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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]

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]

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]

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]

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]

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]

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.)

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]

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.)

We sought to clarify pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth. Colorectal carcinomas resected at Showa University Hospital in Tokyo included 86 with characteristics of polypoid growth (PG) and 21 with those of nonpolypoid growth (NPG). Mutations of APC, Ki-ras, and p53 genes, as well as microsatellite instability (MSI), were analysed using fluorescence-based polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Carcinomas with an NPG pattern were smaller than PG tumours (P<0.0001). Carcinomas with a PG pattern were more likely to harbour Ki-ras mutations (36%) than NPG tumours (0%; P<0.0001). Mutation types in the APC gene differed significantly between PG and NPG carcinomas (P=0.0189), including frameshift mutations in 66% of PG carcinomas but no NPG carcinomas. Presence of a p53 mutation at a 'hot spot' also was more likely in PG carcinomas (37%) than in NPG carcinomas (0%; P=0.0124). No significant difference in presence of MSI was evident between carcinomas with PG and NPG patterns. In conclusion, significant genetic differences were evident between carcinomas with PG and NPG patterns. Genetic changes in NPG carcinomas differed from those of the conventional adenoma-carcinoma sequence. Assuming that some nonpolypoid growth lesions transform rapidly into advanced carcinomas, 20% of all colorectal carcinomas may progress in this manner. [ABSTRACT FROM AUTHOR]

To investigate the role of telomerase activity in colorectal adenoma-carcinomas, telomerase activity, human telomerase RNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA were quantitatively analyzed in human cancerous and precancerous colorectal tissues. Sixty-six colorectal tumor specimens, including 10 invasive carcinomas, 6 mucosal carcinomas and 50 adenomas were evaluated. Ten specimens of normal tissue were also included in the study. Telomerase activity was assayed by semiquantitative fluorescence using the TRAP-ezeTM telomerase detection kit. Analysis of the expression of each telomerase subunit gene was performed by real-time PCR amplification. There was a positive correlation between histological atypia and telomerase activity (ρ = 0.700, p < 0.0001), hTERT mRNA expression (ρ = 0.603, p < 0.0001), and hTERC expression (ρ = 0.290, p < 0.05). There was also a positive correlation between the levels of hTERT mRNA and telomerase activity (r = 0.455, p < 0.01). Significant differences in the levels of hTERT mRNA were shown between normal tissues and the adenomas (p < 0.05) and between the mucosal carcinomas and invasive carcinomas (p < 0.05). The values of hTERC expression in neoplastic tissues were significantly higher than in the normal tissues; however, there were no significant differences between the adenomas and the carcinomas. In summary, although upregulation of hTERC expression is an early event in adenoma development, hTERT mRNA expression is gradually upregulated during the adenoma-carcinoma sequence and may be a rate-limiting determinant of telomerase activity. Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Ampullary adenomas arising in the papilla or the ampulla Vateri, are rare, benign, neoplastic lesions. No specific aetiological factors, such as diet, chemical or environmental causes, have been identified yet. An established risk factor which is accompanied by the development of adenoma is the presence of genetically inherited polyposis syndromes, e.g. familial adenomatosis coli (FAP). Adenomas assume tubular, tubulovillous, or villous architecture and are not different from adenomas arising elsewhere in the gastrointestinal tract. The full neoplastic spectrum, ranging from mild to high grade dysplasia, up to invasive carcinoma, resembles the adenoma-carcinoma sequence of the large bowels. [ABSTRACT FROM AUTHOR]

A rare case of jejunal carcinoma coexisting with adenoma, situated 120 cm distal to the ligament of Treitz in a 53 year old male, is reported herein. We also review cases of adenoma and carcinoma in the jejunum and ileum from the Japanese literature, and discuss the histogenesis of carcinoma of the jejunum and ileum. [ABSTRACT FROM AUTHOR]

In order to examine whether our subdivision of gall-bladder adenoma and adenocarcinoma into nonmetaplastic and metaplastic types is reasonable from the viewpoint of their cytological features, a morphometrical analysis was conducted on 17 adenomas and 59 adenocarcinomas. The morphometrical parameters used were nucleo-cytoplasmic ratio (N/C ratio) and nuclear areas (NA). N/C ratio in the metaplastic type of both adenoma and adenocarcinoma was significantly larger than that in the non-metaplastic. This result shows that the different tumour types are associated with a different N/C ratio. Continuous measurement of N/C ratio and NA in progressing from non-cancerous mucosa to the lesion was made and the data obtained were analysed by the Lowess method. In some adenomas the total area of polypoid lesions was serially measured and these data were also analysed by the Lowess method. The results showed different processes in non-metaplastic and metaplastic types of adenoma and adenocarcinoma from the standpoint of nuclear changes of N/C ratio and NA. These results indicate that our histogenetic classification of adenocarcinoma is reasonable in morphometrical nuclear analysis. We also investigated the adenoma-carcinoma sequence as a possible histogenesis for gall-bladder carcinoma. Eight (72.7%) of 11 metaplastic adenomas and two (33.3%) of six non-metaplastic adenomas had foci of atypical gland proliferation and were considered to be carcinomas. Moreover, these carcinomatous areas were surrounded by severe dysplasia. These findings indicate that adenoma-carcinoma sequence accounts for one of the histogeneses of gall-bladder carcinoma. [ABSTRACT FROM AUTHOR]

To study the proliferative change of epithelium and gene expression in adenoma-carcinoma sequence of gallbladder carcinogenesis. Mutations of K-ras gene and APC gene were detected by PCR-RFLP, and the expression of p53 protein was detected by ABC immunohistochemistry. DNA contents were detected by using a TJTY-300 automatic image analyzer. Cell DNA contents and atypia were increased gradually in the adenoma-carcinoma sequence of gallbladder. Aneuploidy in gallbladder adenoma was associated with the size of adenoma. When the diameter of adenoma was more than 1 cm, the aneuploidy was significantly increased ( P<0.05). APC gene and K-ras gene mutations were detected in the adenoma-carcinoma pathway. and p53 protein overexpression was not detected in this pathway. Adenoma-carcinoma sequence pathway plays an important role in gallbladder carcinogenesis. Gallbladder adenoma has an obvious tendency to malignant transformation, especially in the patients with adenoma of 1 cm in diameter or above. It has molecular abnormalities different from those de novo carcinomas. [ABSTRACT FROM AUTHOR]