Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

Abstract

Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.

Keywords: Chymotrypsin; DCC; Dependence receptors; Kynurenine; Obesity; Serine proteases; Subtilisin.

Fig. 1

A schematic illustrating some of the factors proposed to affect obesity and carcinogenesis. Obesity is associated with hormonal and inflammatory changes summarised under “Mechanism” and including insulin resistance. These factors often act via specific “Receptors” which regulate key “Pathways” responsible for the control of cell viability, proliferation, migration and death. The kynurenine pathway is activated by inflammation and acts via the Aryl Hydrocarbon Receptor (AHR) to modulate transcription factors and microRNAs relevant to BMI regulation as well as regulating feedback on inflammation. Kynurenines can affect feeding directly via glutamate receptors (NMDAr) in the brain and possibly via the G-protein coupled receptor GPR35. Fatty acid metabolism can affect inflammatory cytokine production and T cell balance in the immune system.

Fig. 2

The kynurenine pathway is initiated by the oxidation of tryptophan via the enzymes IDO and TDO, with downstream catabolites having toxic, antioxidant and cell-protective activity. Several feedback circuits involving the kynurenines, regulation of the Aryl Hydrocarbon Receptor (AHR), T cell production and balance and activity of the cell survival modulator GCN2 place the pathway in a central position to integrate many aspects of metabolic and feeding control. Quinolinic acid as an agonist and kynurenic acid as an antagonist at NMDA receptors contribute to the activity of feeding regulatory systems in the hypothalamus. Effects on β-catenin activation and translocation as well as key enzymes in the determination of cell viability, such as MAPK and ERK1/2 account for the effects of kynurenines on carcinogenesis.

Fig. 3

A. The transmembrane Dependence Receptors Deleted in Colorectal Cancer (DCC), neogenin and unc5 are receptors for the group of netrin ligands. The balance between intrinsic activity of these receptors which induces apoptosis, and the inhibitory effect of netrin binding which also directly promotes cell proliferation, maintains cells in a state of optimum viability. Serine proteases such as chymotrypsin in the digestive tract and systemic circulation, or exogenous chymotryptic enzymes such as subtilisin deplete cells of their Dependence Receptors, allowing netrin to drive proliferation unopposed, potentially leading to carcinogenesis.