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Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus HO, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
Gastric cancer remains a leading cause of cancer-related mortality. Identifying dietary and other modifiable disease determinants has important implications for risk attenuation in susceptible individuals. Our primary aim was to estimate the association between dietary and supplemental intakes of calcium and magnesium and the risk of incident gastric cancer. We conducted a prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons Diet and Health Study. We used Cox proportional hazard modeling to estimate the association between calcium and magnesium intakes with risk of incident gastric adenocarcinoma (GA) overall and by anatomic location, noncardia GA (NCGA) and cardia GA (CGA). A total of 536,403 respondents (59% males, 41% females) were included for analysis, among whom 1,518 incident GAs (797 NCGA and 721 CGA) occurred. Increasing calcium intake was associated with lower risk of GA overall (p-trend = 0.05), driven primarily by the association with NCGA, where the above median calcium intakes were associated with a 23% reduction in risk compared to the lowest quartile (p-trend = 0.05). This magnitude of NCGA risk reduction was greater among nonwhite ethnic group and Hispanics (hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.24-1.07, p-trend = 0.04), current/former smokers (HR 0.58, 95% CI: 0.41-0.81), obese individuals (HR 0.54, 95% CI: 0.31-0.96) and those with high NCGA risk scores (HR 0.50, 95% CI: 0.31-0.80). Among men only, increasing magnesium intake was associated with 22-27% reduced risk of NCGA (p-trend = 0.05), while for the cohort, dietary magnesium intake in the highest vs. lowest quartile was associated with a 34% reduced risk of NCGA (HR 0.66, 95% CI: 0.48-0.90). These findings have important implications for risk factor modification. Future investigations are needed not only to confirm our results, but to define mechanisms underlying these associations.
© 2019 UICC.
The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes, such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16 mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso mice was equivalent to wild-type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild-type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16 samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.
BACKGROUND - The American Thyroid Association guidelines task force currently recommends definitive thyroidectomy or lobectomy after an indeterminate thyroid biopsy in children. This recommendation is based on evidence of a greater incidence and a higher risk of malignancy compared with adults in earlier pediatric studies. Such management may lead to overtreatment and unnecessary surgery for many children in the United States.
METHODS - The objective of the current study was to re-evaluate pediatric thyroid nodules and assess the overall percentages and malignancy rates for indeterminate thyroid biopsies in children. In total, 302 pediatric thyroid fine-needle aspirations (FNAs) were analyzed retrospectively (2001-2018). Distribution percentages and malignancy rates were calculated for each category of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).
RESULTS - Two indeterminate TBSRTC groups (atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for a follicular neoplasm) had much lower distribution percentages and malignancy rates compared with earlier pediatric series and American Thyroid Association guidelines. A meta-analysis further supported these findings and demonstrated distinctly different malignancy rates for the indeterminate groups (atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignancy), suggesting the need for TBSRTC category-specific management recommendations rather than a nondiscriminatory, up-front surgical approach.
CONCLUSIONS - Adult patients with indeterminate preoperative thyroid cytopathology are followed by repeat biopsy and possibly molecular testing before undergoing definitive surgery. However, in children, the guidelines are considerably more aggressive and recommend definitive surgery after the first indeterminate thyroid biopsy. Here, the largest pediatric cohort to date with meta-analysis is presented, and the authors propose a re-evaluation of this up-front approach to pediatric thyroid care.
© 2019 American Cancer Society.
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
AIMS - Colorectal carcinoma (CRC) often has a mucinous component, with more than 50% mucin by volume defining the mucinous subtype of CRC. The prognostic impact of the mucinous phenotype remains unclear.
METHODS AND RESULTS - We evaluated 224 CRC with at least 5% mucinous component (herein 'mCRC') for patient sex, age, race and outcome; tumour size, location, stage and microsatellite instability (MSI) status; percentage of glands producing mucin; percentage of tumour volume composed of mucin; whether tumoral epithelium floated in mucin pools; tumour budding; signet ring cells (SRCs); and peritumoural inflammation (PI). We related these features to disease-specific survival and compared outcomes to 499 stage-matched, conventional colorectal adenocarcinomas. Factors predicting worse prognosis in mCRC on univariable analysis included non-MSI-high status (P = 0.0008), SRC (P = 0.0017) and lack of PI (P = 0.0034). No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. The percentage of glands producing mucin and percentage tumour volume composed of mucin did not affect prognosis, including at the recommended 50% cut-off for subtyping mCRC. Disease-specific survival for mCRC and adenocarcinomas were similar after accounting for stage.
CONCLUSIONS - Stage-matched mCRCs and adenocarcinomas have similar outcomes, with no prognostic significance to morphological subtyping. Histological characteristics of mCRC, including percentage of tumour volume comprised of mucin, were not predictive of outcome.
© 2018 John Wiley & Sons Ltd.
Gastric adenocarcinoma develops in metaplastic mucosa associated with infection in the stomach. We have sought to evaluate the precise lineage changes in the stomachs of insulin-gastrin (INS-GAS) mice infected with and/or intestinal flora (Altered Schaedler's Flora; ASF). Stomachs from groups infected with contained progressive spasmolytic polypeptide-expressing metaplasia (SPEM) compared with germ-free and mice infected with ASF alone. The overall phenotype of the -infected mice was dominated by Ulex europaeus lectin (UEAI)-positive foveolar hyperplasia that was distinct from GSII/CD44v9-positive SPEM. However, in the mice with co-infected with ASF, we identified a subpopulation of UEAI-positive foveolar cells that co-expressed intestinal mucin 4 (MUC4). These regions of foveolar cells were variably positive for CD44v9 as well as TFF3. Interestingly, an intravascular lesion identified in a dual /ASF-infected mouse expressed both UEAI and . Finally, we identified an increase in the number of tuft cells within the mucosa of -infected groups. Our findings suggest that infection promotes foveolar hyperplasia as well as metaplasia, while co-infection may promote progressive foveolar and metaplastic lesions as well as dysplasia. Grading of gastric lesions in mice as preneoplastic requires multiple immunostaining markers to assign lineage derivation and behavior.
While many studies have demonstrated that canonical NF-κB signaling is a central pathway in lung tumorigenesis, the role of non-canonical NF-κB signaling in lung cancer remains undefined. We observed frequent nuclear accumulation of the non-canonical NF-κB component p100/p52 in human lung adenocarcinoma. To investigate the impact of non-canonical NF-κB signaling on lung carcinogenesis, we employed transgenic mice with doxycycline-inducible expression of p52 in airway epithelial cells. p52 over-expression led to increased tumor number and progression after injection of the carcinogen urethane. Gene expression analysis of lungs from transgenic mice combined with in vitro studies suggested that p52 promotes proliferation of lung epithelial cells through regulation of cell cycle-associated genes. Using gene expression and patient information from The Cancer Genome Atlas (TCGA) database, we found that expression of p52-associated genes was increased in lung adenocarcinomas and correlated with reduced survival, even in early stage disease. Analysis of p52-associated gene expression in additional human lung adenocarcinoma datasets corroborated these findings. Together, these studies implicate the non-canonical NF-κB component p52 in lung carcinogenesis and suggest modulation of p52 activity and/or downstream mediators as new therapeutic targets.