Archive

Research Area: Cancer

Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance).

Fadelu, T., S. Zhang, D. Niedzwiecki, X. Ye, L.B. Saltz, R.J. Mayer, R.B. Mowat, R. Whittom, A. Hantel, A.B. Benson, D.M. Atienza, M. Messino, H.L. Kindler, A. Venook, S. Ogino, K. Ng, K. Wu, W. Willett, E. Giovannucci, J. Meyerhardt, Y. Bao, C.S. Fuchs, 2018. Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance). J Clin Oncol. 36(11):1112-1120.

Purpose: Observational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known. Patients and Methods: We conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. Results: After a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality. Conclusion: Diets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer.

Role of omega-3 polyunsaturated fatty acids in preventing gastrointestinal cancers: current status and future perspectives.

Lee, H.J., Y.M. Han, J.M. An, E.A. Kang, Y.J. Park, J.Y. Cha, K.B. Hahm, 2018. Role of omega-3 polyunsaturated fatty acids in preventing gastrointestinal cancers: current status and future perspectives. Expert Rev Anticancer Ther. 17:1-15.

Although inflammation is defensive and healing process that maintains organ homeostasis, unresolved inflammation can lead to diseases. Polyunsaturated fatty acids (PUFAs), especially n-6 PUFAs abundant in Western diet, are precursors of pro-inflammatory mediators, whereas n-3 PUFAs possess anti-inflammatory properties. Therefore, interest in the cancer-preventive effect of n-3 PUFAs is increasing. Areas covered: We have observed significant reductions of gastrointestinal tumorigenesis in the Fat-1 transgenic mouse as evidenced that the decrease in Helicobacter pylori-infected gastric tumorigenesis, colon, biliary, and pancreatic cancer was seen in Fat-1 mice producing n-3 PUFAs. However, despite many studies showing benefits, evidence-based medicine regarding molecular pathology, epidemiology, and clinical achievement of cancer prevention of n-3 PUFAs are still limited. Expert commentary: Primary deficiency of eicosapentaenoic acids and docosahexaenoic acids in Western diets can explain the risk of cancer development and the importance of n-3/n-6 PUFA ratio in reducing cancer risk. Alteration of cell membrane composition during carcinogenesis is particularly important, due to increased rate of lipid/cholesterol synthesis in cancerous tissues. Here, we discuss that direct incorporation of n-3 PUFAs in the cell membrane corrects abnormal cellular proliferation and decreases inflammation-associated carcinogenesis. This is exemplified by cancer-preventive effects of n-3 PUFAs as fat sources for gastrointestinal cancers.

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

Koh, S.J., Y.I. Choi, Y. Kim, Y.S. Kim, S.W. Choi, J.W. Kim, B.G. Kim, K.L. Lee, 2018. Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice. Eur J Nutr. doi: 10.1007/s00394-018-1704-3.

PURPOSE: Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. METHODS: COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10-/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. RESULTS: WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10-/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). CONCLUSIONS: WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis.

Guan, F., T. Tabrizian, A. Novaj, M. Nakanishi, D.W. Rosenberg, D. Huffman, 2018. Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis. Front. Nutr. doi.org/10.3389/fnut.2018.00037

Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.

The relationship between nut intake and risk of colorectal cancer: a case control study.

Lee, J., A. Shin, J.H. Oh, J. Kim, 2018. The relationship between nut intake and risk of colorectal cancer: a case control study. Nutrition Journal. 17:37 https://doi.org/10.1186/s12937-018-0345-y

Background: Nut consumption is known to reduce the risk of obesity, diabetes mellitus, and cardiovascular disease. However, in previous studies, portion sizes and categories of nut consumption have varied, and few studies have assessed the association between colorectal cancer risk and nut consumption. In this study, we investigated the relationship between nut consumption and colorectal cancer risk. Methods: A case-control study was conducted among 923 colorectal cancer patients and 1846 controls recruited from the National Cancer Center in Korea. Information on dietary intake was collected using a semi-quantitative food frequency questionnaire with 106 items, including peanuts, pine nuts, and almonds (as 1 food item). Nut consumption was categorized as none, < 1 serving per week, 1–3 servings per week, and ≥3 servings per week. A binary logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) for the association between nut consumption and colorectal cancer risk, and a polytomous logistic regression model was used for sub-site analyses. Results: High nut consumption was strongly associated with reduced risk of colorectal cancer among women (adjusted ORs: 0.30, 95%CI: 0.15–0.60 for the ≥3 servings per week group vs. none). A similar inverse association was observed for men (adjusted ORs: 0.28, 95% CI: 0.17–0.47). In sub-site analyses, adjusted ORs (95% CIs) comparing the ≥3 servings per week group vs none were 0.25 (0.09–0.70) for proximal colon cancer, 0.39 (0.19–0.80) for distal colon cancer, and 0.23 (0.12–0.46) for rectal cancer among men. An inverse association was also found among women for distal colon cancer (OR: 0.13, 95% CI: 0.04–0.48) and rectal cancer (OR: 0.40, 95% CI: 0.17–0.95). Conclusions: We found a statistically significant association between high frequency of nut consumption and reduced risk of colorectal cancer. This association was observed for all sub-sites of the colon and rectum among both men and women, with the exception of proximal colon cancer for women.

The IL-6 gene promoter SNP and plasma IL-6 in response to diet intervention.

Rana, B.K., S.W. Flatt, D.D. Health, B. Pakiz, E.L. Quintana, L. Natarajan, C.L. Rock, 2017. The IL-6 gene promoter SNP and plasma IL-6 in response to diet intervention. Nutrients. 9, 552; Doi:10.3390/nu9060552

We recently reported that interleukin-6 (IL-6), an inflammatory marker associated with breast pathology and the development of breast cancer, decreases with diet intervention and weight loss in both insulin-sensitive and insulin-resistant obese women. Here, we tested whether an individual’s genotype at an IL6 SNP, rs1800795, which has previously been associated with circulating IL-6 levels, contributes to changes in IL-6 levels or modifies the effect of diet composition on IL-6 in these women. We genotyped rs1800795 in overweight/obese women (N = 242) who were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet in a 1-year weight loss intervention study of obesity-related biomarkers for breast cancer incidence and mortality. Plasma IL-6 levels were measured at baseline, 6 and 12 months. At baseline, individuals with a CC genotype had significantly lower IL-6 levels than individuals with either a GC or GG genotype (p < 0.03; 2.72 pg/mL vs. 2.04 pg/mL), but this result was not significant when body mass index (BMI) was accounted for; the CC genotype group had lower BMI (p = 0.03; 32.5 kg/m² vs. 33.6 kg/m²). We did not observe a 2-way interaction of time*rs1800795 genotype or diet*rs1800795 genotype. Our findings provide evidence that rs1800795 is associated with IL-6 levels, but do not support a differential interaction effect of rs1800795 and diet composition or time on changes in circulating IL-6 levels. Diet intervention and weight loss are an important strategy for reducing plasma IL-6, a risk factor of breast cancer in women, regardless of their rs1800795 genotype.

Effects of walnut consumption on colon carcinogenesis and microbial community structure.

Nakanishi, M., Y. Chen, V. Qendro, S. Miyamoto, E. Weinstock, G.M. Weinstock, D.W. Rosenberg, 2016. Effects of walnut consumption on colon carcinogenesis and microbial community structure.Cancer Prev Res. 9(8):692-703.

Walnuts are comprised of a complex array of biologically active constituents with individual cancer-protective properties. Here, we assessed the potential benefit of whole walnut consumption in a mouse tumor bioassay using azoxymethane (AOM). In study 1, a modest reduction (1.3-fold) in tumor numbers was observed in mice fed a standard diet (AIN-76A) containing 9.4% walnuts (15% of total fat). In Study 2, the effects of walnut supplementation were tested in the Total Western Diet (TWD). There was a significant reduction (2.3-fold; p<0.02) in tumor numbers in male mice fed TWD containing 7% walnuts (10.5% of total fat). Higher concentrations of walnuts lacked inhibitory effects, particularly in female mice, indicating there may be optimal levels of dietary walnut intake for cancer prevention. Since components of the Mediterranean diet have been shown to affect the gut microbiome, the effects of walnuts were therefore tested in fecal samples using 16S rRNA gene sequencing. Carcinogen treatment reduced the diversity and richness of the gut microbiome, especially in male mice, which exhibited lower variability and greater sensitivity to environmental changes. Analysis of individual operational taxonomic units (OTUs) identified specific groups of bacteria associated with carcinogen exposure, walnut consumption and/or both variables. Correlation analysis also identified specific OTU-clades that were strongly associated with the presence and number of tumors. Taken together, our results indicate that walnuts afford partial protection to the colon against a potent carcinogenic insult, and this may be due in part to walnut-induced changes to the gut microbiome.

Walnut phenolic extract and its bioactive compounds suppress colon cancer cell growth by regulating colon cancer stemness.

Lee, J., Y.S. Kim, J. Lee, S.C. Heo, K.L. Lee, S.W. Choi, Y. Kim, 2016. Walnut phenolic extract and its bioactive compounds suppress colon cancer cell growth by regulating colon cancer stemness.Nutrients. 8, 439; doi:10.3390/nu8070439.

Abstract: Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133+CD44+ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133+CD44+ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the β-catenin/p-GSK3β signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs.

 

Compositional analysis of walnut lipid extracts and properties as an anti-cancer stem cell regulator via suppression of the self-renewal capacity.

Chung J, Kim YS, Lee J,  Le JH, Choi SW, Kim Y., 2016. Compositional analysis of walnut lipid extracts and properties as an anti-cancer stem cell regulator via suppression of the self-renewal capacity.Food Sci. Biotechnol. 25(2): 623-629.

Colon cancer is a leading cause of cancer-related deaths worldwide. Effects of walnut (Juglans regia L.) lipid extracts (WLEs) on the self-renewal capacity of cancer stem cells (CSCs) in colon cancer were investigated. The dominant component of WLEs was α-linoleic acid (64.6%), followed by α-linolenic acid (14.6%), and oleic acid (12.6%). A higher concentration of γ-tocopherol (37.1%) was also present than of α-tocopherol (0.6%). CD133+CD44+CSCs treated with WLEs showed inhibition of colony formation and sphere formation, indicating a decrease in the self-renewal capacity. Treatment with WLEs also resulted in down-regulation of protein levels, including Notch1, phospho-GSK3β (p- GSK3β), and β-catenin, which are associated with CSCs and the self-renewing capacity. WLEs rich in essential fatty acids and γ-tocopherol can exert therapeutic actions on colon cancer via targeting of CSCs.

Urolithin A causes p21 up-regulation in prostate cancer cells.

Sánchez-González, C., C.J. Ciudad, M. Izquierdo-Pulido, V. Noé V., 2016. Urolithin A causes p21 up-regulation in prostate cancer cells. Eur J Nutr. 55(3):1099-112.

Purpose: Walnuts contain several bioactive compounds, including pedunculagin, a polyphenol metabolized by microbiota to form urolithins, namely urolithin A (UA). The aim of this study was to determine gene expression changes in prostate cancer cells after incubation with UA. Methods: We performed a genomic analysis to study the effect of UA on LNCaP prostate cells. Cells were incubated with 40 µM UA for 24 h, and RNA was extracted and hybridized to Affymetrix Human Genome U219 array. Microarray results were analyzed using GeneSpring v13 software. Differentially expressed genes (p < 0.05, fold change > 2) were used to perform biological association networks. Cell cycle was analyzed by flow cytometry and apoptosis measured by the rhodamine method and by caspases 3 and 7 activation. Cell viability was determined by MTT assay. Results: We identified two nodes, FN-1 and CDKN1A, among the differentially expressed genes upon UA treatment. CDKN1A was validated, its mRNA and protein levels were significantly up-regulated, and the promoter activation measured by luciferase. Cell cycle analysis showed an increase in G1-phase, and we also observed an induction of apoptosis and caspases 3 and 7 activation upon UA treatment. Conclusion: Our results indicate a potential role of UA as a chemopreventive agent for prostate cancer.