Location: Jean Mayer Human Nutrition Research Center On Aging
2024 Annual Report
Objectives
Vitamins and Carcinogenesis Lab
Objective 1: Define the cellular pathways by which obesity, obesigenic diets, and the intake of the 1-carbon nutrients modulate the risk of developing cancers of the colorectum and other common cancers in both animal models and human samples, and exploit these mechanistic insights in order to devise targeted means of mitigating cancer risk.
• Sub-objective 1A: Determine whether the pro-inflammatory/pro-carcinogenic NF'B pathway plays the predominant role in mediating the obesity-promoted increased risk of colorectal carcinogenesis.
• Sub-objective 1B: Determine whether supplemental levels of dietary vitamin B6 provide additional suppression of obesity-promoted tumorigenesis and colonic inflammation when combined with curcumin + salsalate, beyond that provided by the two latter agents alone.
Objective 2: Examine how modifications in the microbiome alter biochemical and molecular processes that lead to colorectal cancer, and explore how intentional manipulations of the microbiome, or its products, can be exploited for cancer prevention.
Objective 3: In both genetic and chemically-induced rodent models of colorectal carcinogenesis examine whether select alternative protein sources (e.g. insect-based foodstuffs) suppress pro-carcinogenic pathways and tumorigenesis compared to soy protein and other dietary sources of protein more common in the American diet.
Nutrition and Cancer Biology Lab
Objective 1: Investigate mechanistically the anti-inflammatory and anti-carcinogenic effect of phytochemical-rich whole food approaches, and purified phytochemicals as well as their derivatives, in preventing inflammation-promoted (e.g., induced by a high-sugar diet, diabetes, and aging) cancer development.
Objective 2: Determine the ability of phytochemical-rich whole foods and dietary phytochemicals to prevent cancer development in liver and colon by targeting multiple signaling pathways (e.g. membrane and nuclear receptors) and inter-organ crosstalk (among liver, pancreas, mesenteric adipose tissue, and gut microbiome).
Approach
Vitamins and Carcinogenesis Lab
We will identify novel strategies by which colorectal cancer (CRC), and other cancers that commonly afflict elderly Americans, can be prevented. Our aim is to lessen the risk that accompanies cancer-promoting features typifying the U.S. diet, such as its obesigenic character and emphasis on processed animal meat. Using a combination of in vitro experiments and animal models we identify biochemical and molecular pathways that mediate the effects of specific nutrients or dietary patterns on carcinogenesis. We then identify means of modulating those pathways to mitigate cancer risk. We will examine how the inflammatory state created by obesity and high-fat diets activates procancerous pathways in the colon. We are exploring the use of pharmacologic, nutritional, and microbial agents to block those pathways. The third objective is an exploratory aim, designed to generate preliminary data. We will examine whether substituting protein-rich powder derived from roasted crickets attenuates the enhanced risk of CRC that accompanies the habitual consumption of processed meats which are a prominent source of protein in the American diet. This strategy has the added value of promoting food sustainability. Our research will provide novel avenues for reducing the societal burden of common age-related cancers.
Nutrition and Cancer Biology Lab
We will conduct animal studies to investigate how one dietary phytochemical, xanthophyll beta-cryptoxanthin (BCX), inhibits metabolic syndrome, nonalcoholic fatty liver disease and liver cancer (hepatocellular carcinoma) development in the liver. Of particular interest is understanding how BCX prevents the development of hepatocellular carcinoma in rodents consuming a diet high in refined carbohydrates (HRCD). We will examine the protective effects of intact BCX, independent of its metabolites, regulating key cell signaling pathways in both young and old animals. We will examine multiple organs (liver, pancreas, adipose tissue, and gut) as well as how these organs communicate, while noting gender differences. Specifically, we will use genetically-altered carotenoid cleavage enzyme (beta-carotene 15,15’-oxygenase and beta-carotene 9’,10’-oxygenase) double knockout mice strains to determine whether HRCD-induced liver metabolic syndrome and tumorigenesis can be prevented by intact BCX itself or sweet red pepper extract (SRPE)-rich in BCX. We will treat mice (male and female) with a single injection of a hepatic carcinogen, diethylnitrosamine (DEN), followed by continued exposure to HRCD with or without BCX (or SRPE) intervention. We will examine the effects of dietary BCX intervention against fatty liver, inflammation, fibrosis, and in livers. We will investigate the protective effects of xanthophyll BCX against HRCD-promoted HCC in both young and old mice respectively. We will determine if the BCX protective action process a common mechnism or pathway, such as intestinal permeability/gap junction/adipose/liver axis, salvage pathway of NAD+ biosynthesis enzyme, and circadian transcription factors, and thereby reducing aging/metabolic syndrome-associated liver cancer development.
Progress Report
Vitamins and Carcinogenesis Lab
A. Our focus on finding ways to block low-grade inflammation of the colonic mucosa – an important pathway by which colorectal cancer evolves – has continued. We published our mouse study that demonstrated a significant degree of anti-tumorigenic synergy is produced by combining supplemental curcumin and vitamin B6 in the diet, and we included mechanistic data in that paper that began to elaborate the molecular pathways by which this synergy occurs. This work is directly relevant to Objective #1.
B. We have also been quite interested in how the colonic milieu of the older individual predisposes to colorectal cancer and we published a study in a mouse model demonstrating that a colonic microbiome derived from an older animal is pro-tumorigenic when implanted in a young animal. This work is directly relevant to Objective #2.
C. Our work in cricket powder revealed that >95 percent of the previously reported vitamin B12 in cricket powder is actually non-bioavailable analogues of vitamin B12.This is immediately relevant to Objective #3.
D. Over the past 5 years this project has substantially advanced our understanding of how obesity produces an inflammatory environment within the colon, and how that promotes the risk of colorectal cancer. In mouse models, we have identified dietary and microbiologic agents that block this inflammation, thereby suppressing tumorigenesis, and we have defined biochemical and molecular pathways by which these anticancer effects are mediated. Further, in multiple instances we have demonstrated anti-tumor synergy between these agents when used in combination. We have combined our established expertise in colorectal cancer prevention with our efforts in agricultural sustainability, examining whether insect-based protein powders have anti-tumorigenic potential as well as other health benefits.
Nutrition and Cancer Biology Lab
Progress was made on Objective 1 and Objective 2 in the 5-year project period. We investigated the anti-inflammatory and anti-carcinogenic effect of dietary phytochemical carotenoids in preventing cancer development by targeting multiple signaling pathways and inter-organ crosstalk. The significant progress is our demonstrations that provitamin A carotenoid (e.g., beta-cryptoxanthin (BCX) from sweet red pepper) and non-provitamin A carotenoid (e.g., lycopene from tomatoes) can inhibit metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) and liver cancer known as hepatocellular carcinoma (HCC). Our demonstration that the protective effects of BCX and lycopene are independent of its cleavage metabolites provided important insights regarding the mechanisms of the bioactivity of carotenoids, which are critically needed for future human studies involving carotenoids for the prevention of chronic diseases.
A. Under Objective 1, the efficacy of an equivalent dosage of dietary carotenoid BCX from either a purified form or extracted form of sweet red pepper against cancer development was investigated in animal models. We demonstrated that: a) sweet red pepper extract (SRPE) rich in BCX inhibits high refined carbohydrate/sugar diet (HRCD)-induced metabolic syndrome and nonalcoholic fatty liver disease (NAFLD); b) BCX concentrate feeding alleviates HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment and glucose metabolism, independent of BCO1 and BCO2; c) BCX treatment, independent of its provitamin A activity, significantly inhibited cigarette smoking-induced-inflammatory cell infiltration, hyperplasia in the bronchial epithelium, and enlarged alveolated airspaces regardless of sex; d) the ablation of sirtuin 1 deacetylate activity in female and male mice fed with high sugar diet developed more severity of NAFLD compared with wild type mice; and e) the lack of sirtuin 1 deacetylate activity plays a vital role in the susceptibility of lungs to age-associated pulmonary emphysema, which is associated with increased cellular senescence independent of inflammatory response.
B. We also examined whether dietary tomato powder feeding as a whole food inhibits NAFLD and HCC dependent on SIRT1 activity. We found that tomato powder feeding (equivalent to dietary lycopene intake of 8.1 mg or 2-3 median size of raw tomatoes (~300 g wet weight per day in humans) significantly reduced plasma levels of triglycerides, hepatic steatosis score, and inflammatory foci in both wild type mice and mutation mice with ablated sirt1 activity at comparable hepatic lycopene concentrations. Interestingly, in the absence of sirt1 activity, tomato powder feeding still decreased hepatic levels of oxidative stress biomarkers and lowered the mRNA expression of IL-6 in mesenteric adipose tissue and the protein concentration of IL-6 in both plasma and the liver. We concluded that dietary tomato feeding, independent of SIRT1 activity, ameliorates HFD-induced NAFLD, oxidative stress and inflammatory responses in the liver and mesenteric adipose tissue.
C. Under Objective 2, we investigated in animal models whether the protective effects of phytochemicals against cancer development are associated with systemic metabolomic, gut microbial profiles and inflammation in adipose tissue. We demonstrated that a) the protection of HRCD-induced NAFLD by BCX is through different mechanisms in different tissues (liver, gut and adipose tissue), depending on the presence or absence of BCO1 and BCO2 in double knockout (DKO) mice; b) BCX-mitigated NAFLD was significantly associated with increased hepatic lipid beta-oxidation and cholesterol efflux, and with suppressed lipogenesis and inflammatory cytokines in the mesenteric adipose tissue; c) the protective effect of BCX feeding is through shifting relevant systemic biomarkers and metabolomic profiles including ceramide, cholesterol ester, triglyceride, and phospholipid classes; d) DKO mice possessed significantly reduced alpha diversity and significant compositional differences in gut microbiota which contribute to NAFLD development; e) NAFLD pathogenesis in response to HRCD is sexually dimorphic and is more severe in male mice compared to female mice, potentially through differences in adiponectin, metabolic endotoxemia, and the gut microbiome; and f) BCX inhibited lipopolysaccharide-induced elevation of IL-6 and TNF-alpha mRNA levels in a dose-dependent manner was associated with reduced Ak strain transforming phosphorylation and stabilized I¿Ba protein in in vitro cell culture experiment. Together, our studies indicate that BCX can serve as an effective protective agent against inflammation, independent of its cleavage metabolites including vitamin A.
Accomplishments
Review Publications
Crossland, N.A., Beck, S., Tan, W.Y., Lo, M., Mason, J., Zhang, C., Crott, J. 2023. Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice. Gut Microbes. https://doi.org/10.1080/19490976.2023.2288187.
Wu, X., Ueland, P.M., Roper, J., Koh, G., Liang, X., Crott, J.W., Yilmaz, O.H., Bronson, R.T., Mason, J.B. 2021. Combined supplementation with vitamin b-6 and curcumin is superior to either agent alone in suppressing obesity-promoted colorectal tumorigenesis in mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxab320.