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Underrated enemy – from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract

Nonalcoholic fatty liver disease (NAFLD) is intrahepatic ectopic lipid deposition which is present despite a lack of other causes of secondary hepatic fat accumulation. It is the most common chronic liver disorder in the welldeveloped countries. NAFLD is a multidisciplinary disease that affects various systems and organs and is inextricably linked to simple obesity, metabolic syndrome, insulin resistance and overt diabetes mellitus type 2. The positive energy balance related to obesity leads to a variety of systemic changes including modified levels of insulin, insulin- like growth factor-1, adipokines, hepatokines and cytokines. It is strongly linked to carcinogenesis and new evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors. This article focuses on the association between NAFLD and extrahepatic gastrointestinal tract cancers, aiming to shed light on the pathomechanism of changes leading to the development of tumors.


Introduction
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized disorder characterized by intrahepatic ectopic lipid deposition which is present despite a lack of other causes of secondary hepatic fat accumulation (e.g., heavy alcohol consumption, hepatitis B or C, autoimmune hepatitis, toxins, etc.) [1]. It is the most common chronic liver disorder in the well-developed countries. The estimated prevalence of NAFLD ranges from 10% to 25%. The prevalence depends on several factors including age, gender, ethnicity, kind of diet and life style (physical activity) [2][3][4]. The term NAFLD encompasses various histological diagnoses from pure (simple) steatosis -nonalcoholic fatty liver (NAFL), through nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The definition of NAFL is the presence of hepatic steatosis with no evidence of hepatocellular injury revealed by ballooned hepatocytes. NASH is defined as the presence abdominal obesity in the latter [9]. The "multi parallel hits hypothesis" postulates multiple metabolic and environmental factors impacting together on genetically predisposed subjects [10]. The presence of NAFLD is closely associated with extrahepatic serious abnormalities including cardiovascular system with atherosclerosis/cardiovascular disease (CVD) and hypertension, endocrinopathies, T2DM, chronic kidney disease and osteoporosis [11]. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD are associated with an increased risk of incident T2DM and hypertension [12]. It is strongly linked with carcinogenesis and not only leads to HCC, but also is proven to be an independent risk factor of colorectal polyps and cancer development. Although the basic liver pathology refers to hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and HCC, the majority of deaths among NAFLD patients can be assigned to cardiovascular disease [13]. New evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortal-ity among cancer survivors [14]. This article focuses on the association between NAFLD and extrahepatic gastrointestinal tract cancers in order to shed light on the growing problem of complications among patients with NAFLD.

Pathogenesis Insulin resistance
Insulin plays a great role as a metabolic regulator, but it also acts as a growth factor with proliferative and mitogenic activities (Fig. 1) [15,16]. Insulin resistance is often considered as the primary cellular defect in the development of T2DM. The definition of IR assumes that it is a state which requires higher-than-normal insulin concentrations to obtain suitable biological effects [17,18]. The combination of IR and consequent hyperinsulinemia leads to hyperglycemia and the development of conditions associated with T2DM. However, the majority of obese and insulin-resistant subjects initially do not develop hyperglycemia because of the compensatory capacity of the islets of Langerhans and an elevated hormone output [19][20][21]. The positive energy balance related to obesity leads to an excess of circulating FFAs, increased oxidative stress and accelerated IR [7]. Short-term exposure to FFAs results in increased insulin secretion following a meal and enables storage of excess energy as fat, while long-term exposure to FFAs involves impaired glucose metabolism, reduced insulin biosynthesis and beta cell loss [22,23]. There is also evidence of the important role of chronic hepatitis C as a special type of metabolic disease, associated with hepatic steatosis due to lipid metabolism abnormalities, but also IR and T2DM as a result of impaired glucose metabolism [24]. Activation of the insulin receptor (Ir) under hyperinsulinemic condition results in up-regulation of the mitogenic pathway [25]. The insulin receptor is a transmembrane receptor which belongs to the large class of tyrosine kinase receptors. Ligands of this receptor include insulin, insulin growth factor (IGF)-1 and IGF-2 [15]. Alternative splicing of the Ir gene causes presence of two isoforms -IrA and IrB. These receptors are tetrameric proteins consisting of two α-and two β-subunits. Indeed IrA differs from IrB by the exclusion of exon 11, and the additional 12 amino acids remain present at the C-terminus of the IR α-subunit [26,27]. The isoforms of IR differ in affinity for IGFs, internalization and recycling rate, which is higher and greater in favor of IrA [28,29]. Consequently, IrB exhibits an association with metabolic and differentiating signals and is highly specific for insulin, while IrA plays an essential role in mitogenic and antiapoptotic signals induced mainly by IGF-2 (with lesser affinity for IGF-1) [28,30].
As a growth factor to stimulate mitogenesis insulin activates the Ras-Raf-Map kinase signaling pathway [31]. Insulin binds to its receptor on the cell membrane, leading to phosphorylation/activation of insulin receptor substrates (IRSs). The Shc protein binds phosphorylated Ir and IRS-1, whereupon they serve as effective adapters for the GRB2-SOS complex. The complex activates Ras and the mitogen activated protein kinase (MAPK) cascade [32,33]. The Ras-MAPK pathway leads to activation of genes involved in the mitogenic response to insulin and the IGFs, promoting inflammation and atherogenesis [34,35].
Insulin growth factors have primary structural homology to proinsulin. Most of them are produced by hepatocytes in response to growth hormone stimulation [36,37]. In addition to IGFs, the IGF axis includes two receptors -IGF1R and IGF2R -and a family of high-affinity IGF-binding proteins (IGFBPs). IGFs are stimulators of mitogenesis, survival and cellular transformation. Insulin, pro-insulin and IGFs with different affinities and potencies are capable of binding and acti-vating both Ir and IGF-1R. IGF2R has a higher affinity for IGF2, and its main function is modulation of the bioavailability of extracellular IGF-2 [38][39][40].
All IGFBPs serve as growth-inhibitory factors by competitively binding IGFs and preventing their binding to IGF1R, which stimulates cell proliferation. IGFBPs modulate the amount of bioavailable free IGFs and reduce their transfer from the bloodstream to tissue, inhibiting their action [39].
Growing evidence indicates that NAFLD aggravates IR and is an independent risk factor for developing and worsening of existing T2DM. Many studies also demonstrate that fatty liver with IR plays an important role in development of chronic complications, such as CVD, chronic kidney disease and extra-hepatic cancers [11,[41][42][43]. Due to IR progression among patients, hyperinsulinemia leads to higher production of IGF-1, resulting in activation of cellular growth and proliferation and down-regulation of apoptosis [36,38,44]. Up-regulated and uncontrolled cellular growth and proliferation within the organs may contribute to carcinogenesis. Higher IGF expression was associated with tumor progression in colorectal and pancreatic caners [45][46][47]. Increased levels of IGF-1 and its receptor in gastrinomas were related to accelerated tumor growth and aggressiveness, and occurrence of liver metastases [48]. It has been identified that IGF-1 activated various pathways of the epithelial-mesenchymal transition (EMT) in gastric cancer. IGF-1 signaling activated survivin (BIRC5) expression and controlled the expression of EMT biomarkers during the development of gastric cancer [49]. There is also evidence that a higher IGF-1/ IGFBP-3 molar ratio represents increased free IGF-1, which may be a risk factor for pancreatic cancer [50]. IGF-2 expres sion was significantly increased in primary colon tumors [51].

Angiogenesis
Insulin also induces production of a variety of other potential regulators of cell proliferation and differentiation, such as cytokines, adipokines and growth factors including leptin, vascular endothelial growth factor (VEGF) and interleukin(IL)-6 [52][53][54]. Binding to IGF1R, it plays an important role in increased production of VEGF by endothelial cells [37,55,56]. VEGF is not only a trigger and regulator of angiogenesis, vasculogenesis and vascular permeability, but VEGF-mediated signaling influences key aspects of tumorigenesis, including the function of cancer stem cells and tumor initiation [56,57]. The role of VEGF overexpression is proven in gastric cancer, esophageal cancer and colorectal cancer [55,[58][59][60][61].
During chronic inflammation, which is an inherent element of excess hypotrophy of adipose tissue and NAFLD, the accumulation of inflammatory cells collectively with fibrosis leads to hypoxia, by aggravating resistance of damaged tissue to blood flow and oxygen (O 2 ) supply [62,63]. Hypoxia induces angiogenesis as a result of signaling mediated by hypoxia-inducible factors (HIFs) [64]. Three isoforms of HIFα subunits (HIF-1α, HIF-2α, and HIF-3α) expression and the downstream activation of the hypoxic stress response play an important role in many cancers. HIF-1 and HIF-2 play complementary roles in the regulation of erythropoiesis, angiogenesis, cell proliferation and apoptosis. Each HIF regulates a unique subset of target genes. HIFα stabilization has a role in genetic alterations such as mutations in the Wnt/β-catenin signaling pathway in colon carcinoma and other oncogenic events [65][66][67][68].
However, some data show that hypoxia alone could be important in the stimulation of angiogenesis and can also boost inflammation, causing a circle between inflammation and angiogenesis [69]. Interestingly, evidence showed that in morbidly obese patients the activation of angiogenesis was observed very early at the stage of simple steatosis, while in non-obese patients angiogenesis took place later at the level of NASH. In severe obesity, there was also a positive association between the progression of fibrosis and neovascularization activity [65,70].
In a study performed on 72 patients with chronic hepatic disease, infected with hepatitis C virus genotype 1b (BMI < 30 kg/m 2 ), Kukla et al. demonstrated that higher grades of steatosis are positively associated with a more advanced stage of fibrosis and CD34 expression [71]. CD34 is a sialomucin-like glycoprotein expressed on hematopoietic progenitor cells, normal vascular endothelium and fibroblasts, which has been used as an endothelial antigen to emphasize vascular density as a direct indicator of neoangiogenesis in cancers [72].
Low-grade chronic inflammation and IR create a specific microenvironment, which is suitable for cancer development due to stimulation of the IGF-1 axis by hyperinsulinaemia [78]. The chronic inflammatory state is likely to be associated with increased production of IL-6 by adipose tissue. Expression of this cytokine positively correlates with IR both in vivo and in vitro [52,79]. Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-6, IL-8 and plasminogen activator inhibitor-1 (PAI-1), play important roles in cellular proliferation, angiogenesis and negative regulation of apoptosis [80,81].
IL-6 acts through several classic protein kinase cascades such as MAPK and phosphatidylinositoltriphosphate kinase (PI-3 kinase), but can also directly activate the signal transducers and activators of transcription (STAT) factors STAT1 and STAT3, due to the capability of acting by Janus kinases (JAK). Activation of these pathways is a serious unwanted consequence in the context of progression to neoplasia [82]. Furthermore, several experimental studies have shown that IL-6 promotes tumorigenesis and angiogenesis, facilitates metastases and increases treatment resistance [82][83][84]. IL-6 is associated with carcinogenesis in gastric cancer and colorectal cancer [85][86][87]. Increased expression of IL-6 was also found in human pancreatic cancer cells [82,88]. A number of reports also indicate that TNF-α is a very important factor in carcinogenesis. It induces tumor initiation and promotion, mediates proliferation and potentiates invasion of tumor cells. It supports tumor development due to development and persistence of angiogenesis [89,90]. Animal models showed higher expression of TNF-α in colorectal cancer [91]. TNF-α influences cancer development by activating the tumorigenic Wnt signaling pathway [92].

Hedhehog
Hedhehog (Hh) is the best characterized signaling pathway that mediates hepatic fibrosis in NAFLD. This pathway is an accepted master of the wound-healing response, which is a reaction to liver damage [93,94]. Deregulation of wound healing promotes the development of progressive fibrosis, which determines liver prognosis [95]. In healthy hepatocytes Hedgehog pathway activation is properly absent, but injured ballooned hepatocytes are the main source of Hh ligands (mostly Sonic hedgehog, Shh; others: Indian hedgehog, Ihh; and Desert hedgehog, Dhh) in NAFLD [94,96]. In human NAFLD the magnitude of activation of the Hh pathway is related to the severity of liver disease and correlates with the severity of fibrosis [96,97]. The number of Shh expressing ballooned hepatocytes strongly correlates with fibrosis severity, as well as with the severity of the ductular reaction, which is closely related to fibrogenesis and carcinogenesis [96,98]. Hh signaling is associated with inflammatory and chronic degenerative diseases. Overactivation of this signaling may lead to many tumors such as pancreatic cancer [99].

Gut microbiota
Obesity, T2DM and low physical activity induce quantitative and qualitative changes of gut microbiota composition [100]. Dysbiosis of gastrointestinal microorganisms in NAFLD has been confirmed in many studies. There is evidence that children with NAFLD exhibited higher abundance of Gammaproteobacteria, Epsilonproteobacteria and Prevotella spp. than healthy controls [101]. In the case of NASH and obesity the increase of representation of Bacteroidetes and Prevotella was found. In the same study, elevated blood-ethanol concentration was observed among patients with NASH, when compared to healthy subjects and obese patients. The role of alcohol metabolism in oxidative stress and liver inflammation suggests a significant role of the alcohol-producing microbiome in the pathogenesis of NASH [102]. Also the higher Bacteroides concentration is related to NASH development while the increased abundance of Ruminococcus is associated with risk of liver fibrosis [103]. Additionally, the cross talk between the immune system and gut microbiota components plays a key role in maintenance of gastrointestinal epithelial barrier function [104]. Disability of the immune epithelial network leads to dysfunction of tight junctions, increased gut permeability, bacterial translocation and leakage of bacterial components [105,106]. Likewise, reports have demonstrated that a decrease in Akkermansia muciniphila, which is observed in the obese, causes a thinner intestinal mucus layer and promotes gut permeability [107].
Gut microbial enzymes facilitate dietary fat digestion and absorption through formation of micelles, which is possible due to the ability of transformation of the primary bile acids into conjugated bile acids. Studies carried out on mice showed that germ-free (GF) mice or antibiotic treated mice had low concentrations of conjugated bile acids; these results underline the central role of the gut microbiota in regulating bile acid composition, conjugation, and diversity [108][109][110]. Bile acids bind the nuclear farnesoid X receptor (FXR), which is known as a transcription factor controlling their endogenous synthesis and release [111]. Mice with IR and obesity have a low diversity of gut microbiota, associated with a reduction in bile acid composition, higher intestinal expression of FXR and FXR-related genes (FGF15) and decreased hepatic Cyp7a1 [112].
There is strong evidence regarding the role of small intestinal bacterial overgrowth (SIBO) and endotoxemia in NAFLD progression. A critical point is activation of the family of pattern recognition receptors (Toll-like receptors, TLRs) with translocated bacterial endotoxins such as lipopolysaccharide (LPS), bacterial fragments, bacterial DNA and peptidoglycan. Circulating pathogen-associated molecular pattern (PAMPs) and damage-associated molecular patterns (DAMPs) and their interaction with TLRs induce production of reactive oxygen species and activation of the inflammasomes [113][114][115][116]. The inflammasome (NLRP3) is a cytosolic multiprotein complex of receptors from the family of NOD-like receptors, with pro-caspase-1 and an adaptor: apoptosis-associated speck-like CARD-domain containing protein (ASC). Activation of the complex causes autocatalytic cleavage and activation of caspase-1, which activates IL-1β and IL-18 and neutralizes IL-33. The inflammasomes are present in the liver in parenchymal and non-parenchymal cells [117,118]. Increased expression of this multiprotein complex and its components was observed in NASH, which may suggest the key role in NASH development and progression [119,120]. Stimulation of TLRs also results in the production of various inflammatory mediators through transcriptional factor nuclear factor kappaB (NF-κB) and/or c-Jun N-terminal kinase (JNK) activation [121]. Changes in the tumoral genetic and immunological microenvironment can lead to malignancy growth in the colon and influence esophageal and pancreatic tumorigenesis [122][123][124].
In obesity, like NAFLD, leptin levels increase with a simultaneous decrease of adiponectin (Fig. 2) [78,130]. Leptin is a hormone which is mainly produced by adipose tissue and whose function is to control food intake and energy balance [131]. Circulating leptin levels are higher in patients with NAFLD than in controls, and these are associated with increased severity of NAFLD [132,133]. Leptin is associated with increased carcinogenesis, indirectly through regulation of inflammation and oxidative stress or directly through up-regulation of cell proliferation, inhibition of apoptosis, potentiation of angiogenesis and modulation of the immune response [134]. Its pro-cancerogenic activity takes place through the JAK/STAT (Janus kinase/signal transducer and activator of transcription), PI3K/PTEN/Akt/mTOR (phosphoinositide 3-kinase/ phosphatase and tensin homolog/protein kinase B/mammalian target of rapamycin), Raf/MEK/ERK (protooncogene c-RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) pathways [130,135]. There was noted a dependence between elevated levels of leptin and risk of occurrence of esophageal adenocarcinoma in the overweight population [136]. In a study comparing the expression of leptin and adiponectin in esophageal squamous cell carcinoma (122 patients) and normal esophageal mucosa (40 subjects) Duan et al. found that also in esophageal carcinoma there occurs imbalanced expression of adipocytokines and a link of lymph node metastasis and/or tumor stage with expression of leptin and adiponectin, which may have potential significance in carcinogenesis and poor outcomes [137]. Stomach cancer is also linked to leptin levels. Leptin induces proliferation of gastric cancer cells by activating STAT3 and ERK1/2 pathways. It is involved in increasing expression of VEGF and mediating angiogenesis, which is engaged in tumor progression [138,139]. Expression of the leptin receptor (Ob-R) depending on clinical stage was assessed, and it showed a tendency to increase from gastric adenoma (2%), through early gastric cancer (8%), to advanced gastric cancer (18%) [138]. In the same study, an association between leptin expression and incidence of cardia cancer location was demonstrated. Colorectal cancer studies documented a link between increased serum leptin levels and lymph node involvement, microvascular invasion and advanced tumor stage [134,140,141]. Wang et al. confirmed this correlation in a study including 108 patients (57 males/51 females, mean age 58.9 years) with tumors located in the colon in 78 and the rectum in 30 patients. The distribution by TNM stage at diagnosis was: stage I in 24 patients, stage II in 27 patients, stage III in 45 patients, and stage IV in 12 patients [141]. Leptin could regulate proliferation and apoptosis of colorectal cancer through the PI3K/Akt/mTOR signal pathway [141]. At early stages of colorectal cancer it also acts as a growth factor through activation of the signal transducer and activator of transcription 3 (STAT 3) pathway [142].
Adiponectin is a 30 kDa protein hormone produced and secreted almost exclusively by adipocytes, which demonstrates insulin-sensitizing, vascular-protective and anti-inflammatory properties [140]. In serum this adipokine occurs in three forms: trimers, hexamers and high-molecular weight (HMW) multimers, which is the most biologically active isoform [143,144]. Three APN receptors have been discovered -AdipoR1, AdipoR2 and T-cadherin. The first two have been reported to be expressed in several cancer  [144,145]. Through these receptors adiponectin affects many pathways showing anti-carcinogenic activity. It activates AMP-activated protein kinase (AMPK), which plays a central role in disturbing cellular growth signaling via mTOR and inhibits adhesion and migration of tumor cells [146,147]. It also acts as an inhibitory factor of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, which is activated in a few types of cancers by promoting cellular growth and proliferation by insulin-and growth factor-induced signaling [147]. Adiponectin down-regulates carcinogenesis-promoting glycogen synthase kinase-3β (Wnt-GSK3β) pathways, extracellular regulated kinase 1 or 2 (ERK1/2), Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways and NF-κB [147][148][149]. Hypoadi ponectinemia extends the production pro-inflammatory cytokines including TNF-α and IL-6, acting as a pro-inflammatory factor and tumor cell proliferation and angiogenesis promoter [78,145]. In NAFLD reduced levels of adiponectin were found [150][151][152]. Adiponectin serum levels are dependent on abdominal adiposity distribution, with a decreased amount in obese individuals [152]. Lower levels of adiponectin were found to be associated with cancer development. The relationship was confirmed for colorectal, gastric and esophageal cancers [153][154][155][156]. Yıldırım et al. [153] studied 62 patients (30 males/32 females, aged 64 years, BMI 22.2 kg/m 2 ) with esophageal cancer classified into two types based on the histological characteristics: adenocarcinoma and squamous cell carcinoma of the esophagus. They found that the serum adiponectin level in the cancer group was significantly lower than that in the healthy control group. Moreover, it was gradually decreasing with increase in tumor stage. Additionally, the patients with esophageal adenocarcinoma had lower levels of adiponectin than patients with squamous cell carcinoma. Ishikawa et al. [154] in a study of 75 gastric cancer patients divided into two groups depending on the degree of malignancy of differentiated (32 males/11 females) and un-differentiated (22 males/10 females) gastric cancer found that a reduced adiponectin level was associated with an increased risk for gastric cancer and it had a potential role in tumor progression, especially in undifferentiated type cancers in the upper stomach. A study performed on 165 Chinese male patients of the Han nationality aged ≥ 35 years and with pathologically diagnosed colorectal cancer (CRC) -intraepithelial carcinoma and submucosally invasive carcinoma as early cancer (patients aged 62.1 years, with BMI 23.5 kg/m 2 ) and pathological stage T2 or higher was defined as advanced cancer (patients aged 61.8 years, with BMI 22.4 kg/m 2 ) -confirmed that a decreased level of adiponectin was a strong risk factor for both early and advanced CRC [155].

Wnt-GSK 3b -glycogen synthase kinase-3b pathway, PI3K/AKT -phosphatidylinositol 3-kinase/protein kinase BPathway, JAK/STAT -janus kinase/signal transducer and activator of transcription pathway, AMPK-AMP -activated protein kinase, ERK 1/2 -extracellular regulated kinase 1 or 2, NF-kb -nuclear factor kappaB, MMP-7 -matrix metalloproteinase 7, VEGF -vascular endothelial growth factor, p38-MAPK-p38 mitogen-activated protein kinase pathway, IL-6 -interleukin-6, SDF-1, stromal cell-derived factor 1, TNF-α -tumor necrosis factor α, AP-1 -activator protein-1 cells in vitro and in vivo
Resistin is a 12.5-kDa protein of the "resistin-like molecules" (RELMs) family secreted from adipocytes, but it is also produced by monocytes and macrophages [11,157]. Some authors have reported higher circulating resistin levels in NAFLD than in control groups [158,159]. An increased level of resistin was found in patients with NASH compared to those with simple steatosis, and it was linked to the severity of liver inflammation and fibrosis in those patients [160]. Resistin was suggested to play a pivotal role in adipocyte maturation through the influence on lipid metabolism. Higher levels of resistin may also be related to development of obesity-mediated IR, T2DM and inflammation [161,162]. Resistin stimulates growth, differentiation and migration of endothelial cells, which is substantial in the processes of cancerogenesis and angiogenesis [163]. Although levels of resistin might be elevated in obesity-related cancers, it cannot be labeled as a risk predictor of these tumors' occurrence. Higher resistin levels can be considered as a substantive biomarker of obesity-related cancer risk [164]. In a study performed on 85 patients with histologically confirmed gastroesophageal cancer (male/female 61/24; age 60 years) compared to 60 healthy individuals (male/female 47/13; age 58) serum resistin levels were found to be higher in cancer patients compared to controls. Resistin concentration was associated with cachexia and gastroesophageal cancer metastasis development [165]. Resistin stimulates the expression of stromal cell-derived factor 1 (SDF-1), which works as a growth and survival factor in gastric cancer cells. It acts through TLR4 and activation of NKκB and p38 MAPK pathways [166].
Visfatin is an adipokine with multipotential activities, which is expressed not only in visceral adipose tissue but also by peripheral, bone marrow and hepatic lymphocytes, pneumocytes and hepatocytes [129,167]. Visfatin exerts both extracellular (cytokine-like) and intracellular (enzymatic) functions, which are responsible for its role in the immune, metabolic and stress responses [125]. Visfatin mediates biosynthesis of nicotinamide adenine dinucleotide (NAD) by conversion of nicotinamide to nicotinamide mononucleotide. NAD biosynthesis is involved in inflammation, cellular differentiation and tumor progression through downstream regulators such as sirtuins and poly (ADP-ribose) polymerase (PARP). The sirtuins are responsible for regulation of both cell survival and TNF-α secretion [168][169][170]. Visfatin demonstrates mostly pro-inflammatory activity by inducing cyto-kines such as TNF-α and IL-6 [171]. Visfatin directly interacts not only with Ir but also with the insulin-like growth factor receptor, and can afterwards promote cancer cell proliferation [172]. Some authors reported higher visfatin levels in NAFLD compared to controls [173]. Elevated levels of visfatin were observed in gastric and colorectal cancers [168,174,175]. In gastric cancer visfatin levels can reflect the stage of progression. Moreover, elevated preoperative plasma visfatin levels were a poor prognostic factor of 5-year mortality and overall survival in gastric cancer patients [176]. The results of a case-control study by Nakajima et al. carried out on 115 colorectal cancers patients (69 males and 46 females, aged 63.7 years, BMI 22.9 kg/m 2 ) with mainly recognized well-differentiated adenocarcinoma showed that visfatin may be a good biomarker of cancer malignancy independently of BMI and stage of progression [177]. Visfatin induces stromal SDF-1 expression in colorectal cancer, which is mediated through β1 integrin activation, the ERK and p38 MAPK intracellular signaling cascades, and transcription factors such as NF-κB and activator protein-1 (AP-1) [178].
Chemerin is an adipokine whose expression has been found in different tissues, including the liver, pancreas, lung and adipose tissue. It has been shown to be associated with BMI, plasma triglycerides, blood pressure and IR [179][180][181]. Some studies have demonstrated both a pro-and anti-inflammatory chimeric nature of chemerin [182]. Kukla et al. reported that levels of chemerin were higher in NAFLD patients than in healthy individuals. In their study they compared 41 Polish patients (26 males and 15 females) with biopsy-proven NAFLD with up-regulated ALT activity, aged 45.7 years, with BMI 30.4 kg/m 2 [179]. The levels of chemerin are generally higher in obesity and IR conditions and decrease after weight loss [183]. Chemerin exerts an insulin-sensitizing effect on β cells and adipocytes [184,185]. It also has been shown to be involved in the development of inflammation. An elevated serum level of chemerin is positively associated with increased expression of visceral adipose tissue macrophage and proinflammatory cytokines such as TNF-α [183,186]. Some data indicated higher chemerin levels to be associated with the occurrence of esophageal, gastric and colorectal cancers [187][188][189][190]. A study of 36 gastric cancer patients (19 males and 17 females, aged 47-83 years) by Wang et al. showed elevated levels of chemerin in gastric cancer patients compared to controls. Chemerin levels were related to advanced clinical stages and non-intestinal type of gastric cancer [189]. Jian et al. demonstrated in a group of 196 gastric cancer patients (112 males, 84 females, BMI 23.0 kg/m 2 ) with mainly histological recognition of adenocarcinoma that preoperative increased levels of chemerin are independently associated with poor prognosis of 5-year mortality, adverse events and short overall survival [188]. Chemerin increases phosphorylation of ERK1/2 and p38 MAPKs and enhances the invasiveness of gastric cancer cells by upregulation of VEGF, matrix metalloproteinase 7 (MMP-7) and IL-6 [189]. These factors are well-recognized negative predictors of gastric cancer outcome [191][192][193].

Association between NAFLD and gastrointestinal cancer Esophageal and gastric cancer
Esophageal cancer is the sixth leading cause of cancer death worldwide [194]. High BMI, which is the main risk factor of NAFLD development, is also listed among all proven risk factors of esophageal adenocarcinoma [195]. NAFLD is independently associated with increased risk of erosive oesophagitis, which may be complicated by oesophageal ulcers, peptic stricture, Barrett's esophagus and oesophageal adenocarcinoma. Also general and central obesity uncomplicated with NAFLD are included among risk factors of esophageal adenocarcinoma, although they have less significance than when associated with NAFLD [196]. Some data also confirm a relationship between MS and development of Barrett's esophagus, which is considered to be a pre-cancerous condition for esophageal adenocarcinoma [197,198]. Taking into account the influence of MS and obesity on the occurrence of carcinogenic risk factors, it seems that there should be a link between NAFLD and the development of gastric cancer. However, only one retrospective study has confirmed such a relationship. The study included 1840 Turkish patients who underwent esophagogastroscopy, 14 of whom (9 males/5 females, aged 56-85 years) were diagnosed with distal gastric cancer. NAFLD was found in 35.7% of cancer patients. The incidence of NAFLD was higher in gastric cancer patients compared to the average incidence in the Turkish population [199].

Pancreatic cancer
Pancreatic cancer is one of the most common causes of cancer mortality worldwide and is emerging as a growing health problem due to the distinctly poor prognosis [200,201]. Some data have shown an association between pancreatic cancer and obesity. There is evidence that being overweight especially in early adulthood is strongly connected with an increased risk of pancreatic cancer independently of T2DM prevalence. The duration of overweight and obesity is also relevant, being considerably longer among patients who developed pancreatic cancer. Likewise, a meta-analysis showed an increase of pancreatic cancer risk together with increasing waist circumference [202][203][204]. A meta-analysis published in 2011 revealed T2DM as a risk factor of pancreatic cancer regardless of gender. The same study showed that T2DM can be considered as an etiologic factor and an early manifestation of pancreatic cancer [205]. NAFLD should be considered as an independent risk factor of pancreatic cancer, but further studies are needed to clarify and confirm this suggestion.

Colorectal cancer
The risk of colorectal cancer is higher for inflammatory bowel disease and in the case of a history of colorectal cancer in first-degree relatives, increased BMI, red meat intake, cigarette smoking, low physical activity, and low vegetable and fruit consumption [206]. NAFLD is associated with higher prevalence of colorectal lesions and cancer. Hwang et al. presented evidence for an association between NAFLD and increased prevalence of colorectal adenomatous polyps. The study included 2971 participants who underwent colonoscopy, hepatic ultrasonography scanning and biochemical tests such as serum glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Adenomatous polyps were diagnosed in 556 (19.1%) subjects. The prevalence of NAFLD in the group of participants with colorectal lesions was 41.5% versus 30.2% in the control group. Multivariate analysis revealed NAFLD to be associated with increased risk of colorectal adenomas (OR 1.28; 95% CI: 1.03-1.60). Higher risk of NAFLD was significant in patients with many adenomatous polyps [207]. The next retrospective cohort study by Lee et al., which included 5517 women who underwent life insurance company health examinations, confirmed those results. Conducted ultrasonography and exclusion criteria allowed NAFLD to be diagnosed in 15.1% of studied patients. The incidence of adenomatous polyps in patients with NAFLD vs. without NAFLD was respectively 628.0 vs. 185.2/10 5 persons/year (RR 1.94; 95% CI: 1.11-3.40), while that of colorectal cancer was 233.6 vs. 27.0/10 5 persons/year (RR 3.08; 95% CI: 1.02-9.34) [208].
Stadlmayr et al. performed a cross-sectional study including 1211 participants and obtained similar results. The prevalence of colorectal lesions was 34% in the NAFLD group and 21.7% in the control group (p < 0.001). Additionally, the study confirmed incidence of colorectal lesions to be dependent on patients' sex. The analysis showed that 40% of male patients with NAFLD included in the study had colorectal lesions compared to 28.3% of those without NAFLD (p = 0.010), whereas 25.6% of female patients with NAFLD had colorectal lesions compared to 17.2% of those without NAFLD (p = 0.014). Patients with NAFLD had a higher number of tubular adenomas and colorectal carcinomas, and it was independent of gender [209]. Moreover, some data showed that patients with NAFLD had more multiple polyps [210], which were more often located in the right and transverse colon [211,212]. Interestingly, patients with NASH had a higher prevalence of adenomas and advanced neoplasms than those with NAFL [212]. Lin et al. found that patients diagnosed with NAFLD were more often complicated with colorectal cancer, which predominantly was located in the sigmoid colon [213]. The majority of the studies showed comparable results, which are collated in Table 1.
However, Touzin et al. in a retrospective cohort study, which included 233 patients, aged 54.7 ± 6.0 years, who underwent screening colonoscopies, did not confirm those results. In the ultrasound 94 (40.3%) participants were diagnosed with NAFLD. Colonic adenomas appeared in 24.4% of patients with versus 25.1% of those without NAFLD [214]. A prospective observational study conducted by Basyigit et al. including 127 patients found the prevalence of colorectal carcinoma to be significantly lower in patients with NAFLD (4.6%) compared to those without NAFLD (24.2%) (p = 0.001). Additionally, the incidence of adenomas was higher in the control group than in NAFLD patients (25.8% vs. 20.0%), but the difference was not statistically significant [215].

Conclusions
NAFLD is a growing health problem worldwide and has been described as a "global pandemic". NAFLD is related to increased risk of development of some extrahepatic cancers. Additionally, it is associated with an increased risk of all-cause and cancer-specific mortality among cancer survivors. Therefore, it is important to reveal the pathomechanism of changes leading to the development of tumors and provide novel therapeutic approaches. NAFLD is a multidisciplinary disease that affects various systems and organs and is inextricably linked to simple obesity, metabolic syndrome, IR and overt T2DM.
Many factors influence the development of carcinogenesis in the course of NAFLD: • IR plays a major role in NAFLD-related carcino genesis. Stimulation of the IGF-1 factor axis by hyper- insulinemia leads to enhancement of proliferative and anti-apoptotic pathways. • Chronic inflammation, aggravated by proinflammatory cytokines and factors, such as TNF-α, IL-6, IL-8, PAI-1 and NF-κB, which are overexpressed in obesity and NAFLD, accelerates cellular proliferation and angiogenesis, and modulates cellular signaling pathways, which are essential in carcinogenesis. • Dysbiosis, which is closely associated with obesity, T2DM and NASH, weakens the intestinal barrier. Infiltration of bacterial fragments and products, such as endotoxins, activates TLRs, contributing to exacerbation of the inflammatory process in the liver and adipose tissue, activation of fibrogenesis and up-regulation of oxidative stress and IR. • Dysregulation of adipose tissue derived hormonesadipokines -influences inflammation, fibrosis, angiogenesis, apoptosis and IR, with predominance of the pro-carcinogenic effect. All these factors are suggested to play a critical role in extrahepatic tumor development. The predominance of pro-carcinogenic risk factors in NAFLD patients results from intricate and multi-faceted mechanisms which still are not fully explained and need further research.

Disclosure
Authors report no conflict of interest.