Obesity and the Impact on Cutaneous Melanoma: Friend or Foe?

Abstract

Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favorable outcomes and this has been termed the "obesity paradox". In melanoma, the connection between obesity and the increased incidence is not as strong as for other cancer types with some but not all studies showing an association. However, several recent studies have indicated that increased body mass index (BMI) improves survival outcomes in targeted and immune therapy treated melanoma patients. The mechanisms underlying how obesity leads to changes in therapeutic outcomes are not completely understood. This review discusses the current evidence implicating obesity in melanoma progression and patient response to targeted and immunotherapy, and discusses potential mechanisms underpinning these associations.

Keywords: immunotherapy; melanoma; obesity; targeted therapy.

Figure 1

Signaling pathways activated by obesity-induced factors. Circulating factors increased in obesity can activate several signaling pathways that impact on cell growth, proliferation and survival through the regulation of both transcriptional factors and cellular proteins. RTK: receptor tyrosine kinase. GPER: G-protein coupled estrogen receptor. TF: Transcription factor. cAMP: Cyclic adenosine 3′,5′-monophosphate. PKA: protein kinase A. MITF: Microphthalmia-associated transcription factor. MYC: Myc Proto-Oncogene. RAF: RAF family of serine/threonine kinases. MEK: Mitogen-activated protein kinase kinase (also known as MAP2K). ERK: extracellular-signal-regulated kinase (also known as MAPK). PI3K: Phosphoinositide-3-kinase. AKT: Protein kinase B. JAK: Janus kinase. STAT: signal transducer and activator of transcription. LXR: The liver X receptor. RXR: retinoid X receptor. APOE: apolipoprotein E.

Figure 2

Crosstalk between adipocytes and dietary fat with signalling and metabolism in melanoma cells. Dietary fat and adipocyte-derived lipids have been uncovered as a potential fuel source that can drive melanoma progression. Adipocytes directly transfer lipids to melanoma cells via the fatty acid transporter (FATP; also known as solute carrier family 27, SLC27A) family of proteins and via adipocyte-derived exosomes to promote fatty acid oxidation. Circulating lipids associated with a high-fat diet lead to increased serum levels of acetoacetate, a metabolite that selectively promotes interaction between the mutant BRAF^V600 protein and MEK1, thereby promoting oncogenic signaling and tumor growth. BRAF: BRAF serine/threonine kinase. MEK: Mitogen activated protein kinase kinase (also known as MAP2K).