Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches

Abstract

Now recognized as a global health crisis, obesity has been linked to an increased risk of many types of cancer, including those of the breast, colon, rectum, uterus, gallbladder, and ovary. Obesity and cancer share several characteristics at the cellular, molecular, and epigenetic levels. Obesity is characterized by chronic inflammation of the adipose tissue (AT), resulting in genotoxic stress that further induces metabolic complications and contributes to the initiation and progression of cancer. The excessive accumulation of AT provides adipokines and lipids to engage tumor cells with stromal and immune cells to infiltrate carcinomas and secrete a plethora of cytokines, chemokines, and growth factors within the tumor microenvironment (TME) that contribute to carcinogenesis. Obesity also alters the metabolic reprogramming of immune cells, including macrophages, neutrophils, and T cells, thereby providing a suitable environment for the growth and progression of cancer. Obesity-associated metabolic dysregulation also perturbs the gut microbiome, which produces metabolites that can further increase the risk of cancer progression. This review will discuss links between obesity and cancer progression, including several crucial pathways that bridge the crosstalk between obesity-associated changes in AT inflammation, immune cells, adipokines, chemokines, and tumor cells to support cancer progression. We will also discuss our insights into the mechanisms by which obesity-driven factors influence metabolic reprogramming and touch base on how obesity mediates microbiome dysbiosis to alter metabolite and affect cancer progression. Altogether, this review highlights the crossroads of the obesity-cancer axis, describes its salient features, and presents possible therapeutic approaches for obesity-related cancers.

Keywords: Adipokines; Adipose tissue; Cancer; Glucagon-like peptide-1; Metabolic reprogramming; Metabolism; Microbiome; Obesity.

Graphical abstract

Figure 1

The obese adipose tissue (AT) microenvironment interacts with tumor cells during cancer progression. During obesity, immune cells including M1 macrophages, neutrophils, dendritic cells, and T cells infiltrate the obese AT, leading to chronic low-grade inflammation. Obese AT and cancer cells communicate via the cytokine-chemokine network, angiogenic factors, and adipokines to create a pro-inflammatory, tumor-promoting microenvironment to support cancer growth. The key adipokine leptin activates the STAT3 signaling pathway. Obese AT triggers inflammatory signaling pathways such as NF-κB, leading to increased production of IL-6, and further activation of STAT3 signaling. STAT3 also triggers the Pim signaling pathways that promote cancer cell survival and proliferation. IL-6/STAT3 signaling also promotes angiogenesis by inducing expression of VEGF, which drives cellular proliferation and migration to support tumor growth and metastasis. TNF-α produced by M1 macrophages induces production of matrix metalloproteinases (MMPs), which further associate with cancer cell metastasis. NF-κB activation in the cancer cells also lead to the metastatic cascade. Tumor-associated macrophages also produce cytokines that promote angiogenesis and obese adipocytes, and cancer cells express FABP4 at their interfaces that support metastasis by promoting immune invasion.

Figure 2

Immune cell metabolism and hypoxia drive cancer progression. During obesity, adipocytes and resident immune cells in the obesogenic microenvironment become deprived of oxygen (hypoxic), as do macrophages, T-cells, and tumor cells in the tumor microenvironment, leading to hypoxia-driven metabolic reprogramming. For tumor cells, these metabolic changes contribute to tumor progression. Under hypoxic conditions in the AT, IFN-γ activates the PI3K/AKT/NF-κB signaling pathway to induce expression of hypoxia inducible factor 1α (HIF-1α), which promotes metabolic reprogramming in M1 macrophages and activated T cells. This process contributes to T-cell exhaustion and inflammation, thereby affecting immune cell function. In tumor cells, HIF-1α secreted by these immune cells activates PI3K/AKT pathways to increase HIF-1α levels and triggers expression of angiogenic genes like VEGF. HIF-1α also recruits growth factors (e.g., IGF2) to tumor cells, increasing their proliferation. HIF-1 is also associated with decreased adiponectin and elevated leptin expression.

Figure 3

Microbiome composition and diversity in mice with HFD-induced obesity. The percentage of total 16s rRNA gene reads in mice fed on low fat and high fat diet (HFD) that map to various phyla (heat map) The pie and stack bar plots reveal differences in major bacterial phyla in mice fed on low fat diet and HFD.