High salt and fat intake, inflammation, and risk of cancer

Abstract

BACKGROUND: Inflammatory conditions are involved in the pathophysiology of cancer. Recent findings have revealed that excessive salt and fat intake is involved in the development of severe inflammatory reactions.

METHODS: A literature search was performed on various online databases (PubMed, Scopus, and Google Scholar) regarding the roles of high salt and fat intake in the induction of inflammatory reactions and their roles in the etiopathogenesis of cancer.

RESULTS: The results indicate that high salt and fat intake can induce severe inflammatory conditions. However, various inflammatory conditions have been strongly linked to the development of cancer. Hence, high salt and fat intake might be involved in the pathogenesis of cancer progression via putative mechanisms related to inflammatory reactions.

CONCLUSION: Reducing salt and fat intake may decrease the risk of cancer.

Keywords

cancer / inflammation / nutrition / salt / fat

Introduction

Inflammatory responses play crucialroles in tumor progression and responses to cancer chemotherapy (Grivennikov et al., 2010). Interestingly,the development of inflammatory conditions is linked to dietary patterns.Recent studies indicated the role of excess dietary salt and fat inthe development of severe inflammatory reaction (Binger et al., 2015; Catta-Preta, et al., 2012; Dutheil et al., 2016). Moreover,epidemiological studies revealed the role of high dietary salt andfat intake as a risk factor for cancer (D’Elia et al., 2012; Han et al., 2015). Therefore, important questions arise:does high salt and fat intake increase the risk of cancer via putativemechanisms related to inflammatory reactions?

Theory

i) Cancer is associated with inflammatoryconditions.

ii) High salt and fat intake inducessevere inflammatory reactions.

iii) High salt and fat intake maycontribute to cancer progression via induction of inflammatory reactions.

Inflammation and cancer

Inflammation has been linked to cancerdevelopment or exacerbation (Coussensand Werb,2002; Lin andKarin,2007). Chronic inflammation also increases therisk of cancer (Grivennikov et al.,2010). A systematic review of clinical studies demonstratedthat the concentrations of cytokines TNFa, IL-6, IL-8, IL-10, IL-18, and TGFb were increased in cancer patients (Lippitz,2013). However, the role of Th17 cells andIL-17 in cancer development is controversial because these cells andcytokines can have a dichotomous role as tumor suppressor and tumorpromoter depending on the cancer type (Alizadeh et al., 2013; Guéry and Hugues,2015; Hemdan,2013).

Nutrition and cancer

Epidemiological studies revealedthat a healthy diet containing fruits, vegetables, whole grains, fish,low fat, and less red meat, which is also known as “Mediterranean”diet, has been associated with decreased inflammatory conditions (Barbaresko et al., 2013; Eichelmann et al., 2016; Schwingshackl and Hoffmann,2014).Conversely, a “Western” diet, which is high in fat, protein,sodium, and sugar, has been associated with increased inflammatoryconditions (Barbaresko et al., 2013; Manzel et al., 2014). Hence, dietary patterns may be associated with an increase ordecrease cancer risk (Wicki and Hagmann,2011). In this regard, the results of a recent meta-analysis revealedthat the Mediterranean diet significantly decreased the risk of theoverall cancer mortality/incidence (Schwingshackl and Hoffmann, 2014). Another meta-analysisrevealed that the Western dietary pattern is associated with an increasedrisk of colorectal cancer (Yusof andShah,2012).

High salt intake induces inflammatory reactions: implicationfor cancer progression

High salt intake-induced inflammation

Salt is an essential macronutrientthat plays multifunctional roles in physiologic conditions (Kotchenet al., 2013). Excessive salt intake is a major cause of hypertensionand stroke (Mozaffarian et al., 2014). Interestingly, different studies revealed that high salt intakeinduces severe inflammatory reactions, but inhibits regulatory T celldevelopment and anti-inflammatory cytokine production (Binger et al., 2015). On the one hand,excessive salt intake augments T helper-17 pathway and inflammatorycytokines such as IL-17, IL-23, TNF-a, IL-2, and nuclear factor-kB(NF-kB) in a mouse model of multiplesclerosis (experimental autoimmune encephalomyelitis (EAE)) (Kleinewietfeld et al., 2013; Wu et al., 2013; Krementsov et al., 2015;Hucke et al., 2016; Jörg et al., 2016). On the otherhand, high salt treatment not only inhibits the suppressive functionof regulatory T cells, but also stimulates these cells to secreteIFNg (Hernandez et al., 2015). Furthermore, high salt intakereduces the ability of macrophages to secrete anti-inflammatory cytokinesIL-4 and IL-13 (Binger et al., 2015). A high salt diet also exacerbates blood-brain barrier disruptionin a mouse model of cerebral ischemia (Zhang et al., 2015) and experimental colitis in mice(Monteleone et al., 2016). Clinical investigations showed that a salt-enriched diet enhancesthe disease activity of multiple sclerosis, an inflammatory autoimmunedisorder (Farez et al., 2015). Yi et al. (2015) reported that healthy individuals with high dietary salt intakehad a higher number of monocytes than those with normal salt intake.Remarkably, decreased concentrations of inflammatory cytokines andincreased production of anti-inflammatory cytokine IL-10 were observedafter reducing salt intake. Therefore, high dietary salt intake inducesinflammatory conditions.

Linking high salt intake and cancer

Several evidences showed that excessivesalt intake is an important risk factor for gastric cancer (Nagini,2012). A meta-analysis ofcase control studies demonstrated that high salt intake is significantlyassociated with increased risk of gastric cancer (D’Elia,et al., 2012). Faehet al. (2014) comparedthe cancer mortality among 17,733 Swiss men and women who added saltto their prepared meals. Results revealed that cancer mortality riskincreased by 30% in people who always added salt to their meals thanthose who never added salt (Faeh etal., 2014). Previous studies reported that Helicobacter pylori infection induces gastriccarcinogenesis. Interestingly, different studies showed that highsalt intake enhances H. pylori colonization(Fox et al., 1999),exacerbates H. pylori-induced gastriccarcinogenesis (Gaddy et al., 2013; Kato et al., 2006; Nozaki et al., 2002; Xu et al., 2015),and increases gastric inflammation (Gaddy et al., 2013; Loh et al., 2015) associated with increased gastricpH (Gaddy et al., 2013) and oxidative stress (Loh et al.,2015). Furthermore, in vitro studies revealed that ahigh NaCl treatment for breast cancer induces inflammatory cytokines(IL-17, IL-6 and TNF-a), increasesthe activities of nitrogen and oxygen (RNS/ROS) species, enhancesthe expression of vascular endothelial growth factor (VEGF)-A, andpromotes cancer (Amara et al., 2016; Amara et al., 2016). These data suggest that a high salt intake can induce inflammatoryreactions and lead to cancer progression.

High fat intake induces inflammatory reactions: implicationfor cancer progression

High fat intake induced inflammation

A high fat diet is a major causeof obesity and other related disorders (Teodoro et al., 2014). Fats, especially one with saturatedfats and trans-fats, is associated with increased risk of mortalityof different diseases (Wang et al.,2016). A high fat diet is also associated with increasedinflammatory conditions. In this regard, Catta-Preta et al. (Catta-Preta,et al.) found that a high fat diet increases the levels of resistin(also known as adipose tissue-specific secretory factor (ADSF)), leptin,and IL-6 in mice (Catta-Preta, et al.). MaxGulhane et al., (Gulhane et al., 2016) demonstratedthat a high fat diet induces obesity, disrupts mucosal barrier integrity,and exacerbates colitis in mice. Moreover, they noted an increasein the oxidative stress and enhancement of the mRNA expression ofinflammatory cytokines (TNF-a,IL-1b, and IL-17) in the colonof mice that were fed an enriched fat diet (Gulhane et al., 2016). Timmermanset al. (2014) studied the effects of a high fat diet on the course of EAE inmice. Results showed that a high fat diet exacerbates the severityand neuroinflammation of EAE in mice that were fed a high fat dietcompared with those in the control group (Timmermans et al., 2014). Dutheil et al. (Dutheil et al., 2016) reported thata high fat diet induces anxiety and anhedonic behaviors associatedwith increased inflammatory cytokines (e.g., IL-6, IL-1b, TNF-a) corticosterone levels in rats. Another study demonstrated thatage affects the inflammatory response to a high fat diet, while Kim et al. (2016) found that agedmice had higher expression levels of inflammatory cytokines (TNF-a, IL-1b, IL-6, IL-12, IL-17A), monocyte chemoattractant protein-1 (MCP-1),and TLR4, associated with increased oxidative stress in their liverand kidney due to old age, than middle-aged mice (Kim et al., 2016). Moreover, a highfat diet exacerbates collagen-induced arthritis (Jhun et al., 2012), IBD (Paik,Fierce,Treuting et al., 2013), and trinitrobenzenesulfonic acid-induced colitis (Okada et al., 2013) in mouse models.It is worth noting that not only high dietary fat induces inflammation.Internal adipose tissues secrete inflammatory cytokines that act asmediators of obesity-associated cancer development (reviewed in (Howe et al., 2013)).

Link between high fat intake and cancer

Different investigations demonstratedthat high dietary fat intake increases the risk of cancer. The resultof a meta-analysis of observational studies revealed that high totalfat intake is positively associated with increased risk of gastriccancer (Han et al., 2015). Furthermore, a high fat intake is associated with increased riskof mortality among men with non-metastatic prostate cancer (Richman et al., 2013) and women withbreast cancer (Kroenke et al., 2013). In mouse models, a high fat diet promoted the development of prostatecancer, improved the levels of cytokines and chemokines, and decreasedthe survival rate (Cho et al., 2015). In a rat model of colon carcinoma, a high fat diet promoted azoxymethane-inducedcolon carcinogenesis (Reddy and Maeura,1984). Another study found that a high fat diet enhances mammary tumorgrowth and increases the levels of inflammatory cytokines (e.g., IL-6and MCP1) and leptin in a mouse model of breast cancer (Cowen et al., 2015). Taken together,a high fat intake induces inflammatory reactions and may lead to cancerdevelopment.

Concluding remarks

There are strong links between inflammationand cancer. High salt and fat intake induced inflammatory reactions,which subsequently led to the progression of cancer. The synergisticeffects of high salt and high fat intake need further consideration.Thus, reducing salt and fat intake may decrease the risk of cancer.

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