Effect of Short-Chain Fatty Acid Acetate on Colon Cancer

Acetate is a short chain fatty acid produced as a result of fermentation of ingested fibers by the gut microbiota. While it has been shown to reduce cell proliferation in some cancer cell lines1,2, more recent studies on liver3 and brain4 tumours suggest that acetate may actually promote tumour growth. Acetate in the cell is normally converted into acetyl-coA by two enzymes and metabolized; mitochondrial (ACSS1) and cytosolic (ACSS2) acetyl-coA synthetase. In the mitochondria acetyl-coA is utilized in the TCA cycle. In the cytosol it is utilized in lipid synthesis. In this study, the effect of acetate treatment on the growth of HT29 colon cancer cell line and its mechanism of action was assessed. HT29 human colorectal adenocarcinoma cells were treated with 10mM NaAc and cell viability, cellular bioenergetics and gene expression were investigated. Cell viability was assessed 24 hours after treatment using an MTT assay (Sigma, UK, n=8). Cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was measured by XFe Analyzer (Seahorse Bioscience, USA). After a baseline reading cells were treated and OCR and ECAR measurements were observed for 18 hours (n=4). Total mRNA was isolated 24 hours after treatment using RNeasy kit (Qiagen, USA). Quantitative PCR reactions were performed using Taqman gene expression assays and Taqman Universal PCR Master Mix (ThermoFisher Scientific, UK) on Applied Biosystems 7500 Fast Real-Time PCR System (Life Technologies, USA) and analysed using ΔΔCt method (n=3). Acetate treatment led to a significant reduction in cell viability (15.9%, Figure 1). OCR, an indicator of oxidative phosphorylation, was significantly increased (p<0.0001) while ECAR, an indicator of glycolysis, was significantly reduced (p<0.0001, Figure 2). Gene expression of ACSS1 was increased by 1.7 fold of control (p=0.07) and ACSS2 expression was reduced to 0.6 fold of control (p=0.06, Figure 3). In conclusion, in colon cancer cells acetate supplementation induces cell death and increases oxidative capacity. These changes together with the trending decrease in ACSS2 expression suggest suppression of lipid synthesis pathways. We hypothesize that the reduced tumor growth by acetate is a consequence of the suppression of ACSS2 and lipid synthesis, both effects reported previously to reduce tumor growth3–5. These effects clearly warrant further investigation.

Prévention et dépistage du cancer en Suisse : fréquence et déterminants

Contexte : Après les maladies cardiovasculaires, le cancer est la deuxième cause de mortalité en Suisse. Les cancers de la prostate, du sein, du côlon-rectum, du col utérin et le mélanome cutané représentent, en termes d'incidence et de mortalité, la moitié du fardeau du cancer en Suisse. Des moyens de prévention primaire et/ou secondaire contribuent à réduire la fréquence et la mortalité due à ces cinq cancers. Cependant, l'attitude face à la prévention diffère selon les individus et dépend de multiples facteurs socio-économiques, environnementaux, culturels et comportementaux. Objectif : Évaluer la fréquence et identifier les déterminants des pratiques de dépistage des cancers de la prostate, du sein, du côlon-rectum, du col utérin et du mélanome cutané en Suisse. Matériel et méthode : Les données utilisées sont issues de l'Enquête suisse sur la santé 2007. Une pondération statistique permet d'extrapoler les résultats à la population générale. Des modèles de régression logistique multivariée ont été construits afin de décrire l'association entre pratique du dépistage et facteurs sociodémographiques, style de vie, état de santé, recours aux prestations de santé et soutien social. Résultats : En 2007, selon les méthodes et fréquences recommandées en Suisse et dans les tranches d'âge concernées, 49% des hommes ont effectué un dépistage du cancer prostatique, 13% du cancer colorectal et 33,7% du mélanome cutané. Chez les femmes, 17,9% ont réalisé un dépistage du cancer du sein, 8,7% du cancer colorectal, 36,8% du mélanome cutané et 50,2% du cancer du col utérin. Globalement et pour les deux sexes, l'âge, le lieu de résidence, le niveau de formation, la classe socioprofessionnelle, le revenu d'équivalence du ménage, la pratique d'autres dépistages des cancers, le nombre de visites médicales et de jours d'hospitalisation au cours des 12 mois précédents déterminent le recours au dépistage des cancers d'intérêt. Chez les hommes, la présence d'un médecin de famille et, chez les femmes, la franchise annuelle, influencent aussi la pratique du dépistage. Conclusion : Les prévalences du dépistage varient notablement selon le type de cancer. Le recours aux dépistages des cancers dépend de facteurs sociodémographiques, de l'utilisation des services de santé et de la pratique d'autres dépistages, mais peu, voire pas, du style de vie, de l'état de santé et de la sécurité et du soutien sociaux. Les facteurs identifiés sont souvent communs aux différents types de cancer et rendent possible l'établissement d'un profil général d'utilisateurs du dépistage des cancers. Les stratégies visant à améliorer la compliance aux examens de dépistage devraient considérer les facteurs qui en déterminent le recours et mieux cibler les segments de la population qui les sous-utilisent.

Decision analysis of the effectiveness of lung cancer screening using autofluorescence bronchoscopy and computed tomography

Background: Lung cancer (LC) is the leading cause of cancer death in the developed world. Most cancers are associated with tobacco smoking. A primary hope for reducing lung cancer has been prevention of smoking and successful smoking cessation programs. To date, these programs have not been as successful as anticipated. Objective: The aim of the current study was to evaluate whether lung cancer screening combining low dose computed tomography with autofluorescence bronchoscopy (combined CT & AFB) is superior to CT or AFB screening alone in improving lung cancer specific survival. In addition, the extent of improvement and ideal conditions for combined CT & AFB screening were evaluated. Methods: We applied decision analysis and Monte Carlo simulation modeling using TreeAge Software to evaluate our study aims. Histology- and stage specific probabilities of lung cancer 5-year survival proportions were taken from Surveillance and Epidemiologic End Results (SEER) Registry data. Screeningassociated data was taken from the US NCI Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), National Lung Screening Trial (NLST), and US NCI Lung Screening Study (LSS), other relevant published data and expert opinion. Results: Decision Analysis - Combined CT and AFB was the best approach at Improving 5-year survival (Overall Expected Survival (OES) in the entire screened population was 0.9863) and in lung cancer patients only (Lung Cancer Specific Expected Survival (LOSES) was 0.3256). Combined screening was slightly better than CT screening alone (OES = 0.9859; LCSES = 0.2966), and substantially better than AFB screening alone (OES = 0.9842; LCSES = 0.2124), which was considerably better than no screening (OES = 0.9829; LCSES = 0.1445). Monte Carlo simulation modeling revealed that expected survival in the screened population and lung cancer patients is highest when screened using CT and combined CT and AFB. CT alone and combined screening was substantially better than AFB screening alone or no screening. For LCSES, combined CT and AFB screening is significantly better than CT alone (0.3126 vs. 0.2938, p< 0.0001). Conclusions: Overall, these analyses suggest that combined CT and AFB is slightly better than CT alone at improving lung cancer survival, and both approaches are substantially better than AFB screening alone or no screening.

Associations Between Personal Cancer History and Lung Cancer Risk

The study aim was to investigate the relationship between factors related to personal cancer history and lung cancer risk as well as assess their predictive utility. Characteristics of interest included the number, anatomical site(s), and age of onset of previous cancer(s). Data from the Prostate, Lung, Colorectal and Ovarian Screening (PLCO) Cancer Screening Trial (N = 154,901) and National Lung Screening Trial (N = 53,452) were analysed. Logistic regression models were used to assess the relationships between each variable of interest and 6-year lung cancer risk. Predictive utility was assessed through changes in area-under-the-curve (AUC) after substitution into the PLCOall2014 lung cancer risk prediction model. Previous lung, uterine and oral cancers were strongly and significantly associated with elevated 6-year lung cancer risk after controlling for confounders. None of these refined measures of personal cancer history offered more predictive utility than the simple (yes/no) measure already included in the PLCOall2014 model.

Predicting the Risk of Lung Cancer in Never-smokers

Despite being considered a disease of smokers, approximately 10-15% of lung cancer cases occur in never-smokers. Lung cancer risk prediction models have demonstrated excellent ability to discriminate cases from non-cases, and have been shown to be more efficient at selecting individuals for future screening than current criteria. Existing models have primarily been developed in populations of smokers, thus there was a need to develop an accurate model in never-smokers. This study focused on developing and validating a model using never-smokers from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression analysis, with six-year follow-up, was used for model building. Predictors included: age, body mass index, education level, personal history of cancer, family history of lung cancer, previous chest X-ray, and secondhand smoke exposure. This model achieved fair discrimination (optimism corrected c-statistic = 0.6645) and good calibration. This represents an improvement on existing neversmoker models, but is not suitable for individual-level risk prediction.

Probiotics and cancer: from in vitro to human studies

Studies in cell cultures and animal models provide evidence that probiotics can beneficially influence various stages in development of colon cancer including tumor initiation, promotion and metastasis. For example, oral administration of Lactobacillus and Bifidobacterium strains can prevent genotoxic damage to the colonic epithelium (considered to be an early stage of the carcinogenic process). Administration to rats of probiotics reduced the incidence of carcinogen-induced pre-cancerous lesions (aberrant crypt foci) in the colon. Furthermore a combination of Bifidobacterium longum and inulin (a prebiotic) was more effective than either treatment alone. In this latter study, the dietary treatments were given after exposure to the carcinogen, which suggests that the protective effects were being exerted at the promotional phase of carcinogenesis. L. acidophilus feeding has been shown to decrease the incidence of colon tumors in rats challenged with a carcinogen and B. longum reduced the incidence of carcinogeninduced colon, liver and mammary tumors. There is limited evidence from epidemiological studies for protective effects of products containing probiotics in humans, but a number of recent dietary intervention studies in healthy subjects and in polyp and cancer patients have yielded promising results on the basis of biomarkers of cancer risk and grade of colorectal tumors.

A comparison of the anticancer properties of isoxanthohumol and 8-prenylnaringenin using in vitro models of colon cancer

The hops plant (Humulus lupulus L.) is an essential ingredient in beer and contains a number of potentially bioactive prenylflavonoids, the predominant being the weakly estrogenic isoxanthohumol (Ix), which can be converted to the more strongly estrogenic 8-PN by the colonic microbiota. The aim of this study was to investigate the biological activity of 8-PN and Ix using in vitro models representing key stages of colorectal carcinogenesis, namely cell growth and viability (MTT assay), cell-cycle progression (DNA content assay), DNA damage (Comet assay), and invasion (Matrigel assay). A significant decrease in Caco-2 cell viability was noted after both 8-PN and Ix treatments at the higher doses (40 and 50 μM, respectively) although the impact on cell cycle differed between the two compounds. The decreased cell viability observed after Ix treatment was associated with a concentration-dependent increase in G2/M and an increased sub-G1 cell-cycle fraction, whereas treatment with 8-PN was associated with an elevated G0/G1 and an increased sub-G1 cell-cycle fraction. Significant antigenotoxic activity was noted at all 8-PN concentrations tested (5-40 μM). Although significant antigenotoxic activity was also noted with Ix treatment at ≤25 μM, at a higher dose, Ix itself exerted genotoxic activity. In a dose-dependent manner, both compounds inhibited HT115 cell invasion with reductions up to 52 and 46% for Ix and 8-PN, respectively, in comparison to untreated cells. This study demonstrated that both Ix and its gut microbial metabolite 8-PN exert anticancer effects on models of key stages of colon tumourigenesis.