Risk Factor For Carcinogenesis Research Articles

Management of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis patients

BackgroundHepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established.AimTo investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies.MethodsWe studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment.ResultsIn 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events.ConclusionHCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable.Trial registrationThis trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 − 238, registered on 4 Feb 2020.

Cytolethal Distending Toxin Modulates Cell Differentiation and Elicits Epithelial to Mesenchymal Transition.

The bacterial genotoxin, cytolethal distending toxin (CDT), causes DNA damage in host cells, a risk factor for carcinogenesis. Previous studies have shown that CDT induces phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process involved in cancer initiation and progression. We investigated different steps of EMT in response to Helicobacter hepaticus CDT and its active CdtB subunit using in vivo and in vitro models. Most of the steps of the EMT process were induced by CDT/CdtB and observed throughout the study in murine and epithelial cell culture models. CdtB induced cell-cell junction disassembly, causing individualization of cells and acquisition of a spindle-like morphology. The key transcriptional regulators of EMT (SNAIL and ZEB1) and some EMT markers were upregulated at both RNA and protein levels in response to CDT/CdtB. CdtB increased the expression and proteolytic activity of matrix metalloproteinases, as well as cell migration. A range of these results were confirmed in Helicobacter hepaticus-infected and xenograft murine models. In addition, colibactin, a genotoxic metabolite produced by Escherichia coli, induced EMT-like effects in cell culture. Overall, these data show that infection with genotoxin-producing bacteria elicits EMT process activation, supporting their role in tumorigenesis.

Redox signaling-mediated tumor extracellular matrix remodeling: pleiotropic regulatory mechanisms.

The extracellular matrix (ECM), a fundamental constituent of all tissues and organs, is crucial for shaping the tumor microenvironment. Dysregulation of ECM remodeling has been closely linked to tumor initiation and progression, where specific signaling pathways, including redox signaling, play essential roles. Reactive oxygen species (ROS) are risk factors for carcinogenesis whose excess can facilitate the oxidative damage of biomacromolecules, such as DNA and proteins. Emerging evidence suggests that redox effects can aid the modification, stimulation, and degradation of ECM, thus affecting ECM remodeling. These alterations in both the density and components of the ECM subsequently act as critical drivers for tumorigenesis. In this review, we provide an overview of the functions and primary traits of the ECM, and it delves into our current understanding of how redox reactions participate in ECM remodeling during cancer progression. We also discuss the opportunities and challenges presented by clinical strategies targeting redox-controlled ECM remodeling to overcome cancer. The redox-mediated ECM remodeling contributes importantly to tumor survival, progression, metastasis, and poor prognosis.A comprehensiveinvestigationof the concrete mechanism of redox-mediatedtumor ECM remodeling and the combination usage of redox-targeted drugs withexisting treatment meansmay revealnew therapeutic strategyfor future antitumor therapies.

PECAM-1 drives β-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus

BackgroundDiabetes mellitus (DM) is considered to be a risk factor in carcinogenesis and progression, although the biological mechanisms are not well understood. Here we demonstrate that platelet-endothelial cell adhesion molecule 1 (PECAM-1) internalization drives β-catenin-mediated endothelial-mesenchymal transition (EndMT) to link DM to cancer.MethodsThe tumor microenvironment (TME) was investigated for differences between colon cancer with and without DM by mRNA-microarray analysis. The effect of DM on colon cancer was determined in clinical patients and animal models. Furthermore, EndMT, PECAM-1 and Akt/GSK-3β/β-catenin signaling were analyzed under high glucose (HG) and human colon cancer cell (HCCC) supernatant (SN) or coculture conditions by western and immunofluorescence tests.ResultsDM promoted the progression and EndMT occurrence of colon cancer (CC). Regarding the mechanism, DM induced PECAM-1 defection from the cytomembrane, internalization and subsequent accumulation around the cell nucleus in endothelial cells, which promoted β-catenin entry into the nucleus, leading to EndMT occurrence in CC with DM. Additionally, Akt/GSK-3β signaling was enhanced to inhibit the degradation of β-catenin, which regulates the process of EndMT.ConclusionsPECAM-1 defects and/or internalization are key events for β-catenin-mediated EndMT, which is significantly boosted by enhanced Akt/GSK-3β signaling in the DM-associated TME. This contributes to the mechanism by which DM promotes the carcinogenesis and progression of CC.Graphical DGwaByYkG3wJb4rQDf3DUNVideo

Usefulness of the aldehyde breath test for predicting metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharyngeal squamous cell carcinoma.

The rate of metachronous recurrence after endoscopic submucosal dissection for early-stage esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma is as high (10-15%). The acetaldehyde breath test may detect acetaldehyde dehydrogenase 2 gene polymorphisms. Therefore, we evaluated its usefulness in assessing metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. A total of 76 patients underwent endoscopic submucosal dissection for esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma and were followed up for at least 3years (non-recurrence group: 52 patients; recurrence group: 24 patients). The risk factors for carcinogenesis were compared between the recurrence and non-recurrence groups, and the acetaldehyde-to-ethanol ratio was assessed. The cutoff acetaldehyde-to-ethanol ratio that correlated with recurrence was established, and the cumulative recurrence rate was evaluated. The recurrence group had a higher acetaldehyde-to-ethanol ratio, daily alcohol consumption, and Lugol-voiding lesion grade than the non-recurrence group in the univariate analysis. The cutoff acetaldehyde-to-ethanol ratio for recurrence was 28.1 based on the receiver operating characteristic curve. The multivariate analysis revealed an acetaldehyde-to-ethanol ratio of > 28.1 and a Lugol-voiding lesion grade associated with carcinogenesis. Patients with an acetaldehyde-to-ethanol ratio of ≥ 28.1 had a significantly high recurrence rate using the Kaplan-Meier method. The acetaldehyde-to-ethanol ratio detected using the acetaldehyde breath test could be a novel biomarker of metachronous recurrence after endoscopic submucosal dissection in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. UMIN000040615.

Cancer and idiopathic inflammatory myopathies –association of autoantibodies with carcinogenesis

The relationship between cancer development in the course of idiopathic inflammatorymyopathies (IIM) has already been noticed at the beginning of the 20th century. However, theunderlying mechanisms remain not fully understood. Risk factors for carcinogenesis in patientswith IIM include male sex, older age, and the presence of specific subtypes of inflammatorymyopathies and clinical manifestations, including dermatomyositis, dysphagia, severe skinchanges, leukocytoclastic vasculitis, acute disease onset and immunosuppressive therapyresistance. The presence of certain autoantibodies in the serum of patients with IIM is a factorof considerable importance in the stratification of cancer risk. Anti-TIF1γ autoantibodies, which might be present in even 38-80% of cancer cases in adult IIM patients, are antibodies with a wellstudiedrelationship with carcinogenesis. The relationship of other antibodies found in IIM withthe risk of carcinogenesis is still discussed. This group includes anti-NXP2, anti-HMGCR, anti-SAE1 and anti-Mi2 antibodies. Due to the contrary reports on the role of these antibodies incancer development and their relatively low prevalence in IIM, the unambiguous classificationas risk factors requires further research in larger study groups. The potential autoantibodiesutility in cancer screening in IIM patients could help detect cancer early, improving prognosisand long-term survival.

Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators.

Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators.

The Effect of Smoking on Progression from Ductal Carcinoma In Situ to Invasive Ductal Breast Carcinoma: A Retrospective Study.

If ductal carcinoma in situ (DCIS) is diagnosed by needle biopsy, invasion is often found by removing the entire tumor and performing pathological examination. Smoking is a risk factor for carcinogenesis in breast cancer. We examined the correlation between the risk of invasion found by postoperative pathology and smoking history in patients diagnosed with DCIS by preoperative biopsy. We examined 128 patients who were diagnosed with DCIS by preoperative biopsy. Multivariate analysis was performed on the risk factors for invasion diagnosed by postoperative pathological examination in all cases diagnosed with DCIS by preoperative biopsy. Multivariate analysis was performed on the risk factors for invasion diagnosed by postoperative pathological examination in all cases diagnosed with DCIS by preoperative biopsy. Number of pack-years was not an independent factor (p=0.349, OR=0.329), but current-smoker status (p=0.006, OR=not calculable) was an independent factor with VAB (p=0.018, OR=0.327). Tobacco components may have an influence on the progression from DCIS to invasive ductal carcinoma.

The effect of IL-1β on MRP2 expression and tamoxifen toxicity in MCF-7 breast cancer cells.

Chronic inflammation is considered to be a risk factor for carcinogenesis, tumor development and metastasis by providing tumor-related factors. We aimed to evaluate the effect of cytokine interleukin-1β (IL-1β) as a key mediator of inflammation on multidrug resistance associated protein 2 (MRP2) expression and tamoxifen toxicity in estrogen receptor positive (ER+) MCF-7 breast cancer cells. The effects of IL-1β on tamoxifen toxicity following 20-day treatment of MCF-7 cells with IL-1β and/or 17β-estradiol (E2) were measured by MTT assay. Furthermore, the effects of IL-1β and/or E2 on the mRNA expression and protein levels of MRP2 and NF-κB (p65) in breast cancer cells were evaluated by QRT-PCR and Western blot analysis, respectively. Treatment of breast cancer cells with IL-1β+E2 decreased the sensitivity to 4-OH tamoxifen compared to both E2-treated and untreated cells. The mRNA expression levels of MRP2 and NF-κB (p65) were significantly increased following treatment with IL-1β+E2, compared to control. In addition, breast cancer cells treatment with IL-1β+E2 increased protein expression of MRP2 and it had no significant effect on NF-κB/p65 protein expression in these cells. Increased expression of mRNA and protein level of MRP2 following 20-day treatment of MCF-7 cells with IL-1β + E2 might be a possible elucidation for the increased tamoxifen resistance which was observed in these cells. More researches are essential to clarify the molecular mechanisms of inflammation on drug-resistance in the tumor environment in order to reducing or eliminating chemotherapy resistance and developing more effective treatment strategies.

Predictive Value of IL-6 Combined with NLR in Inflammation and Cancer

The strong association between inflammation and cancer is reflected by the high interleukin-6 (IL-6) levels in the tumor microenvironment, where it promotes carcinogenesis by regulating all hallmarks of cancer and multiple signaling pathways. In this study, we investigated the prognostic value of IL-6 and other clinical indexes in inflammatory and cancer patients. All the patients were divided into the inflammation group (n = 400) and the cancer group (n = 672) composed of hematological malignancies group (n = 338) and solid tumors group (n = 334). Continuous variables were measured by one-way ANOVA and t-test, and the independent risk factors for carcinogenesis were determined by multivariate logistic regression analysis. The receiver operating characteristic (ROC) curves subsequently performed the predictive value of significant serological parameters and the Corheatmaps illustrated the correlation of these parameters in every case. Our retrospective study revealed that various serological indexes could reflect carcinogenesis in inflammatory patients, as significant differences existed in many indexes between them. It was notable that indicator composed of IL-6 and neutrophils/lymphocytes ratio (NLR) occupied the superior position of Area Under Curve (AUC) values in cancer cases, especially in patients with solid tumors (AUC = 0.85). The newly-found indicator could also be referred as an independent risk factor, which provided us with novel clues on the investigation of more reliable and affordable clinical indexes in tumor prediction.

Down-regulation of miR-215 attenuates lipopolysaccharide-induced inflammatory injury in CCD-18co cells by targeting GDF11 through the TLR4/NF-kB and JNK/p38 signaling pathways.

Ulcerative colitis (UC) is a risk factor for carcinogenesis of colorectal cancer, which is associated with disruption of the epithelial barrier and disorder of the inflammatory response. It has been reported that the expression of microRNA (miR)-215 is upregulated in patients with long-term UC. The present study aimed to investigate the effects of miR-215 on lipopolysaccharide (LPS)-induced inflammatory injury in CCD-18Co cells, as well as to identify the underlying possible molecular mechanisms. CCD-18Co cells were treated with 1 µg/ml LPS to induce inflammatory injury. Reverse transcription-quantitative PCR was performed to determine the expression of miR-215 in LPS-treated CCD-18Co cells. Moreover, a dual luciferase reporter system assay was used to evaluate the interaction of miR-215 and growth differentiation factor 11 (GDF11) in CCD-18Co cells. The expression of miR-215 was significantly upregulated in LPS-treated CCD-18Co cells. Knockdown of miR-215 significantly alleviated the inflammatory response and oxidative stress in LPS-treated CCD-18Co cells. In addition, GDF11 was identified as a direct binding target of miR-215 in CCD-18Co cells. Knockdown of miR-215 significantly increased the expression of GDF11, but decreased the expression levels of Toll-like receptor (TLR)4, phosphorylated (p)-p65, iNOS, p-p38 and p-JNK in LPS-treated CCD-18Co cells. Collectively, the present findings indicated that knockdown of miR-215 alleviated oxidative stress and inflammatory response in LPS-treated CCD-18Co cells by upregulating GDF11 expression and inactivating the TLR4/NF-κB and JNK/p38 signaling pathways.

On the relationship of anthropogenic air pollution by particulate matter with cancer risk

In the review the author highlights contemporary concepts about the relation between the air pollution by the particulate matter (PM) and human morbidity and mortality due to oncological diseases (OD). The author used materials of the articles indexed in the PubMed and RISC databases. The role of air pollution by PM as a risk factor of carcinogenesis in dependence on size, origin, chemical composition and concentration in air is discussed. PM of road-transport origin contains transitional metals acknowledged as most dangerous and is the result the operational wear of motor transport, road surface, and vehicle emissions. Long-term exposure to PM with an aerodynamic diameter ≤2.5 increases risk of appearance of OD of different localization. Dose-dependent action of PM was established. Reduction in air pollution by PM is accompanied by decrease of premature mortality of population, including from OD, and it can be examined as a modifiable risk factor. The results of the meta-analysis of literature data about the economic damage, caused by morbidity and mortality from OD led to the conclusion that reduction in PM concentration is the most realistic and effective method to decrease these social and economic losses. The accumulated carcinogenic risk provides for the lifelong probability of the development of OD, which requires the active medical examination of workers after the curtailment of work with carcinogens for early diagnostics and treatment of OD. The important preventive measure is to decrease the level of air pollution independently on their initial concentration.

ON THE RELATIONSHIP OF ANTHROPOGENIC AIR POLLUTION BY PARTICULATE MATTER WITH CANCER RISK

In the review the author highlights contemporary concepts about the relation between the air pollution by the particulate matter (PM) and human morbidity and mortality due to oncological diseases (OD). The author used materials of the articles indexed in the PubMed and RISC databases. The role of air pollution by PM as a risk factor of carcinogenesis in dependence on size, origin, chemical composition and concentration in air is discussed. PM of road-transport origin contains transitional metals acknowledged as most dangerous and is the result the operational wear of motor transport, road surface, and vehicle emissions. Long-term exposure to PM with an aerodynamic diameter ≤2.5 increases risk of appearance of OD of different localization. Dose-dependent action of PM was established. Reduction in air pollution by PM is accompanied by decrease of premature mortality of population, including from OD, and it can be examined as a modifiable risk factor. The results of the meta-analysis of literature data about the economic damage, caused by morbidity and mortality from OD led to the conclusion that reduction in PM concentration is the most realistic and effective method to decrease these social and economic losses. The accumulated carcinogenic risk provides for the lifelong probability of the development of OD, which requires the active medical examination of workers after the curtailment of work with carcinogens for early diagnostics and treatment of OD. The important preventive measure is to decrease the level of air pollution independently on their initial concentration.

Awareness of gastrointestinal tract malignancies among the population of Lublin province (Eastern Poland) - A cross-sectional study.

Currently, malignancies are the most severe medical problems worldwide. Numerous, already known risk factors in carcinogenesis could be potentially avoided. Some cancer risk factors have been recognized and have become the targets of primary prophylaxis. The aim of the study was to ascertain the state of knowledge about risk factors, primary prevention and early detection of malignancies of gastrointestinal tract (GIT) in the urban and rural population of the Lublin province in Eastern Poland. The study was cross-sectional. The originally designed questionnaire was applied to the group of 1,352 patients, representatives of both the rural and urban environments of the Lublin province during random appointments with their general practitioner (GP). The study showed low awareness of the issues connected with GIT malignancies within the studied group. The problem was particulary apparent in the rural population. In order to raise general awareness of cancer, different means should be applied in urban and rural populations. GPs and the media were found to have the leading rols in the promotion of primary prevention.

The microbiota of the bilio-pancreatic system: a cohort, STROBE-compliant study.

Background: The gut microbiota play an essential role in protecting the host against pathogenic microorganisms by modulating immunity and regulating metabolic processes. In response to environmental factors, microbes can hugely alter their metabolism. These factors can substantially impact the host and have potential pathologic implications. Particularly pathogenic microorganisms colonizing pancreas and biliary tract tissues may be involved in chronic inflammation and cancer evolution.Purpose: To evaluate the effect of bile microbiota on survival in patients with pancreas and biliary tract disease (PBD).Patients and Methods: We investigated 152 Italian patients with cholelithiasis (CHL), cholangitis (CHA), cholangiocarcinoma (CCA), gallbladder carcinoma (GBC), pancreas head carcinoma (PHC), ampullary carcinoma (ACA), and chronic pancreatitis (CHP). Demographics, bile cultures, therapy, and survival rates were analyzed in cohorts (T1 death <6 months; T2 death <12 months; T3 death <18 months, T3S alive at 18 months).Results: The most common bacteria in T1 were E. coli, K. pneumoniae, and P. aeruginosa. In T2, the most common bacteria were E. coli and P. aeruginosa. In T3, there were no significant bacteria isolated, while in T3S the most common bacteria were like those found in T1. E. coli and K. pneumoniae were positive predictors of survival for PHC and ACA, respectively. E. coli, K. pneumoniae, and P. aeruginosa showed a high percentage of resistant bacteria to 3CGS, aminoglycosides class, and quinolone group especially at T1 and T2 in cancer patients.Conclusions: An unprecedented increase of E. coli in bile leads to a decrease in survival. We suggest that some strains isolated in bile samples may be considered within the group of risk factors in carcinogenesis and/or progression of hepato-biliary malignancy. A better understanding of bile microbiota in patients with PBD should lead to a multifaceted approach to rapidly detect and treat pathogens before patients enter the surgical setting in tandem with the implementation of the infection control policy.

Risk analysis of the canceration of colorectal large polyps

To analyze the risk factors of carcinogenesis of large colorectal polyps (diameter ≥ 10 mm) found by colonoscopy. Clinicopathological and follow-up data of 418 consecutive patients who were diagnosed as colorectal polyps with diameter≥10 mm by colonoscopy at two endoscopy centers of the Affiliated Wuxi Second People's Hospital, Nanjing Medical University (n=207) and Zhongshan Hospital, Fudan University (n=211) from January 2015 to December 2016 were retrospectively collected. High-grade intraepithelial neoplasia and cancer were defined as malignancy in this study. Chi square test was used for univariate analysis, and logistic regression was used for multivariate analysis (in patients with multiple polyps, if the pathological findings were all low grade intraepithelial neoplasia, one polyp with the largest diameter was selected to enter the model; in patients with high grade intraepithelial neoplasia, one polyp of high grade intraepithelial neoplasia with the largest diameter was selected to enter the model). Associated risk factors of malignancy were analyzed. Among the 418 patients, 278(66.5%) were male and 140(33.5%) were female, with mean age of (58.7±10.2) (range 15-87) years old. Of 398 patients undergoing endoscopic treatment with resected 456 polyps, 142 cases with 150 polyps were malignant, including 134 polyps of high-grade intraepithelial neoplasia and 16 polyps of intra-mucosal cancer. The other 20 patients showed negative elevation signs after endoscopic submucosal injection and were transferred to surgery, of whom 20 polyps were resected. Histological examination of these 20 polyps indicated invasive cancer. Univariate analysis showed that age ≥ 50 years [40.5% (150/370) vs. 25.0% (12/48), χ² =4.323, P=0.041], multiple polyps [77.5%(31/40) vs. 34.7%(131/378), χ² =12.900, P=0.001], polyp locating at rectum [59.0%(36/61) vs. 32.3%(134/415), χ² =22.736, P=0.000], polyp diameter ≥31 mm [74.1%(20/27) vs. 33.4%(150/449), χ² =36.493, P=0.000] and tubular villous adenoma [67.4%(120/178) vs. 16.8%(50/298), χ² =71.810, P=0.000] were associated with malignancy. Multivariate analysis showed that age ≥ 50 years(OR=2.473, 95%CI:1.209-5.058, P=0.013), multiple polyps (OR=2.472, 95%CI: 1.300-4.702, P=0.006), polyp locating at rectum (OR=1.253, 95%CI: 1.091-1.439, P=0.001) and the polyp diameter ≥31 mm (OR=1.500, 95%CI:1.196-1.881, P=0.000) were independent risk factors for malignancy of large colorectal polyps. The mean follow-up time was (9.6±4.2) months. During the follow-up period, 86 patients (20.5%) who received endoscopic resection developed recurrent adenoma which all were successfully removed by colonoscopic polypectomy. Two patients(0.5%) developed colon cancer 6 months after endoscopic resection and both underwent radical surgery and chemotherapy. Their previous pathology from endoscopic resection was tubular villous adenoma and high grade intraepithelial neoplasia. All the patients were alive during the follow-up period. Age ≥50 years old, multiple polyps, polyps locating at rectum and polyps with diameter ≥ 31 mm are the risk factors of malignancy. Emphasized examination should be recommended for those with the above mentioned risk factors to avoid missed diagnosis and misdiagnosis. The choice of endoscopic treatment must be reasonable for curative resection.

Fibrosis in metastatic lymph nodes is clinically correlated to poor prognosis in colorectal cancer.

BackgroundTumor microenvironment including fibrosis has a pivotal role in cancer growth and distant metastasis. Fibrosis is a known risk factor for carcinogenesis, but its biological role in disease invasion and metastasis in colorectal cancer (CRC) remains unclear. In particular, there is no report on how fibrosis of metastatic lymph nodes (MLNs) in CRC contributes to prognosis.MethodsWe reviewed 94 colorectal adenocarcinoma patients with MLNs who underwent colectomy. Both the primary tumors and MLNs were analyzed for alpha-smooth muscle actin (α-SMA) expression and collagen deposition.ResultsHigher α-SMA expression and collagen deposition in MLNs were associated with significantly shorter relapse-free survival and overall survival in CRC patients. α-SMA expression in MLNs (HR, 1.53; p = 0.034) was independent predictive factor of overall survival in multivariate Cox proportional hazards regression analysis of clinicopathological factors. In the Stage III patient subgroup, α-SMA expression in MLNs was a strong prognostic marker (HR, 3.01; p = 0.006). On the other hand, higher α-SMA expression and collagen deposition in primary tumors were associated with short overall survival, but they were not significant factors in multivariate Cox regression analyses. In MLNs, the podoplanin signals co-localized with α-SMA expression and were confirmed by the dual immunofluorescence staining, implying that the MLN stromal cells were fibroblastic reticular cells.ConclusionBoth high collagen deposition and high α-SMA expression in MLNs predicted poor prognosis in CRC.

High Consumption of Green Tea Suppresses Urinary Tract Recurrence of Urothelial Cancer via Down-regulation of Human Antigen-R Expression in Never Smokers.

Smoking is a risk factor for carcinogenesis and progression of urothelial cancer (UC). Green tea polyphenol inhibits these malignant behaviors and suppresses human antigen R (HuR) expression, which is associated with malignant aggressiveness. This study aimed to clarify the anti-cancer effects of green tea based on the smoking status of UC patients. Three hundred and sixty (260 with bladder cancer, BC and 100 with upper tract UC) patients were divided into three groups based on consumption of green tea: low (<1 cup/day, n=119), middle (1-4 cup/day, n=160), and high (>5 cup/day, n=81). HuR immunoreactivity was evaluated immunohistochemically in formalin-fixed specimens. In never smokers, multivariate analysis showed that the frequency of green tea consumption was a significant predictor (middle: hazard ratio, HR, 0.36, p=0.002; high: HR, 0.20, p=0.003) of urinary tract recurrence. A high consumption of green tea was associated with low rates of urinary tract recurrence and up-grading in UC patients. In BC, high consumption was associated with a lower risk of up-grading (p=0.011) and up-staging (p=0.041) in recurrent cancer. HuR expression in the high-consumption group was lower (p=0.019) than that in other groups. These significant findings were not detected in ever smokers. High consumption of green tea suppressed urinary tract recurrence and the risks of up-grading and up-staging by recurrence in never smokers. Our results suggested that HuR expression played important roles in such mechanisms.

Bacterial infection increases risk of carcinogenesis by targeting mitochondria.

As up to a fifth of all cancers worldwide, have now been linked to microbial infections, it is essential to understand the carcinogenic nature of the bacterial/host interaction. This paper reviews the bacterial targeting of mediators of mitochondrial genomic fidelity and of mitochondrial apoptotic pathways, and compares the impact of the bacterial alteration of mitochondrial function to that of cancer. Bacterial virulence factors have been demonstrated to induce mutations of mitochondrial DNA (mtDNA) and to modulate DNA repair pathways of the mitochondria. Furthermore, virulence factors can induce or impair the intrinsic apoptotic pathway. The effect of bacterial targeting of mitochondria is analogous to behavior of mitochondria in a wide array of tumours, and this strongly suggests that mitochondrial targeting of bacteria is a risk factor for carcinogenesis.

Abstract 1920: Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas

Abstract Background: Chronic inflammation is known to be a risk factor of carcinogenesis and tumor development, and it was demonstrated that oral aspirin intake reduced cancer-related death including pancreatic ductal adenocarcinoma (PDAC) through inhibiting prostaglandin synthases. On the other hand, cancer stem cells (CSCs) refer to a subset of tumor cells that have self-renewal ability and generate plenty of non-CSC cells that comprise a tumor. Prostaglandin E2 (PGE2) and inhibition of 15-PGDH, which is an enzyme degrading PGE2, promoted hematopoietic and tissue stem cell fraction, however, little is known about the role of PGE2 accumulation for CSC fraction. A number of CSC marker candidates have been explored to date, and Aldehyde dehydrogenase 1 (ALDH1) was identified as one of CSC markers in PDAC. The aim of this study is to elucidate the functional role of PGE2 in ALDH1 positive CSC fraction during tumor development in pancreas. Methods: The clonogenic growth potential of ALDH1-positive PDAC cells was assessed in vitro by growth assays and sphere formation assays. We next investigated the expression of ALDH1 and self-renewal related genes in PDAC cell lines with PGE2 or 15-PGDH inhibitor treatment. We further conducted functional experiments using siALDH1 in PDAC progression. Furthermore, we examined the effect of PGE2 for pancreatic tumorigenesis using Kras-driven genetic mouse model treated with 15-PGDH inhibitor. Finally, ALDH1 and Ki67 expression was examined by immunohistochemistry in 121 primary surgical specimens of PDAC and analyzed a relationship with clinicopathological factors and clinical outcomes. Results: The number of ALDH1-positive cells was significantly increased by PGE2 treatment, and PGE2 promoted growth and sphere formation potential in PDAC cells. In addition, 15-PGDH inhibitor induced PGE2 accumulation and gave rise to ALDH1-positive cells harboring high proliferating potential in PDAC cells. The growth and sphere formation potential were inhibited by silencing ALDH1 expression in PDAC cells. We next found that the expression of Nanog and Oct-4 genes was regulated by PGE2-ALDH1 signaling. Furthermore, 15-PGDH inhibitor induced ALDH1 expression and promoted PanIN formation in Kras-driven genetic mouse model. Finally, a high level of ALDH1 expression was significantly associated with large tumor size and high Ki67expression, and poor prognosis in PDAC patients. Conclusion: Current findings suggested that PGE2 positively regulated ALDH1 expression, and the growth and sphere formation potential were promoted by regulating self-renewal related genes expression, resulting in poor prognosis of PDAC patients. Inhibiting PGE2-ALDH1 signaling could lead to the suppression of tumor growth in PDAC patients. Citation Format: Kota Arima, Takatsugu Ishimoto, Masaki Ohmuraya, Keisuke Miyake, Tsugio Eto, Hirohisa Okabe, Yuki Kitano, Kensuke Yamamura, Takayoshi Kaida, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Hideo Baba. Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1920. doi:10.1158/1538-7445.AM2017-1920