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Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.
Powell AE, Vlacich G, Zhao ZY, McKinley ET, Washington MK, Manning HC, Coffey RJ
(2014) Am J Physiol Gastrointest Liver Physiol 307: G16-23
MeSH Terms: Adenomatous Polyposis Coli, Animals, Cell Transformation, Neoplastic, Colon, Colonoscopy, Disease Models, Animal, Genes, APC, Hypertrophy, Membrane Glycoproteins, Mice, Mice, Transgenic, Neoplastic Stem Cells, Nerve Tissue Proteins, Positron-Emission Tomography, Precancerous Conditions, Retinal Pigment Epithelium, Time Factors
Show Abstract · Added May 20, 2014
Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.
Copyright © 2014 the American Physiological Society.
1 Communities
4 Members
0 Resources
17 MeSH Terms
Associations between dietary fiber and colorectal polyp risk differ by polyp type and smoking status.
Fu Z, Shrubsole MJ, Smalley WE, Ness RM, Zheng W
(2014) J Nutr 144: 592-8
MeSH Terms: Adenomatous Polyps, Adult, Aged, Case-Control Studies, Colonic Polyps, Colonoscopy, Colorectal Neoplasms, Dietary Fiber, Female, Humans, Male, Middle Aged, Precancerous Conditions, Risk Factors, Risk Reduction Behavior, Smoking, Tennessee
Show Abstract · Added March 10, 2014
The association of dietary fiber intake with colorectal cancer risk is established. However, the association may differ between cigarette smokers and nonsmokers. We evaluated this hypothesis in a large colonoscopy-based case-control study. Dietary fiber intakes were estimated by self-administered food frequency questionnaire. Unconditional logistic regression analysis was used to estimate ORs and 95% CIs with adjustment for potential confounders. Analysis also was stratified by cigarette smoking and sex. High dietary fiber intake was associated with reduced risk of colorectal polyps (P-trend = 0.003). This association was found to be stronger among cigarette smokers (P-trend = 0.006) than nonsmokers (P-trend = 0.21), although the test for multiplicative interaction was not statistically significant (P = 0.11). This pattern of association was more evident for high-risk adenomatous polyps (ADs), defined as advanced or multiple ADs (P-interaction smoking and dietary fiber intake = 0.09). Among cigarette smokers who smoked ≥23 y, a 38% reduced risk of high-risk ADs was found to be associated with high intake of dietary fiber compared with those in the lowest quartile fiber intake group (P-trend = 0.004). No inverse association with dietary fiber intake was observed for low-risk ADs, defined as single nonadvanced ADs. Cigarette smoking may modify the association of dietary fiber intake with the risk of colorectal polyps, especially high-risk ADs, a well-established precursor of colorectal cancer.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage.
Chaturvedi R, Asim M, Piazuelo MB, Yan F, Barry DP, Sierra JC, Delgado AG, Hill S, Casero RA, Bravo LE, Dominguez RL, Correa P, Polk DB, Washington MK, Rose KL, Schey KL, Morgan DR, Peek RM, Wilson KT
(2014) Gastroenterology 146: 1739-51.e14
MeSH Terms: Animals, Apoptosis, Cell Line, Cell Survival, Cell Transformation, Neoplastic, Coculture Techniques, Colombia, DNA Damage, Disease Progression, Enzyme Activation, Epithelial Cells, ErbB Receptors, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Honduras, Humans, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidoreductases Acting on CH-NH Group Donors, Phosphorylation, Precancerous Conditions, Principal Component Analysis, Protein Multimerization, Receptor, ErbB-2, Signal Transduction, Stomach Neoplasms, Tennessee
Show Abstract · Added March 5, 2014
BACKGROUND & AIMS - The gastric cancer-causing pathogen Helicobacter pylori up-regulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects.
METHODS - SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H. pylori-infected Egfr(wa5) mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. A phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsy specimens from Colombian and Honduran cohorts were analyzed by immunohistochemistry.
RESULTS - SMOX expression and DNA damage were decreased, and apoptosis increased in H. pylori-infected Egfr(wa5) mice. H. pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damage(high) apoptosis(low) cells. Phosphoproteomic analysis showed increased EGFR and erythroblastic leukemia-associated viral oncogene B (ERBB)2 signaling. Immunoblot analysis showed the presence of a phosphorylated (p)EGFR-ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damage(high) apoptosis(low) cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR-ERBB2, and pERBB2 were increased predominantly in tissues showing gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR-ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress.
CONCLUSIONS - In an analysis of gastric tissues from mice and patients, we identified a molecular signature (based on levels of pEGFR, pERBB2, and SMOX) for the initiation of gastric carcinogenesis.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
0 Communities
9 Members
0 Resources
31 MeSH Terms
Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry.
Shi C, Merchant N, Newsome G, Goldenberg DM, Gold DV
(2014) Arch Pathol Lab Med 138: 220-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Diagnosis, Differential, Humans, Immunohistochemistry, Mucin-1, Neoplasm Grading, Neoplasm Staging, Pancreas, Pancreatectomy, Pancreatic Cyst, Pancreatic Ducts, Pancreatic Neoplasms, Pancreatitis, Chronic, Precancerous Conditions, Tissue Array Analysis
Show Abstract · Added March 10, 2014
CONTEXT - PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC.
OBJECTIVE - To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas.
DESIGN - Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9.
RESULTS - PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue.
CONCLUSIONS - PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Incidental atypical proliferative lesions in reduction mammoplasty specimens in patients with a history of breast cancer.
Li Z, Fadare O, Hameed O, Zhao C, Desouki MM
(2014) Hum Pathol 45: 104-9
MeSH Terms: Adult, Aged, Breast Neoplasms, Carcinoma in Situ, Carcinoma, Ductal, Breast, Carcinoma, Intraductal, Noninfiltrating, Carcinoma, Lobular, Cell Proliferation, Female, Humans, Incidental Findings, Mammaplasty, Middle Aged, Precancerous Conditions, Prevalence, Retrospective Studies
Show Abstract · Added March 7, 2014
We recently reported the prevalence of atypical proliferative lesions (APL) in reduction mammoplasty specimens from patients that were treated mainly for macromastia with no known history of breast cancer. The current study is to investigate the prevalence of APLs in breast reduction specimens from patients with a history of breast cancer and compare it to that from patients without a history of breast cancer. A retrospective chart review of pathology records on patients that underwent reduction mammoplasty from 2006 to 2012 generated 179 cases. Laterality, specimen weight, number of blocks submitted and presence of APL were recorded and analyzed. We defined APL as invasive carcinoma, ductal (DCIS) or lobular carcinoma in situ, atypical ductal or lobular hyperplasia (ADH or ALH), and flat epithelial atypia (FEA). The presence of papillomas, radial scars and fibroadenomas were also recorded. At least 1 APL was identified in 23 (12.8%) of 179 specimens including invasive lobular carcinoma (n = 3), DCIS (n = 1), ADH/FEA (n = 9) and lobular carcinoma in situ/ALH (n = 10). The most common APL in this cohort was lobular neoplasia (5.6%) followed by ADH and FEA (5.0%). Invasive carcinoma and DCIS was identified in 2.3% of this cohort. In conclusion, the frequency of detection of APLs in patients with history of breast cancer is significantly higher than that in patients without history of breast cancer (12.8% versus 4.3%). Our data assessed the prevalence of APLs in this setting and, therefore, provide new information on decision-making for contralateral breast reduction in patients with history of breast cancer.
© 2013.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Identification and manipulation of biliary metaplasia in pancreatic tumors.
Delgiorno KE, Hall JC, Takeuchi KK, Pan FC, Halbrook CJ, Washington MK, Olive KP, Spence JR, Sipos B, Wright CV, Wells JM, Crawford HC
(2014) Gastroenterology 146: 233-44.e5
MeSH Terms: Animals, Bile Ducts, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, HMGB Proteins, Humans, Metaplasia, Mice, Mice, Transgenic, Pancreatic Ducts, Pancreatic Neoplasms, Pancreatitis, Precancerous Conditions, Proto-Oncogene Proteins p21(ras), SOXF Transcription Factors, Signal Transduction
Show Abstract · Added January 17, 2014
BACKGROUND & AIMS - Metaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis.
METHODS - We analyzed pancreatic tissue and tumors that developed in mice that express an activated form of Kras (Kras(LSL-G12D/+);Ptf1a(Cre/+) mice). Normal bile duct, pancreatic duct, and tumor-associated metaplasias from the mice were analyzed for tuft cell and biliary progenitor markers, including SOX17, a transcription factor that regulates biliary development. We also analyzed pancreatic tissues from mice expressing transgenic SOX17 alone (ROSA(tTa/+);Ptf1(CreERTM/+);tetO-SOX17) or along with activated Kras (ROSAtT(a/+);Ptf1a(CreERTM/+);tetO-SOX17;Kras(LSL-G12D;+)).
RESULTS - Tuft cells were frequently found in areas of pancreatic metaplasia, decreased throughout tumor progression, and absent from invasive tumors. Analysis of the pancreatobiliary ductal systems of mice revealed tuft cells in the biliary tract but not the normal pancreatic duct. Analysis for biliary markers revealed expression of SOX17 in pancreatic metaplasia and tumors. Pancreas-specific overexpression of SOX17 led to ductal metaplasia along with inflammation and collagen deposition. Mice that overexpressed SOX17 along with Kras(G12D) had a greater degree of transformed tissue compared with mice expressing only Kras(G12D). Immunofluorescence analysis of human pancreatic tissue arrays revealed the presence of tuft cells in metaplasia and early-stage tumors, along with SOX17 expression, consistent with a biliary phenotype.
CONCLUSIONS - Expression of Kras(G12D) and SOX17 in mice induces development of metaplasias with a biliary phenotype containing tuft cells. Tuft cells express a number of tumorigenic factors that can alter the microenvironment. Expression of SOX17 induces pancreatitis and promotes Kras(G12D)-induced tumorigenesis in mice.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
2 Members
0 Resources
16 MeSH Terms
Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men.
Schwartz LM, Castle PE, Follansbee S, Borgonovo S, Fetterman B, Tokugawa D, Lorey TS, Sahasrabuddhe VV, Luhn P, Gage JC, Darragh TM, Wentzensen N
(2013) J Infect Dis 208: 1768-75
MeSH Terms: Adolescent, Adult, Anal Canal, Anus Neoplasms, CD4 Lymphocyte Count, California, Chlamydia Infections, Confidence Intervals, Demography, HIV Infections, HIV Seropositivity, Homosexuality, Male, Humans, Logistic Models, Male, Middle Aged, Papillomaviridae, Papillomavirus Infections, Precancerous Conditions, Risk Factors, Sexual Behavior, Smoking, Young Adult
Show Abstract · Added March 5, 2014
BACKGROUND - Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM.
METHODS - Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer.
RESULTS - Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection.
CONCLUSIONS - We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Barrett's esophagus surveillance: time to rethink if one size fits all?
Vaezi MF, Kahrilas PJ
(2013) Gastroenterology 145: 503-5
MeSH Terms: Adenocarcinoma, Barrett Esophagus, Esophageal Neoplasms, Female, Humans, Male, Precancerous Conditions
Added March 7, 2014
0 Communities
1 Members
0 Resources
7 MeSH Terms
Evidence for enhanced telomerase activity in Barrett's esophagus with dysplasia and adenocarcinoma.
Merchant NB, Dutta SK, Girotra M, Arora M, Meltzer SJ
(2013) Asian Pac J Cancer Prev 14: 679-83
MeSH Terms: Adenocarcinoma, Aged, Barrett Esophagus, Biomarkers, Tumor, Endoscopy, Digestive System, Esophageal Neoplasms, Esophagus, Gastric Mucosa, Gastritis, Humans, Hyperplasia, Inflammation, Middle Aged, Precancerous Conditions, Telomerase
Show Abstract · Added March 26, 2014
BACKGROUND - Dysplasia and adenocarcinoma developing in Barrett's esophagus (BE) are not always endoscopically identifiable. Molecular markers are needed for early recognition of these focal lesions and to identify patients at increased risk of developing adenocarcinoma. The aim of the current study was to correlate increased telomerase activity (TA) with dysplasia and adenocarcinoma occurring in the setting of BE.
MATERIALS AND METHODS - Esophageal mucosal biopsies were obtained from patients (N=62) who had pathologically verified BE at esophagogastroduodenoscopy (EGD). Mucosal biopsies were also obtained from the gastric fundus as controls. Based on histopathology, patients were divided into three groups: 1) BE without dysplasia (n=24); 2) BE with dysplasia (both high grade and low grade, n=13); and 3) BE with adenocarcinoma (n=25). TA was measured by a PCR-based assay (TRAPeze® ELISA Telomerase Detection Kit). Statistical analyses were performed using one-way ANOVA and post-hoc Bonferroni testing.
RESULTS - TA was significantly higher in biopsies of BE with dyplasia and BE with adenocarcinoma than in BE without dysplasia. Subgroup analyses did not reveal any significant correlations between TA and patient age, length of BE, or presence of gastritis.
CONCLUSIONS - Telomerase activity in esophageal mucosal biopsies of BE may constitute a useful biomarker for the early detection of esophageal dysplasia and adenocarcinoma.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Key considerations and current perspectives of epidemiological studies on human papillomavirus persistence, the intermediate phenotype to cervical cancer.
Sudenga SL, Shrestha S
(2013) Int J Infect Dis 17: e216-20
MeSH Terms: Female, Humans, Papillomaviridae, Papillomavirus Infections, Phenotype, Precancerous Conditions, Risk Factors, Uterine Cervical Neoplasms
Show Abstract · Added August 15, 2017
Persistent infection with human papillomavirus (HPV) causes essentially all precancerous cervical lesions and cervical cancer in females and thus is an important intermediate phenotype to cervical cancer. A majority of infected individuals naturally clear HPV viral infection, but the virus persists in a subset of infected hosts and the mechanism for this differential outcome is not well described. Most of the epidemiological studies have been cross-sectional in nature, and even with longitudinal studies, the definition of HPV persistence or clearance has not been well defined. There is no consensus on the correct time interval between HPV DNA tests, or how to utilize HPV persistence information in clinical management because there is no treatment for HPV. While most studies are performed with the endpoint of cancer, the intermediate phenotype has been overlooked. Epidemiological studies of HPV persistence suffer with several challenges in definitions, study designs, and analyses that undermine its importance in identifying and understanding the interactions between the viral and host genomes in the process of HPV infection pathogenesis. We have evaluated the current status of HPV persistence and provide perspectives on how the field would benefit from a research focus on intermediate phenotype in epidemiological studies.
Copyright © 2013 International Society for Infectious Diseases. All rights reserved.
0 Communities
1 Members
0 Resources
8 MeSH Terms