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Adiponectin and JNK: metabolic/inflammatory pathways affecting gastrointestinal carcinogenesis
  1. Herbert Tilg,
  2. Arthur Kaser
  1. Christian Doppler Research Laboratory for Gut Inflammation, Medical University Innsbruck, Austria
  1. Correspondence to Dr Herbert Tilg, Christian Doppler Research Laboratory for Gut Inflammation and Clinical Division of Gastroenterology and Hepatology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; Herbert.Tilg{at}i-med.ac.at

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The incidence of obesity and associated disorders has dramatically increased worldwide. Obese individuals exhibit an increased risk of developing diseases such as atherosclerosis, diabetes, non-alcoholic fatty liver disease and cancer. Breast, prostate or colorectal cancer (CRC) are leading cancers in the Western world. Epidemiological studies indicate that obesity represents a significant risk factor for the development of these cancers, although the exact mechanisms have not yet been identified. Research in the past years has characterised important pathways that link metabolism with the immune system and vice versa.1 Although, currently, there is still limited evidence, inflammatory/immune mediators released by many cell types including adipocytes could be attractive candidates for linking obesity with cancer. Two reports in this issue of Gut (see pages 1583 and 1637) provide further evidence that molecules regulating metabolic/inflammatory pathways might be involved in gastrointestinal carcinogenesis.2 3

Adipocytokines: key immune mediators derived mainly from adipocytes

Obesity is associated with a chronic inflammatory state characterised by abnormal cytokine and acute-phase protein production, and increased activity of inflammatory signalling pathways. Many of the interactions between metabolic and immune pathways are mediated by a complex network of soluble mediators derived from immune cells and adipocytes, ie, adipocytokines. Adiponectin and leptin are the most abundant adipocytokines produced by adipocytes.

Adiponectin is a pleiotropic molecule with immunomodulatory, anti-inflammatory, cardio-protective, insulin-sensitising and anti-angiogenic effects.4 Recently, it has been shown that patients with various cancers, including gastric, colorectal, endometrial, prostate and breast cancer, have low levels of circulating adiponectin.5 6 7 Decreased adiponectin serum concentrations are correlated with the development of colorectal adenomas/CRC. Moreover, certain genetic variants in the adiponectin gene have been associated with CRC development.8 9 Adiponectin has been demonstrated to inhibit CRC cell growth through activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of mammalian-target-of-rapamycin pathways.10 Fujisawa and colleagues recently demonstrated that adiponectin is able to suppress colorectal carcinogenesis.11 They found a significant increase in proliferation of the colonic epithelium in adiponectin-deficient mice fed a high-fat diet. Adiponectin might also be of relevance in oesophageal and hepatic cancer. Activation of adiponectin receptor type 1 by globular adiponectin is able to inhibit leptin-stimulated cell proliferation of oesophageal carcinoma cells.12 Furthermore, adiponectin inhibits apoptosis of a Barrett adenocarcinoma cell line.13 Hepatic tumour formation is accelerated in an adiponectin-knockout mouse model of non-alcoholic steatohepatitis.14 Although the mechanistic implications of adiponectin signalling in these specific tumour models remain to be identified, adipocytokines could indeed constitute a link between obesity and several gastrointestinal cancers.

Adiponectin isoforms: how important?

Adiponectin circulates in various isoforms and some biological effects are isoform-dependent. Whereas high-molecular weight (HMW) adiponectin has more pro-inflammatory functions,15 the low-molecular weight (LMW) isoform has more anti-inflammatory properties by suppressing pro-inflammatory cytokines/chemokines and inducing anti-inflammatory cytokines such as interleukin 10 (IL10).16 In this issue of Gut, Rubenstein et al (see page 1583) present a clinical study demonstrating that high levels of LMW adiponectin are associated with a decreased risk of Barrett’s oesophagus among patients with gastro-oesophageal reflux disease (GORD). This simple correlative study, however, cannot offer a clear pathophysiological concept why LMW adiponectin might be protective. Information on the degree of tissue inflammation is not given, as the anti-inflammatory mode of action of LMW adiponectin might be well linked to the development of Barrett’s oesophagus after repeated episodes of an inflammatory attack. Still, this study is another small piece of evidence that adipocytokines and their biological effects might be linked to malignancy.

JNK, diet and colorectal carcinogenesis: another “metabolic” player in gastrointestinal cancer?

c-Jun N-terminal kinases (JNKs) were initially characterised by their activation in response to cell stress such as ultra-violet (UV) irradiation. JNKs have since been characterised to be involved in proliferation, apoptosis, motility, metabolism and DNA repair. Dysregulated JNK signalling is now believed to contribute to many diseases involving neurodegeneration, chronic inflammation, metabolic syndrome, cancer and ischaemia–reperfusion injury.17 Activation of JNK/c-Jun has been observed in many different tumours including CRC, and over-expression and activation of JNK may play an important role in progression of this cancer18 Therefore, Endo and colleagues (see page 1637) addressed the important question whether this pathway might be involved in early colorectal carcinogenesis initiated by a metabolic challenge, ie, high fat diet, and compared this to a regular diet. Tumours were initiated by repeated administration of azoxymethane. The metabolic challenge with a high-fat diet resulted in the occurrence of aberrant crypt foci and enhanced cell proliferation in the colonic epithelium. This phenomenon was paralleled by increased epithelial JNK activity, and specific JNK inhibitors could suppress enhanced cellular proliferation under high fat diet. In contrast, inhibition of JNK did not affect proliferation in mice fed a regular diet. The important message of this study is the fact that high-fat diet is able to activate this critical and multivalent JNK pathway and this might be accompanied by an “insulin resistant” epithelial cell.

What are the implications of these findings? In case of genetic susceptibility, a high-fat diet might be able to affect expression of molecules which link metabolism, inflammation and cancer. Increased JNK expression might not necessarily reflect tissue inflammation although inflammation was not studied/observed in this model. A certain diet therefore might have “tumour-promoting” potential which might be of importance for humans as the prevalence of obesity is correlated with the increased incidence of CRC. There might also be a link between JNK and the other discussed molecule ie, adiponectin, as one of the early papers has demonstrated that adiponectin might be able to suppress JNK activity. Although speculative, it might be hypothesised that decreased adiponectin levels as observed in obesity might fail to control JNK expression in various tissues including the epithelial cell throughout the gut and vice versa.19 20

Great effort has been made towards understanding the molecules linking obesity, inflammation and cancer. It is now evident that there are prototypic adipocytokines/pathways, such as adiponectin, which are synthesised mainly in fat tissue, circulate at high concentrations, and function in a hormone-like manner. There is no doubt that studies as presented in this issue of Gut will help to further clarify underlying mechanisms in obesity-associated gastrointestinal cancers. Finally, these studies might also unravel pathways which are involved in food-related carcinogenesis, an aspect which has so far been vastly neglected by the scientific community.

REFERENCES

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Footnotes

  • Funding Supported by the Christian Doppler Research Society.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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