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EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis.
Hardbower DM, Coburn LA, Asim M, Singh K, Sierra JC, Barry DP, Gobert AP, Piazuelo MB, Washington MK, Wilson KT
(2017) Oncogene 36: 3807-3819
MeSH Terms: Animals, Carcinogenesis, Colitis, Colon, Colonic Neoplasms, Dextran Sulfate, ErbB Receptors, Humans, Immunity, Innate, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Precancerous Conditions, Signal Transduction
Show Abstract · Added March 12, 2017
Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31 blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
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3 Members
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17 MeSH Terms
Bivariate Poisson models with varying offsets: an application to the paired mitochondrial DNA dataset.
Su PF, Mau YL, Guo Y, Li CI, Liu Q, Boice JD, Shyr Y
(2017) Stat Appl Genet Mol Biol 16: 47-58
MeSH Terms: Antineoplastic Agents, Base Sequence, Cancer Survivors, Computer Simulation, DNA, Mitochondrial, Databases, Nucleic Acid, Genome, Mitochondrial, Humans, Models, Biological, Mutation Rate, Regression Analysis
Show Abstract · Added April 18, 2017
To assess the effect of chemotherapy on mitochondrial genome mutations in cancer survivors and their offspring, a study sequenced the full mitochondrial genome and determined the mitochondrial DNA heteroplasmic (mtDNA) mutation rate. To build a model for counts of heteroplasmic mutations in mothers and their offspring, bivariate Poisson regression was used to examine the relationship between mutation count and clinical information while accounting for the paired correlation. However, if the sequencing depth is not adequate, a limited fraction of the mtDNA will be available for variant calling. The classical bivariate Poisson regression model treats the offset term as equal within pairs; thus, it cannot be applied directly. In this research, we propose an extended bivariate Poisson regression model that has a more general offset term to adjust the length of the accessible genome for each observation. We evaluate the performance of the proposed method with comprehensive simulations, and the results show that the regression model provides unbiased parameter estimations. The use of the model is also demonstrated using the paired mtDNA dataset.
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11 MeSH Terms
Differences in Patient Outcomes of Prevalence, Interval, and Screen-Detected Lung Cancers in the CT Arm of the National Lung Screening Trial.
Schabath MB, Massion PP, Thompson ZJ, Eschrich SA, Balagurunathan Y, Goldof D, Aberle DR, Gillies RJ
(2016) PLoS One 11: e0159880
MeSH Terms: Aged, Demography, Disease-Free Survival, Early Detection of Cancer, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mass Screening, Middle Aged, Neoplasm Staging, Prevalence, Proportional Hazards Models, Risk, Smoking, Tomography, X-Ray Computed
Show Abstract · Added January 29, 2018
Lung cancer screening identifies cancers with heterogeneous behaviors. Some lung cancers will be identified among patients who had prior negative CT screens and upon follow-up scans develop a de novo nodule that was determined to be cancerous. Other lung cancers will be identified among patients who had one or more prior stable positive scans that were not determined to be lung cancer (indeterminate pulmonary nodules), but in follow-up scans was diagnosed with an incidence lung cancer. Using data from the CT arm of the National Lung Screening Trial, this analysis investigated differences in patient characteristics and survival endpoints between prevalence-, interval-, and screen-detected lung cancers, characterized based on sequence of screening results. Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cohort. Interval cancers were diagnosed following a negative screen at any time point prior to the next screening round. Two cohorts of screen-detected lung cancers (SDLC) were identified that had a baseline positive screen that was that was not determined to be lung cancer (i.e., an indeterminate pulmonary nodule), but in follow-up scans was diagnosed with an incidence lung cancer 12 (SDLC1) or 24 (SDLC2) months later. Two other incidence cohorts had screen-detected lung cancers that had baseline negative screen and upon follow-up scans developed a de novo nodule determined to be cancerous at 12 (SDLC3) or 24 (SDLC4) months later. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed. The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). Moreover, PFS and OS were significantly lower for SDLC3/SDLC4 compared to SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). The findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR = 1.89; 95% CI 1.31-2.74) and OS (HR = 1.80; 95% CI 1.21-2.67) compared to SDLC1/SDLC2 lung cancers (HR = 1.00). Lung cancer patients who develop a de novo nodule that determined to be cancerous (i.e., at least one negative CT screen prior to cancer diagnosis) had poorer survival outcomes compared to patients who had at least one positive screen prior to cancer diagnosis. As such, the observation that de novo screen-detected are associated with poorer survival could be attributed to faster growing, more aggressive cancers that arose from a lung environment previously lacking focal abnormalities.
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17 MeSH Terms
A prospective study of autoantibodies to Ezrin and pancreatic cancer risk.
Sun Y, Wu J, Cai H, Wang S, Liu Q, Blot WJ, Shu XO, Cai Q
(2016) Cancer Causes Control 27: 831-5
MeSH Terms: Aged, Autoantibodies, Case-Control Studies, Cytoskeletal Proteins, Early Detection of Cancer, Enzyme-Linked Immunosorbent Assay, Female, Humans, Logistic Models, Male, Middle Aged, Pancreatic Neoplasms, Prospective Studies, Risk, United States
Show Abstract · Added April 3, 2018
PURPOSE - No biomarker is available for pancreatic cancer early detection, but a small prospective European study involving 16 cases and 32 controls raised the possibility that anti-Ezrin autoantibodies may be associated with risk of pancreatic cancer. We aimed to validate this finding in a case-control study nested within a prospective study in the USA.
METHODS - Levels of anti-Ezrin autoantibodies were examined using ELISA in pre-diagnostic plasma samples of 73 cases and 145 matched controls. Paired t test and paired signed rank tests were used to determine the difference between two groups, and conditional logistic regression was used to evaluate the association between anti-Ezrin autoantibody levels and risk of developing pancreatic cancer.
RESULTS - No association was found between levels of anti-Ezrin plasma autoantibodies and subsequent risk of developing pancreatic cancer.
CONCLUSION - Anti-Ezrin autoantibodies did not appear to be useful as a plasma biomarker for early detection of pancreatic cancer.
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MeSH Terms
Factors Associated with Multiple Biomarkers of Systemic Inflammation.
Navarro SL, Kantor ED, Song X, Milne GL, Lampe JW, Kratz M, White E
(2016) Cancer Epidemiol Biomarkers Prev 25: 521-31
MeSH Terms: Aged, Biomarkers, Cohort Studies, Early Detection of Cancer, Female, Humans, Inflammation, Male, Middle Aged
Show Abstract · Added March 10, 2016
BACKGROUND - While much is known about correlates of C-reactive protein (CRP), little is known about correlates of other inflammation biomarkers. As these measures are increasingly being used in epidemiologic studies, it is important to determine what factors affect inflammation biomarker concentrations.
METHODS - Using age, sex, and body mass index (BMI) adjusted linear regression, we examined 38 exposures (demographic and anthropometric measures, chronic disease history, NSAIDs, dietary factors, and supplement use) of 8 inflammation biomarkers [CRP, IL1β, IL6, IL8, TNFα, and soluble TNF receptors (sTNFR) in plasma; and prostaglandin E2 metabolite (PGE-M) in urine] in 217 adults, ages 50 to 76 years.
RESULTS - Increasing age was associated with higher concentrations of all biomarkers except IL1β. BMI was positively associated with CRP and sTNFR I and II. Saturated fat intake was associated with increased CRP, sTNFRII, TNFα, and IL1β, whereas eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) intake (diet or total) was associated with decreased CRP, TNFα, and IL1β. Results for sex were varied: CRP and IL6 were lower among men, whereas PGE-M and sTNFRI were higher. Higher CRP was also associated with smoking, hormone replacement therapy use, and γ-tocopherol intake; lower CRP with physical activity, and intakes of dietary vitamin C and total fiber.
CONCLUSIONS - Although the associations varied by biomarker, the factors having the greatest number of significant associations (P ≤ 0.05) with the inflammation biomarkers were age, BMI, dietary saturated fat, and EPA+DHA omega-3 fatty acids.
IMPACT - Our results suggest that potential confounders in epidemiologic studies assessing associations with inflammation biomarkers vary across specific biomarkers.
©2016 American Association for Cancer Research.
1 Communities
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9 MeSH Terms
Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.
Crawford EL, Levin A, Safi F, Lu M, Baugh A, Zhang X, Yeo J, Khuder SA, Boulos AM, Nana-Sinkam P, Massion PP, Arenberg DA, Midthun D, Mazzone PJ, Nathan SD, Wainz R, Silvestri G, Tita J, Willey JC
(2016) BMC Pulm Med 16: 16
MeSH Terms: Aged, Aged, 80 and over, Agriculture, Asbestos, Biological Specimen Banks, Bronchi, Bronchoscopy, Cohort Studies, Early Detection of Cancer, Epithelial Cells, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Humans, Incidence, Lung Diseases, Obstructive, Lung Neoplasms, Male, Middle Aged, Occupational Exposure, Prospective Studies, Respiratory Mucosa, Risk Assessment, Smoking, Tomography, Spiral Computed, Vital Capacity
Show Abstract · Added February 16, 2016
BACKGROUND - The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository.
METHODS/DESIGN - Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject.
DISCUSSION - Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk.
TRIAL REGISTRATION - The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.
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26 MeSH Terms
The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice.
Garay J, Piazuelo MB, Majumdar S, Li L, Trillo-Tinoco J, Del Valle L, Schneider BG, Delgado AG, Wilson KT, Correa P, Zabaleta J
(2016) Cancer Lett 371: 90-8
MeSH Terms: Animals, Antigens, Ly, Cells, Cultured, Chemotaxis, Leukocyte, Disease Models, Animal, Disease Progression, Female, Gastric Mucosa, Gastritis, Atrophic, Helicobacter Infections, Helicobacter pylori, Humans, Hyaluronan Receptors, Interferon-gamma, Macrophages, Peritoneal, Mice, Knockout, Neutrophil Infiltration, Neutrophils, Precancerous Conditions, Signal Transduction, Stomach Neoplasms, Time Factors
Show Abstract · Added February 15, 2016
Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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22 MeSH Terms
Pathobiology of Helicobacter pylori-Induced Gastric Cancer.
Amieva M, Peek RM
(2016) Gastroenterology 150: 64-78
MeSH Terms: Female, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Male, Microbiota, Precancerous Conditions, Prognosis, Stomach Neoplasms
Show Abstract · Added February 5, 2016
Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.
Copyright © 2016. Published by Elsevier Inc.
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10 MeSH Terms
Consensus on biomarkers for neuroendocrine tumour disease.
Oberg K, Modlin IM, De Herder W, Pavel M, Klimstra D, Frilling A, Metz DC, Heaney A, Kwekkeboom D, Strosberg J, Meyer T, Moss SF, Washington K, Wolin E, Liu E, Goldenring J
(2015) Lancet Oncol 16: e435-e446
MeSH Terms: Biomarkers, Tumor, Delphi Technique, Humans, MicroRNAs, National Cancer Institute (U.S.), Neoplastic Cells, Circulating, Neuroendocrine Tumors, Prognosis, United States
Show Abstract · Added April 12, 2016
Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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1 Members
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9 MeSH Terms
Evaluation of pro-inflammatory markers plasma C-reactive protein and urinary prostaglandin-E2 metabolite in colorectal adenoma risk.
Davenport JR, Cai Q, Ness RM, Milne G, Zhao Z, Smalley WE, Zheng W, Shrubsole MJ
(2016) Mol Carcinog 55: 1251-61
MeSH Terms: Adenoma, Aged, Biomarkers, Tumor, C-Reactive Protein, Case-Control Studies, Colonoscopy, Colorectal Neoplasms, Dinoprostone, Early Detection of Cancer, Female, Humans, Male, Middle Aged, Risk Assessment, Risk Factors
Show Abstract · Added September 28, 2015
C-reactive protein (CRP) is a pro-inflammatory protein with potential as a biomarker in predicting colon cancer risk. However, little is known regarding its association with risk of colorectal adenomas, particularly by subtypes. We conducted a colonoscopy-based matched case-control study to assess whether elevated plasma CRP levels may be associated with colorectal adenoma risk and further whether this association may be modified by urinary prostaglandin E2 metabolite (PGE-M), a biomarker of systemic prostaglandin E2 production. Included in the study were 226 cases with a single small tubular adenoma, 198 cases with multiple small tubular adenomas, 283 cases with at least one advanced adenoma, and 395 polyp-free controls. No apparent association between CRP level and risk of single small tubular adenomas was found (ptrend  = 0.59). A dose-response relationship with CRP level was observed for risk of either multiple small tubular adenomas (OR = 2.01, 95%CI = 1.10-3.68 for the highest versus lowest tertile comparison; ptrend   = 0.03) or advanced adenomas (OR = 1.81, 95%CI = 1.10-2.96 for the highest versus lowest tertile comparison; ptrend  = 0.02). In a joint analysis of CRP level and PGE-M, risk of multiple or advanced adenoma was greatest among those with highest levels of both CRP and PGE-M in comparison to those with low CRP and low PGE-M (OR = 3.72, 95%CI = 1.49-9.72). Our results suggest that elevated CRP, particularly in the context of concurrent elevated PGE-M, may be a biomarker of multiple or advanced adenoma risk in a screening age population. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
1 Communities
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15 MeSH Terms