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ObjectiveSerrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically.DesignParticipants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models.ResultsSPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively).ConclusionIn a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6–10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. Trial registration number NCT00153816; Results.

The objective of this study was to explore hair mercury level in association with chronic atrophic gastritis, a precancerous stage of gastric cancer (GC), and thus provide a brand new angle of view on the timely intervention of precancerous stage of GC. We recruited 149 healthy volunteers as controls and 152 patients suffering from chronic gastritis as cases. The controls denied upper gastrointestinal discomforts, and the cases were diagnosed as chronic superficial gastritis ( n  = 68) or chronic atrophic gastritis ( n  = 84). We utilized Mercury Automated Analyzer (NIC MA-3000) to detect hair mercury level of both healthy controls and cases of chronic gastritis. The statistic of measurement data was expressed as mean ± standard deviation, which was analyzed using Levene variance equality test and t test. Pearson correlation analysis was employed to determine associated factors affecting hair mercury levels, and multiple stepwise regression analysis was performed to deduce regression equations. Statistical significance is considered if p value is less than 0.05. The overall hair mercury level was 0.908949 ± 0.8844490 ng/g [mean ± standard deviation (SD)] in gastritis cases and 0.460198 ± 0.2712187 ng/g (mean ± SD) in healthy controls; the former level was significantly higher than the latter one ( p  = 0.000 < 0.01). The hair mercury level in chronic atrophic gastritis subgroup was 1.155220 ± 0.9470246 ng/g (mean ± SD) and that in chronic superficial gastritis subgroup was 0.604732 ± 0.6942509 ng/g (mean ± SD); the former level was significantly higher than the latter level ( p  < 0.01). The hair mercury level in chronic superficial gastritis cases was significantly higher than that in healthy controls ( p  < 0.05). The hair mercury level in chronic atrophic gastritis cases was significantly higher than that in healthy controls ( p  < 0.01). Stratified analysis indicated that the hair mercury level in healthy controls with eating seafood was significantly higher than that in healthy controls without eating seafood ( p  < 0.01) and that the hair mercury level in chronic atrophic gastritis cases was significantly higher than that in chronic superficial gastritis cases ( p  < 0.01). Pearson correlation analysis indicated that eating seafood was most correlated with hair mercury level and positively correlated in the healthy controls and that the severity of gastritis was most correlated with hair mercury level and positively correlated in the gastritis cases. Multiple stepwise regression analysis indicated that the regression equation of hair mercury level in controls could be expressed as 0.262 multiplied the value of eating seafood plus 0.434, the model that was statistically significant ( p  < 0.01). Multiple stepwise regression analysis also indicated that the regression equation of hair mercury level in gastritis cases could be expressed as 0.305 multiplied the severity of gastritis, the model that was also statistically significant ( p  < 0.01). The graphs of regression standardized residual for both controls and cases conformed to normal distribution. The main positively correlated factor affecting the hair mercury level is eating seafood in healthy people whereas the predominant positively correlated factor affecting the hair mercury level is the severity of gastritis in chronic gastritis patients. That is to say, the severity of chronic gastritis is positively correlated with the level of hair mercury. The incessantly increased level of hair mercury possibly reflects the development of gastritis from normal stomach to superficial gastritis and to atrophic gastritis. The detection of hair mercury is potentially a means to predict the severity of chronic gastritis and possibly to insinuate the environmental mercury threat to human health in terms of gastritis or even carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells. Polyploidy is a common feature in normal hepatocytes, however, the pathophysiological function of hepatic hyperpolyploidy is unclear. Here, the authors show that genotoxic stress induces accumulation of hyperpolyploid hepatocytes around the centrilobular region of the liver, which may indicate the origin of preneoplastic formation.

In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and α-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.

Bowel cancer is the third most common malignancy of tumors and one of the major causes of cancer-related death. Bowel precancerous conditions can develop without any symptoms, which either makes it difficult for early diagnosis or poses a poor prognosis/gloomy relapse. This study aimed to investigate the effects of Bifidobacterium animalis subsp. lactis TCI604 ( B. lactis ) on inflammatory responses, gut microbiome, and protectiveness against azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colonic precancerous lesions. The AOM/DSS-induced colonic precancerous lesion murine model was studied with 24 female C57BL/6 J mice assigned to the control group, AOM/DSS-induced colonic precancerous lesion group (AOM/DSS), AOM/DSS treated with B. lactis probiotic group ( B. lactis P), and AOM/DSS treated with B. lactis cell-free supernatant group ( B. lactis S). The results showed that both B. lactis P and B. lactis S could attenuate AOM/DSS-induced body weight loss and intestine damage, reduce aberrant crypt foci (ACF) and the formation of colonic polyps, and significantly inhibit pro-inflammatory cytokines and the NF-κB signaling pathway, in which the B. lactis S group outperformed others. Further analysis using 16S rDNA sequencing suggested that both B. lactis P and B. lactis S optimize gut microbiota. Several bacteria, including Muribaculaceae , Prevotellaceae_UCG-001 , Anaerostipes , Ruminococcaceae , Mucispirillum , Clostridia_UCG-014 , and Clostridia _ vadinBB60 that were known in close relation to colonic precancerous lesions, were sequenced at taxonomic level. Our results indicated that both B. lactis P and B. lactis S improved AOM/DSS-induced colonic precancerous lesions by regulating inflammation as well as optimizing gut microbiota, thereby establishing reciprocally cooperative net benefits between probiotics/postbiotics and mice with colonic precancerous lesions. Key points • Prophylactic administration of probiotic and postbiotic of B. lactis is capable of alleviating the AOM/DSS-induced body weight loss and colon shortening, as well as diminishing the development of colonic precancerous lesions, such as the formation of ACF and colonic polyps, in an AOM/DSS mouse model • Either probiotic or postbiotic of B. lactis has a positive role in mediating immune imbalance and colonic inflammation via suppression of inflammatory immune cells, pro-inflammatory cytokines, and the NF-κB signaling pathway • AOM/DSS-induced dysbiosis can be reversed with the probiotic and postbiotic of B. lactis supplementation

Dendrobium officinale is a herb in traditional Chinese medicine where D. officinale polysaccharides (DOP) are the main active ingredient. This study aimed at evaluating DOP efficiency at inhibiting 1-Methyl-2-nitro-1-nitrosoguanidine (MNNG) induced precancerous lesions of gastric cancer (PLGC) in rats through the Wnt/b-catenin pathway and analyzing the variations of serum endogenous metabolites. PLGC was established in male Sprague-Dawley (SD) rats by administering 150 μg/mL MNNG in drinking water for 7 months and giving 0.1 mL of 10% NaCl once weekly during the initial 20 weeks. Treatment with DOP inhibited the progress of PLGC through decreasing the expression of β-catenin by immunohistochemical analysis. The futher study indicated DOP downregulated gene expression of Wnt2β, Gsk3β, PCNA, CyclinD1, and β-catenin, as well as protein expression of Wnt2β, PCNA, and β-catenin. On the other hand, there were nine endogenous metabolites identified after the DOP treatment. Among these, the most significant one is betaine because of its strong antioxidant activity, leading to an anti-tumor effect. DOP can inhibit MNNG-induced PLGC models via regulating Wnt/β-catenin pathway and by changing endogenous metabolites.

Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB-mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.