated with disease progression in colorectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a leading cause of cancer death worldwide. Most colorectal cancers are preventable. Surveillance colonoscopy is used to detect and remove precancerous lesions. Although the majority of precancerous lesions develop sporadically, some have an inherited component. In this review, we summarize the clinical, pathologic, and molecular features of advanced precancerous lesions of the colon. The most common and clinically important intestinal polyposis syndromes, and their genetics, are also discussed. Finally, current recommendations regarding the treatment and surveillance of precancerous lesions, both in the sporadic and in inherited setting, are reviewed. [ABSTRACT FROM AUTHOR]

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases. [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The activation of Hedgehog signaling, which is critical to normal mammalian gastrointestinal development, is implicated in the development of various tumors, including colorectal cancer. In the pancreas, a precursor lesion overexpresses the Sonic hedgehog (Shh) when compared with normal tissue and cancer. The present study was designed to investigate Shh related protein expression in hyperplastic polyps and the adenoma-carcinoma sequence in the colon and rectum. Seventeen hyperplastic polyps, 24 adenomas of the colon, 69 adenocarcinomas (31 well-differentiated, 38 moderately-differentiated), and 30 normal colon samples were used in the study. We checked the expression of Shh, both patched (Ptch) and smoothened (Smo), by immunohistochemistry and compared the expression rate of each group. Almost all adenomas, 22 of 23 (96%), expressed Shh. In other groups, 4 of 17 hyperplastic polyps (24%), 7 of 31 well-differentiated adenocarcinomas (23%), 13 of 38 moderately-differentiated adenocarcinomas (34%) and none of the 30 normal samples expressed Shh. The rate of expression in Ptch and Smo gradually increased in accordance with tumor progression. This result indicates that Shh-related carcinogenesis and Shh expression may be a trigger for the adenoma-carcinoma sequence. This study suggests a potential therapeutic target of hedgehog blockade in carcinogenesis. [ABSTRACT FROM AUTHOR]

The interleukin-8 (IL-8) network is involved in the colorectal cancer (CRC) progression. However, its role during the adenoma–carcinoma transition to date has not been fully investigated. To evaluate the dynamic changes of IL-8 network along the colorectal adenoma–carcinoma sequence, we examined the tissue IL-8 mRNA level in colorectal biopsies from 53 colorectal adenomas, 44 CRCs and 18 controls by quantitative real-time PCR (Q-PCR), and the expressions of IL-8 and its receptors (IL-8RA and IL-8RB) in the tumor microenvironment by immunohistochemistry (IHC) and double IHCs. The results showed that the tissue IL-8 mRNA level began to increase in the precancerous lesions (adenomas) as compared with the controls and became even higher in the CRCs. Significantly, the increase of IL-8 mRNA levels was associated with the increase of dysplastic grades in the adenomas, and also paralleled to the increase of Duke’s stages in the CRCs. IHC results revealed that IL-8 and its receptors, IL-8RA and IL-8RB, were observed both in the stroma and in the adenomatous/cancerous cells. By double IHCs, the IL-8 expression was characterized in macrophages, lymphocytes and myofibroblasts in the tumor stroma. Further double IHC identified the co-expression of IL-8 receptors (IL-8RA and IL-8RB) with CD34 positive tumor-associated microvessels in both the adenomas and CRCs. We, therefore, conclude that activated IL-8 network in the tumor microenvironment may function as a significant regulatory factor for the adenoma progression and the adenoma–carcinoma transition. [ABSTRACT FROM AUTHOR]