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. Author manuscript; available in PMC: 2021 Aug 5.
Published in final edited form as: Adv Cancer Res. 2016 Oct 12;133:1–22. doi: 10.1016/bs.acr.2016.08.001

The Role of Advanced Glycation End-Products in Cancer Disparity

David P Turner *
PMCID: PMC8341423  NIHMSID: NIHMS1725394  PMID: 28052818

Abstract

While the socioeconomic and environmental factors associated with cancer disparity have been well documented, the contribution of biological factors is an emerging field of research. Established disparity factors such as low income, poor diet, drinking alcohol, smoking and a sedentary lifestyle may have molecular effects on the inherent biological make-up of the tumor itself, possibly altering cell signaling events and gene expression profiles to profoundly alter tumor development and progression. Our understanding of the molecular and biological consequences of poor lifestyle is lacking but such information may significantly change how we approach goals to reduce cancer incidence and mortality rates within minority populations. In this review, we will summarize the biological, socioeconomic and environmental associations between a group of reactive metabolites known as advanced glycation end-products (AGEs) and cancer health disparity. Due to their links with lifestyle and the activation of disease associated pathways, AGEs may represent a both a biological consequence and bio-behavioral indicator of poor lifestyle which may be targeted within specific populations to reduce disparities in cancer incidence and mortality.

1. Introduction

Specific populations in the United States and across the world suffer disproportionately high levels of cancer incidence and mortality. Poor diet, low income, and a sedentary lifestyle are interrelated socioeconomic and environmental factors that are known to contribute to cancer disparity. Significantly, these factors are most prevalent in African American (AA) communities which often have the highest levels of cancer incidence and mortality. While socioeconomic and environmental factors are established contributors to cancer health disparity, it is becoming increasingly apparent that molecular differences in tumor biology may also play a significant role. The role of biological factors remains one of the most understudied areas of cancer disparity research. Evidence supporting inherent biological differences in race specific tumors include faster disease progression in AA men with prostate cancer, higher prevalence of triple negative breast cancer in AA women and race specific differences in the expression patterns of multiple key cancer associated genes. Intriguingly, lifestyle choices may also have profound effects on tumor biology which may contribute to cancer disparity outcomes such as its earlier development and/or its progression to more aggressive disease. The molecular composition of the primary tumor plays a critical role in determining a life threatening phenotype, and it is now apparent that the established socioeconomic and environmental risk factors that drive cancer disparity can have profound effects on tumor biology. Factors such as a poor diet and a lack of exercise can alter tumor associated gene expression, non-coding RNAs, chromosomal abnormalities and gene polymorphisms to contribute to health disparity outcomes (Kinseth et al., 2014; Powell & Bollig-Fischer, 2013; Reams et al., 2009). Our understanding of the molecular consequences of poor lifestyle on tumor biology and its contribution to cancer disparity is still in its infancy and is subject to substantial debate. However, approaches that define the biological consequences of cancer health disparity may not only increase our understanding of cancer etiology but also define novel therapeutic targets and potential biomarkers with which to reduce cancer incidence and mortality.

2. Advanced Glycation End-Products

A group of lifestyle linked reactive metabolites have recently come to the fore as a potential biological mechanism driving cancer disparity. Advanced glycation end-products (AGEs) are reactive metabolites produced by the non-enzymatic glycosylation of sugars to biological macromolecules such as protein, DNA and lipids, in a process known as glycation (Fig 1.1). Glycation is a complex and multistep process involving a series of condensation, rearrangement, fragmentation and oxidation reactions driven by the Maillard reaction. Carbohydrates such as fructose and glucose are metabolized by specific molecular pathways to produce essential metabolites that are required for metabolism and energy production (Uribarri et al., 2005; Uribarri et al., 2010). These essential metabolites produce carbohydrate intermediates which react with free amino groups to generate reactive carbonyl species (RCS’s). These RCS are AGE precursors which in turn non-enzymatically react with macromolecules such as proteins, lipids and DNA to produce AGEs (N. A. Ansari, 2008; Thornalley, 2003a, 2003b, 2008; Uribarri et al., 2005; Uribarri et al., 2010). Alternatively, RCS can undergo further oxidation, dehydration, polymerization and oxidative breakdown reactions to give rise to numerous other AGE metabolites. Clearance of AGEs is inefficient and they accumulate in our tissues and organs as we grow older with pathogenic effects (Fig 1.1). Elevated AGE levels lead to protein dysfunction, protein crosslinking, decreased genetic fidelity and aberrant cell signaling which can lead to increased activation of stress response pathways (Duran-Jimenez et al., 2009; Guimaraes, Empsen, Geerts, & van Grunsven, 2010; Riehl, Nemeth, Angel, & Hess, 2009). AGEs contribute to the development and complications associated with most chronic diseases including diabetes, cardiovascular disease, arthritis, and neuro-degenerative disorders to name a few (Ansari & Rasheed, 2010; Singh, Barden, Mori, & Beilin, 2001). Further, disease states such as dyslipidemia, hypertension, and hyperglycemia are critical components of multiple diseases that play a fundamental role in increasing AGE accumulation. Significantly, all of these chronic disease states demonstrate significant health disparity, particularly among AAs.

Figure 1.1.

Figure 1.1

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Through a series of condensation, rearrangement, fragmentation and oxidation reactions driven by the Maillard reaction, sugars covalently attach to biological macromolecules such as proteins to form glycated adducts (1). Glycated proteins either accumulate in our tissues and organs (2) or are proteolytically degraded into reactive metabolites known as advanced glycation end products or AGEs for short (3). AGEs can either further accumulate in our tissues and organs (4) or can function as ligand to a number of receptor molecules. AGE accumulation can alter multiple biological pathways associated with multiple, if not all, chronic diseases (5).

3. AGE metabolites, Lifestyle and Health Disparity

Apart from their endogenous buildup during glucose metabolism, AGEs are also accumulated as a consequence of lifestyle. The total levels of AGEs is a result of: 1) endogenous production during processes such as glucose metabolism, 2) exogenous intake and accumulation from diet and poor lifestyle factors, and 3) excretion from the body in urine and feces (Fig 1.2). It is estimated that around 10–30% of exogenous AGEs are absorbed in the gut but only a third of those are excreted in urine and feces (Cho, Roman, Yeboah, & Konishi, 2007; Uribarri et al., 2010). Over the last few decades, the hallmarks of the Western lifestyle - an unhealthy diet combined with a sedentary lifestyle - have increased sharply. This has led to an increase in the contribution of exogenous sources of AGE accumulation, resulting in earlier aging, earlier disease onset, and worsening disease complications.

Figure 1.2.

Figure 1.2

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AGE accumulation is a balance between their endogenous and exogenous production and their excretion and enzymatic clearance from the body.

3.1. Diet

Many foods are significant contributors to exogenous AGE accumulation (Uribarri et al., 2007; Uribarri et al., 2005; Uribarri et al., 2010; Vlassara, 2005). The typical Western diet which is high in sugar, protein and fat, and low in fruit, grains and vegetables, is particularly AGE laden and associated with increased chronic disease risk (Uribarri et al., 2007; Uribarri et al., 2005; Uribarri et al., 2010; Vlassara, 2005). The way that foods are cooked also has a significant effect on total AGE content. AGEs are naturally present in uncooked meats. Frying, grilling or roasting (i.e. dry heat) accelerates the formation of AGEs in food by approximately ten-fold. Similarly, food processing and manufacturing also accelerates AGE formation and is now a major source of exogenous AGEs. Food manufacturers add AGEs directly to foods in order to improve their appearance and taste. Significantly, processed foods now represent one of the most common food items found in grocery shopping carts especially in low-income families who live in areas with few healthy food choices.

3.2. Obesity

Hyperglycemia, hyperlipidemia and elevated oxidative stress are common features of obesity that increase the endogenous AGE accumulation pool. Decreases in AGEs correlate with reduced body weight and body fat content (Yoshikawa, Miyazaki, & Fujimoto, 2009). The AGE metabolite carboxymethyl-lysine (CML) is extensively studied in animal models of disease, especially within the context of food content and is often used as an indicator of AGE levels in biological systems (Ames, 2008; Han et al., 2013). The differentiation of human pre-adipocytes to adipocytes (fat accumulation) is associated with increased CML levels and may have significant effects on adipose tissue and adipocyte regulation. CML accumulation in the fatty livers of obese individuals is associated with increased steatosis. Increased levels of the AGE precursor methylglyoxyl (MG) is also associated with obesity. Studies in obese rats have shown MG accumulation in serum and fat tissue. AGEs may play an important role in aberrant adipose tissue regulation by altering the expression and secretion of inflammatory adipokines to alter cell signaling pathways and gene expression profiles.

3.3. Sedentary lifestyle

Recent data from the European Prospective Investigation into Cancer and Nutrition Study concludes that a sedentary lifestyle poses twice the risk of premature death as being overweight or obese (Ulf Ekelund, 2015). As shown in human (Yoshikawa et al., 2009) and animal studies (Boor et al., 2009) a more active lifestyle can help maintain a stable level or even reduce circulatory AGE accumulation. In obese rats, regular moderate exercise reduced advanced glycation early diabetic nephropathy, lowered plasma AGE-associated fluorescence as well as overall renal AGE content (Boor et al., 2009). Exercise training of late middle-aged rats lowered AGE accumulation and attenuated cardiac fibrosis and collagen cross-linking resulting in a reduction in age-related mortality between late middle age and senescence (Wright, Thomas, Betik, Belke, & Hepple, 2014). In a type 2 diabetes rat model, regular moderate exercise protocol is more effective in reducing serum level of advanced glycation end products than an irregular, severe exercise program (Salama 2013). In non-diabetic middle-aged women, a 12 week lifestyle modification consisting of an initial educational session followed by encouragement showed that number of daily walking steps significantly correlated with lower AGE levels. Reduced body weight, body fat and serum HDL-cholesterol levels is associated with decreased AGE (Yoshikawa et al., 2009). In patients with hypertension, physical activity inhibited the progression of left ventricular hypertrophy via a reduction in AGE levels (Akihiro 2014).

3.4. Behavioral risk factors

Behavioral risk factors such as tobacco use and alcohol consumption are also associated with elevated exogenous AGE levels. AGE levels are significantly higher in chronic alcohol drinkers (Kalousova 2004) and acetaldehyde-derived AGEs promote alcoholic liver disease (Hayashi 2013). AGE pre-cursors are present in tobacco extracts and in tobacco smoke and can rapidly react with biological macromolecules to for AGE metabolites. Tissue accumulation of AGEs is higher in smokers than non-smokers and tobacco derived AGEs have been demonstrated to accumulate on vessel walls and in the eye (Cerami 1997; Nicholl 1998). Both smoking and alcohol intake as well as lack of sleep were positively correlated with increased AGEs in the skin of Japanese men and women (Keitaro Nomoto, 2012).

3.5. Significance to ethnic and racial health disparity

Environmental, socioeconomic and behavioral risk factors including low income, poor diet, a lack of exercise, excessive drinking and smoking are prevalent in AA communities, are responsible for increased AGE accumulation (Fig 1.3). At over 27%, poverty rates within AAs are amongst the highest in the country (stateofworkingamerica.org). Low-income status is associated with the utilization of cheap, un-healthy and highly processed foods which are AGE-laden and promote obesity. Food deserts are areas with poor or no availability of fresh fruit, vegetables, and other healthful whole foods (i.e. foods with low AGE content). This is largely due to a lack of grocery stores, farmers’ markets, and healthy food providers. Food deserts are largely found in impoverished areas and AAs are statistically more likely to live in designated food deserts than other populations. Additionally, AAs are 1.5 times as likely to be obese as Non-Hispanic Whites. AA women and girls are 80% more likely to be obese than their Non-Hispanic white counterparts (http://minorityhealth.hhs.gov/). A higher percentage of AAs report getting little of no exercise and do not meet federal physical activity guidelines. It is estimated that only 50% of AA men and 35% of AA women do not meet Federal Aerobic Physical Activity Guidelines (https://www.heart.org). Due to the common links between these factors that drive health disparity and the increased accumulation of AGEs, elevated AGE levels may influence risk of cancer and define a metabolic susceptibility difference driving cancer and cancer health disparity.

Fig 1.3.

Fig 1.3

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Environmental, socioeconomic and behavioral risk factors including low income, poor diet, a lack of exercise, excessive drinking and smoking are prevalent in AA communities, are responsible for increased AGE accumulation

4. Mechanisms of AGE pathogenicity

Endogenous and exogenous AGE accumulation can have multiple pathogenic consequences to the function of biological macromolecules. AGEs accumulate in both the intracellular and extracellular compartments to contribute to the onset of multiple diseases, as well as subsequent disease complications. Elevation of the AGE accumulation pool is associated with increases in protein dysfunction, aberrant activation of cellular signaling cascades and compromised genetic integrity. It is not known if the same AGE-mediated pathogenic effects identified in other diseases function in the tumor microenvironment or to what extent AGEs derived as a consequence of health disparity contribute to tumor growth.

4.1. Protein dysfunction

The formation and accumulation of AGEs can alter protein function via a number of interrelated mechanisms including protein-protein crosslinking, charge distribution changes, decreased protein half-life, compromised structural integrity and altered protein conformation. AGE effect on a specific protein depends upon several factors including the inherent reactivity of specific amino groups, glucose concentration and protein half-life (J. L. Wautier & Schmidt, 2004). The non-enzymatic glycosylation of proteins results in the formation of protein crosslinks on long-lived proteins such as collagen and elastin. AGE cross-link formation accumulates over time and is accelerated when glucose levels are high, as seen in diabetic patients. AGE crosslinks have been shown to form at multiple sites within the collagen molecule resulting in increased protein half-life and a stiffening of tissues and arterial walls. This may contribute to cardiovascular complications such as atherosclerosis. AGE crosslinking also results in the aggregation of lens crystallins causing lens opacification and diabetic retinopathy (Ahmed, 2005). The glycation of laminin and fibronectin in diabetic rats decreases key processes of neuronal migration and differentiation which can be prevented by treatment with the AGE inhibitor aminoguanidine (Duran-Jimenez et al., 2009).

4.2. Aberrant cell signaling

AGEs are associated with significant and interrelated increases in the aberrant activation of cell signaling cascades. AGEs function as ligand activators for a number of transmembrane receptors. The best studied is the receptor for advanced glycation end-products (RAGE). RAGE (or AGER) is a member of the immunoglobulin superfamily and is highly expressed during embryonic development. Normal physiological functions of RAGE focus on immune response regulation and include embryonic neuronal growth, myogenesis, dendritic cell mobilization, T cell regulation, stem cell migration and osteoclast maturation. Levels of RAGE are relatively low in adult tissues and its up-regulation is observed in multiple chronic diseases associated with health disparity including cancer. The main mechanistic consequence of RAGE activation by AGE is the increased activation of stress response pathways which also represent potential biological mechanisms of cancer health disparity.

4.2.1. Immune mediated inflammation

Recent research indicates that the biological immune response is implicated in cancer health disparity (Kinseth et al., 2014; Martin, Starks, & Ambs, 2013; Rose et al., 2010). An examination of expression differences based upon tumor composition shows that cytokine signaling associated with an increased immune response is the predominant pathway increased in AA prostate cancer patients (Kinseth et al., 2014). Upon closer analysis, the majority of race specific differential gene expression was found in the stromal compartment of the tumor (Kinseth et al., 2014). A similar race specific increase in immune response gene copy number and gene expression was seen in matched radical prostatectomy tissues (Rose et al., 2010) and in Gleason 6 prostate tumors (Reams et al., 2009). In breast cancer, AA race is a significant risk factor for elevated cytokine levels after controlling for other known risk factors (Park & Kang, 2013).

RAGE is expressed on the surface of most immune cells types and is functionally linked to an increased recruitment of immune cells in a wide range of diseases (Riehl et al., 2009; Rojas et al., 2011). Its stimulation by ligands such as AGE induces the transcriptional activation immune master regulators such as NFkB, STAT3 and HIF1α. This results in the increased expression and secretion of regulatory cytokines such as IL1, IL6 and TNFα (Riehl et al., 2009; Rojas et al., 2011) to produce a persistent and cyclic increase in immune mediated inflammation. Loss of RAGE in inflammatory mouse models confers resistance to induced skin carcinogenesis (Riehl et al., 2009; Rojas et al., 2011). In castrate sensitive and castrate resistant prostate cancer cell lines, AGE is identified as the ligand for RAGE interactions, but other ligands (S100B or amphoterin) are not (Allmen, Koch, Fritz, & Legler, 2008).

4.2.2. Oxidative stress

Clinical and epidemiological evidence identifies AA race as an independent risk factor for elevated oxidative stress and increased reactive oxygen species (ROS) (Fisher et al., 2012; Morris et al., 2012). Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase catalyzes the reduction of superoxide radicals to generate ROS. Significantly, AA human umbilical vein endothelial cells (HUVEC) show higher levels of nitric oxide, lower superoxide dismutase activity, and increased expression of the NAPDH oxidase subunit p47phox protein than their Caucasian counterparts (Feairheller et al., 2011). ROS derived from NAPDH oxidases may elevate risk of cancer, and targeting NAPDH oxidases can inhibit tumor growth (Weyemi, Redon, Parekh, Dupuy, & Bonner, 2013). ROS-generating NADPH oxidases are a critical mediator in oncogenic H-Ras-induced DNA damage (Weyemi et al., 2013). Poor diet, reduced physical activity, alcohol consumption, and cigarette smoking not only increase AGE accumulation levels but also significantly increase the oxidative stress levels in our body (Aseervatham, Sivasudha, Jeyadevi, & Arul Ananth, 2013; Dato et al., 2013) but it is not known if the two are linked.

In multiple chronic diseases, there is a well-established mechanistic link between AGE and elevated oxidative stress (Bansal et al., 2012; Guimaraes et al., 2010; Morita, Yano, Yamaguchi, & Sugimoto, 2013; Peppa, Uribarri, & Vlassara, 2008; Stirban et al., 2008; Stirban et al., 2006; M. P. Wautier et al., 2001). This may also result in a persistent and cyclic increase in ROS levels in tumor cells. Another critical pathogenic consequence of the AGE-RAGE pathway is an increase in reactive oxygen intermediates and the generation of ROS both in vitro and in vivo (Bansal et al., 2012; Guimaraes et al., 2010; Morita et al., 2013; Peppa et al., 2008; Stirban et al., 2008; Stirban et al., 2006; M. P. Wautier et al., 2001). This can lead to aberrant activation of cell signaling cascades and altered gene expression and function as well as DNA damage (Bansal et al., 2012; Guimaraes et al., 2010; Morita et al., 2013; Peppa et al., 2008; Stirban et al., 2008; Stirban et al., 2006; M. P. Wautier et al., 2001). Reactive intermediates generated during AGE formation (i.e., Schiff’s Bases and Amadori products) can directly increase ROS production to further promote stress responses (Li, Sigmon, Babcock, & Ren, 2007; Rojas, Mercadal, Figueroa, & Morales, 2008; Sparvero et al., 2009). In a potential feedback loop oxidizing conditions and ROS presence can further promote the formation of AGEs via the formation of AGE precursors such as MG (Baynes, 2001; Chang & Wu, 2006; Desai et al., 2010; Yao & Brownlee, 2010). Consuming foods that increase AGE levels in the body such as red meat, and those with high fat and carbohydrate content increases oxidative stress and ROS levels. Significantly, anti-oxidants can inhibit AGE induced changes in glucose consumption and lower ROS levels (de Arriba et al., 2003). Furthermore, multiple studies in other diseases indicate that the AGE-RAGE signaling axis induces NAPDH oxidase activity and elevated ROS levels. Pharmacological inhibition of NAPDH oxidases inhibits AGE-mediated generation of reactive oxygen intermediates (ROIs) and AGE stimulated effects are suppressed in gp91phox-null macrophages (M. P. Wautier et al., 2001).

4.3. DNA damage

ROS and AGEs represent some of the most reactive metabolites generated during human metabolism and both have an increased propensity for increasing levels of genotoxic insult to reduce genetic integrity. The biological significance of oxidative DNA damage to cancer has been well established but its etiology is still not fully understood. The perpetual feed-forward loop observed between AGE and ROS leading to a cyclic increase in oxidative stress levels may have critical consequences to cancer-associated DNA damage, but the oxidative dependent and independent implications of AGE mediated DNA damage has not yet been assessed. Significantly, AGE-DNA adducts in non-cancer cell lines produce multi-base deletions, base pair substitutions, tandem mutations, and base-pair additions/deletions (Barea & Bonatto, 2008). DNA nucleotides readily react with reactive carbonyl species (RCS) to form several species of dNTP-AGE which are potentially genotoxic and mutagenic (Barea & Bonatto, 2008; Wuenschell et al., 2010). The major nucleotide AGEs are 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one (dGG) N2-carboxymethyl-deoxyguanosine (CMdG) and 5-glycolyldeoxycytidine (gdC) derived from the metabolite glyoxal, and 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one (dG-MG) and N2-(1-carboxyethyl)-deoxyguanosine (CEdG) derived from the metabolite methylglyoxal. Carboxymethyl-2’deoxyadenosine (CMdA) was recently identified by HPLC and LC/MS spectroscopy from glycoxidative reactions of deoxyadenosine and reactive carbohydrates D-glucose, D-ribose, and L-ascorbic acid (Thornalley, 2003b). Hydrolysis of CMdA gives carboxymethyl adenine (CMA) which is present in human and calf-thymus DNA samples (Thornalley, 2003b). The quantitative assessment of dNTP-AGE adducts and their molecular links with oxidative DNA damage are of likely pathogenic and diagnostic significance and may represent race-specific surrogate measures of metabolic control linked to poor lifestyle and cancer. Immunohistochemical (IHC) and immunofluorescent (IF) staining showed elevated AGE levels in prostate tumor tissue compared to non-cancer prostate tissue

5. AGEs, cancer and cancer disparity

Many of the risk factors associated with cancer disparity such as poor diet, a lack of exercise, and obesity are also associated with the increased accumulation of AGEs. However, while several studies have investigated the role of RAGE in carcinogenesis, investigations regarding the functional contribution of AGEs to the onset and growth of cancer and their potential role as a lifestyle-linked biological factor contributing to cancer disparity is lacking. AGE presence in human tumors was first demonstrated in larynx, breast, and colon by immunohistochemical (IHC) staining (van Heijst, Niessen, Hoekman, & Schalkwijk, 2005) and has since been shown to be also elevated in prostate tumors (Dion Foster et al., 2014).

5.1. Prostate cancer

Exogenous AGE treatment of immortalized prostate cancer cells promotes cell growth, migration, and invasion (Rodriguez-Teja et al., 2014). In prostate tumors, AGE modified basement membrane in the form of collagen crosslinking promotes the invasive properties of prostate epithelial cells and correlates with decreased survival (Rodriguez-Teja et al., 2014). Circulating levels of the AGE metabolite carboxymethyl-lysine (CML) are significantly higher in serum from high grade prostate cancer patients (Gleason grade 7 to 10) compared to that observed in low grade (Gleason grade 4 to 6) (D. Foster et al., 2014; Turner, 2015). Significantly, when stratified by race, circulating and tumoral AGE levels were significantly higher in serum and tissue from AA prostate cancer patients compared to Caucasian (D. Foster et al., 2014; Turner, 2015). This was observed in low grade and high grade tumors. Furthermore, like AGE, highest levels of RAGE were observed in the tumor tissue compared to non-cancer tissue with highest levels again being observed in AA samples (D. Foster et al., 2014; Turner, 2015). RAGE itself is overexpressed in a variety of tumor types (Riehl et al., 2009). Studies support a direct link between RAGE activation and proliferation, survival, migration, and invasion of tumor cells (Riehl et al., 2009; Rojas et al., 2011). Blockade of RAGE suppresses tumor growth in two independent mouse models (Riehl et al., 2009; Rojas et al., 2011). Silencing of RAGE reduces prostate-specific antigen (PSA) expression and inhibits cell proliferation in prostate cancer cell lines and tumor growth in Nude mice (Elangovan et al., 2012). Studies show that the V-domain of RAGE preferentially interacts with AGEs on prostate cancer cells over other ligands (Allmen et al., 2008). Recently the AGE-RAGE signaling axis has been shown to promote prostate cancer cell proliferation by increasing retinoblastoma (Rb) phosphorylation and degradation (Bao et al., 2015). Compared to controls, patients with elevated levels of circulating AGEs associated with increased risk of prostate cancer (Yang et al., 2015).

5.2. Breast cancer

As for prostate, AGE treatment increases the growth, migratory and invasive properties of breast cancer cell lines (Sharaf et al., 2015). In MCF7 breast cancer cells, the diabetes drug metformin inhibits AGE mediated stimulation of growth by suppressing RAGE expression (Ishibashi, Matsui, Takeuchi, & Yamagishi, 2013). In studies examining AGE content in tumors, mass spectrometry analysis identified several AGE modified proteins with known functional significance to breast cancer ((Korwar et al., 2012).

5.3. Pancreatic cancer

The potential link between diet and cancer has been supported by studies in pancreatic cancer. When analyzing dietary consumption of AGEs and pancreatic cancer in the NIH-AARP diet and health study, dietary derived AGEs were associated with a modest increase in risk of pancreatic cancer and may partially explain its positive association with red meat (Jiao et al., 2015). Cooked red meat is a significant source of exogenous AGE and men who consumed the most red meat had the highest risk of pancreatic cancer. However, alternative studies have failed to provide support for an association between AGE levels and pancreatic cancer risk (Grote et al., 2012).

5.4. Other cancers

In colon cancer, activation of the AGE-RAGE signaling axis through a high AGE diet increased colon cancer development in rats (Shimomoto et al., 2012). AGE strongly induced the proliferation of primary acute myeloid leukemia via aberrant MAPK, PI3K and JAK/STAT signaling (Kim et al., 2008).

6. Targeting AGE biology

As previously discussed, AGE accumulation is a significant pathogenic consequence of both endogenous and exogenous factors that promote multiple disease phenotypes. Several AGE-targeting drugs have been developed for the treatment of diabetes and neurodegenerative disorders (Rahbar, 2007) but there use as a potential cancer therapeutic has yet to be examined. Additionally given the link between AGEs and the socioecomonmic and environmental factors that contribute to cancer disparity, opportunities also exist to target AGE levels in our bodies through changes in lifestyle.

6.1. Drug targeting

Strategies to target AGE biology for therapeutic gain are centered on the prevention of AGE formation and the reversal of AGE crosslinks. Direct AGE targeting drugs fall into two categories, AGE inhibitors and AGE breakers. AGE inhibitors target the AGE precursors formed during the Maillard reaction. Such prevention agents include dietary antioxidants (benfortiamine, pyridoxamine, vitamin C, vitamin E,) which prevent the formation of the free radicals to inhibit oxidative AGE precursor development. Natural products such as resveratrol and curcumin through their anti-oxidant and anti-inflammatory properties have also shown AGE inhibiting potential. Aminoguanidine is a nucleophilic hydrazine compound that scavenges RCS’s and forms adducts with AGE precursors including MG. Clinical trials have shown that aminoguanidine prevents nephropathy, peripheral neuropathy and retinopathy but has significant toxicity issues. Pridoxamine (vitamin B complex) is another AGE precursor scavenger, has shown a similar beneficial effect as aminoguanidine and has less toxicity issues. Metformin is a guanidine compound successfully used in the treatment of type 2 diabetes for a number of years (Yamagishi et al., 2008). Metformin has also showed some promise in the treatment of cancer but remains controversial (Kasznicki, Sliwinska, & Drzewoski, 2014; Pulito et al., 2013; Suissa & Azoulay, 2014). Metformin has been shown to inhibit the formation of AGEs and prevents cardiovascular defects associated with increased glycation (Yamagishi et al., 2008). Due to their irreversible nature and effects on protein dysfunction, AGE breakers are an attractive option for targeting AGE accumulation levels. Alagebrium (ALT711) selectively cleaves glucose associated AGE crosslinks by breaking carbon-carbon bonds between carbonyl groups. In diabetic animal studies, treatment with this drug reduces stiffness in arteries, improves endothelial dysfunction, preserves pressure-induced vasodilation, and reverses heart defects through decreases in AGE and RAGE levels (Yamagishi et al., 2008). However, studies in humans have yet to show similar promise.

6.2. Lifestyle change

Reducing AGE levels for therapeutic gain may also be achieved through lifestyle change. Reducing AGE accumulation through self-management strategies may represent a novel paradigm for monitoring symptom status and promoting health behavior modification through cancer prevention initiatives arising through health and nutritional education and community outreach. This would allow for intensive risk reduction and improved identification of high-risk patients requiring defined dietary and physical activity intervention aimed at reducing the rate of AGE accumulation to reduce disease symptoms. While the accumulation of AGEs in our tissues and organs cannot be prevented, we can make changes to our everyday lifestyle to keep their accumulation at a minimum. Avoiding foods associated with a Western diet (i.e.high in protein, sugar, and fat as well as the use of processed foods can significantly affect the rate at which AGEs accumulate in our bodies. Cooking foods with moist heat (boiling, steaming) rather than dry heat (frying, grilling) or substituting high-sugar, oil-based marinades with lemon juice, vinegar, and tomato juice (acidic marinades) can also drastically reduce exogenous AGE intake from the foods we consume. Along with dietary changes, taking steps to change a sedentary lifestyle toward a more active will prevent further AGE accumulation.

7. Concluding remarks

The concept suggesting that AGE metabolites represent a biological consequence of lifestyle contributing to cancer disparity is a novel approach to explaining the increased incidence and mortality observed within diverse populations and may identify novel avenues for therapeutic and lifestyle intervention. From the translational perspective, a greater understanding regarding the role of AGEs in cancer and cancer disparity may:

  1. Provide a greater biological understanding of the potential benefits of lifestyle changes and their contribution to cancer disparity. Given the potential benefits of lifestyle changes and the role of lifestyle associated AGEs in promoting disease phenotypes (Turner, 2015), multidisciplinary efforts may significantly impact cancer prevention initiatives arising through health and nutritional education and community outreach efforts.

  2. Establish a role for AGE mediated increases in stress response and DNA damage as mechanisms contributing to cancer disparity and tumor progression. Due to the higher complications and deaths associated with cancer in specific populations, a greater understanding of the risk factors and biological links associated with cancer disparity will significantly impact minority health.

  3. Set the stage for developing metabolite-based, non-invasive possibly race-specific prognostic markers. The accumulation of AGE metabolites may represent a distinct common disease risk factor associated with early recognition of cancer growth and/or progression. This would allow for intensive risk reduction and improved identification of high-risk patients requiring defined treatment.

  4. Define novel pathways for therapeutic intervention that would significantly impact cancer health disparity. Drugs targeting AGE metabolites have been developed for the treatment of diabetes and neurodegenerative disorders (Yamagishi et al., 2008). Further innovative insights may support targeting AGEs as a dual treatment option and identify protective factors that may underlie cancer disparity.

Sparse information exists about the genetic and biological factors that contribute to differential cancer survival and mortality rates observed in race specific backgrounds. Associating the mechanistic links between glycation and cancer biology has not been examined in detail within the context of a race-specific background. In order to increase our mechanistic understanding of race specific differences in tumor biology we need to develop innovative molecular models with which to test working hypothesis and future potential treatments. The use of primary prostate tumor and patient derived xenograft (PDX) models in particular may successfully demonstrate race specific differences in biological pathways which may be molecularly or genetically manipulated in future studies.

Acknowledgements

DPT’s work was supported in part by grants from the National Institute of Health/ National Cancer Institute (CA176135-Turner, CA194469-Turner and CA157071-Ford).

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