Obesity, the Adipose Organ and Cancer in Humans: Association or Causation?

Abstract

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

Keywords: adipose organ; cancer; obesity.

Figure 1

The role of Adipose Organ in the relationship between Obesity and Cancer. Experimental data indicate that, in addition to genetic, environmental, diet and lifestyle factors, the adipose organ is a key player in the relationship between obesity and cancer in humans. The 17 different cancer types we considered in the present review are represented by circles of different size and colour, based on their association with obesity. Positive associations are indicated by red circles (higher degree) or purple circles (lower degree); negatives association are indicated by blue circles. The degree of association was determined using information from the Continuous Update Project (CUP) database “https://www.aicr.org/research/the-continuous-update-project” (accessed on 24 January 2023), the National Institute of Health website “https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet” (accessed on 24 January 2023) and specific literature (see the main text). Given these associations, we wonder whether weight loss interventions (through bariatric surgery, pharmacotherapy, diet and/or exercise) could revert patients to the healthy condition both for obesity and cancer diseases. However, this has not been fully demonstrated, suggesting that the effects of obesity on cancer depend on multiple exogenous and endogenous factors. Further studies will be necessary to assess whether obesity has a causal effect and obesity therapy a reversible effect on cancer development.

Figure 2

The impact of the obesity-altered adiponiche on carcinogenesis. Weight gain leads to obesity and metabolic disorders whose hallmark is adipose tissue (AT) dysfunction (adiposopathy), which may increase the risk of cancer. Main biological mechanisms of crosstalk between obesity-altered cells of the adiponiche and tumour cells are reported in grey boxes. As depicted in the figure, AT expansion and dysfunction lead to multiple effects represented by the altered secretion of adipocyte-derived lipids and cytokines—upregulation of leptin, FFAs, lipids and oestrogen; hypoxia—the upregulation of VEGF and HIF-1α; inflammation and fibrosis—increased production of pro-inflammatory cytokines, such as TNF-α (activation of (NF)-κB signalling pathway) and IL-6 (stimulation of JAK/STAT3 pathway); ROS production and mitochondrial dysfunction—the upregulation of PI3K, MAPK, PPARγ, and C/EBPβ and calcium increase; changes in immunometabolism—an increase in M1-polarised ATMs and T cells and a decrease in eosinophils and Tregs. These described mechanisms have important implications in the development of cancer, contributing to cell survival, growth and proliferation, metabolic reprogramming, angiogenesis, cell invasion and metastasis. Moreover, weight loss restores the AT phenotype to its state in normal-weight subjects, characterised by an increased oxygen supply and mitochondrial functionality, the release of anti-inflammatory cytokines, and reduced oxidative stress, inflammation and fibrosis. Considering that this reverted condition can be associated with patients’ metabolic improvement and the recovery of a healthy condition, a future aim is to assess whether weight loss can provide similar benefits across cancer patients by reverting their malignant condition. FFAs: free fatty acids; VEGF: vascular endothelial growth factor; HIF-1α: hypoxia-inducible factor 1α; TNF-α: tumour necrosis factor α; (NF)-κB: nuclear factor κB; IL-6: interleukin 6; JAK: Janus kinase; STAT3: signal transducer and activator of transcription 3; ECM: extracellular matrix; PI3K: phosphatidylinositol-3-kinase; MAPK: mitogen-activated protein kinase; PPARγ: peroxisome proliferator-activated receptor γ; C/EBPβ: CCAAT/enhancer binding protein β; ATMs: adipose tissue macrophages; Tregs: regulatory T cells.

Figure 3

Obesity-altered adiponiche and tumour development: some novel proposed mechanisms in mature adipocytes and precursor cells. The adiponiche alterations present in patients with obesity could influence tumour biology and progression in different ways. We recently showed some pathways activated in mature adipocytes and in precursor cells that could be relevant in patients with obesity and cancer. In particular, in hypertrophic adipocytes (yellow cell on the left), CK2 potentiates insulin signalling and glucose uptake through the stimulation of PI3K/AKT pathway, GLUT4 translocation and PTEN inhibition. In addition, CK2 contributes also to IL-6, INF-γ and TNF-α signal transduction cascades, potentiating JAK/STAT and IKK/(NF)-кB signalling pathways, respectively. Moreover, CK2 is involved in regulating the production of adipokines in large adipocytes, leading to the downregulation of adiponectin and the upregulation of leptin. We showed that in the peritumoral AT of patients with EAC, leptin activates different signalling pathways in stromal stem cells (pink cell on the right). In particular, the activation of JAK2/STAT3, PI3K/AKT/mTOR and Ras/Raf/MEK/ERK leads to the increased expression of factors involved in stemness (CD34, NSTM and OCT-4), the epithelial-to-mesenchymal transition (α-SMA), neo-angiogenesis (VEGF) and neo-lymphangiogenesis (VEGF-C). CK2: casein kinase 2; PI3K: phosphatidylinositol-3-kinase; AKT: protein kinase B; GLUT4: glucose transporter type 4; PTEN: phosphatase and tensin homolog; IL-6: interleukin 6; INF-γ: interferon γ; TNF-α: tumour necrosis factor α; JAK: Janus kinase; STAT: signal transducer and activator of transcription; IKK: IκB kinase; (NF)-κB: nuclear factor κB; mTOR: mammalian target of rapamycin; Ras: rat sarcoma; Raf: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; CD34: cluster of differentiation 34; NSTM: nucleostemin; OCT-4: octamer-binding transcription factor 4; EMT: epithelial-to-mesenchymal transition; α-SMA: alpha-smooth muscle actin; VEGF: vascular endothelial growth factor; VEGF-C: vascular endothelial growth factor C.