Genomic, transcriptomic, and proteomic data from several thousand patients and corresponding healthy controls are now publicly available on the internet, for many different pathologies, including different types of cancers. This allows researchers to investigate specific questions and medical hypotheses in silico, directly in the human context, without certain ethical concerns. We previously investigated expression data from several thousand patients, and identified novel potential markers useful for improving the diagnosis of melanoma and other solid cancers [1,2], as well as novel therapeutic approaches that were then validated in vitro by classical bench science [3,4]. In this study we aimed to determine the molecular mechanisms underlying the unexpected protective role of high fat intake in melanoma, given that obesity is a known risk factor in other cancers. The role fat plays in health maintenance as well as disease initiation and progression is being extensively investigated. There is particular interest in the protective role diet may have on cancer, since different cancer types are associated with being overweight or obese; furthermore, increased cancer mortality has been linked to dyslipidemia [5]. In patients with cancer, metabolic alterations impacting carbohydrate and lipid metabolism can activate phosphoinositide 3-kinase (PI3K) pathway–dependent oncogenic signaling, leading to an inflammatory state with increased expression of specific cytokines [6]. Omega-3 polyunsaturated fatty acids (PUFAs) have a beneficial effect by counteracting inflammation in cancer cells, which PUFAs easily diffuse into via the plasma membrane, by stimulating the production of anti-inflammatory metabolites [7]. PUFAs reduce plasma lipid levels and lipoproteins by modulating hepatic lipoprotein secretion [8] and likely by also mitigating dyslipidemia effects. How obesity and diet might impact melanoma onset and therapeutic efficacy has been discussed [9]. Although obesity and abnormal lipid levels in the blood represent established risk factors in other malignancies, they do not seem to impact cutaneous melanoma [10]. In fact, they are only slightly associated with an increased risk of cutaneous melanoma in men [11], although insulin resistance and dyslipidemia seem to promote the growth of uveal melanoma. Interestingly, obesity has been associated with a better prognosis and improved survival in patients undergoing treatment for metastatic melanoma. A higher BMI appears to be a protective factor in melanoma and this phenomenon has been named the obesity paradox [12]. In several other cancers, including colorectal cancer, being overweight and having a higher BMI are known risk factors, rather than protective conditions [13]. Fat metabolism might be differently controlled in different cancer cell types, thereby explaining why dyslipidemia may play divergent roles in different cancers. Scavenger receptors including macrophage receptor with collagenous structure (MARCO) and CD36 recognize and internalize lipoproteins, making them susceptible to degradation [14,15]. Furthermore, fatty acid–binding proteins (FABPs) play an important role in cancer progression and the intracellular transportation of long-chain fatty acids [16]. These molecules exert a pivotal role in regulating lipid metabolism.

The aim of this study was to investigate the expression of genes related to lipid-handling to analyze the molecular basis of the obesity paradox observed in melanoma.

In this study we investigated the expression of different genes involved in lipid metabolism and found a significant difference in melanoma versus controls. This may explain part of the mechanism behind the obesity paradox observed in patients undergoing treatment for metastatic melanoma. The mechanisms underlying the association between dyslipidemia and melanoma remain controversial; this is due to the different metabolic controls within bulk melanoma cells and cancer stem cells or metastasis-initiating cells [21,22]. Metastasis-initiating cells display high CD36 levels, which may indicate a crucial contribution of dietary lipids in the promotion of metastasis [23]. Furthermore, as we previously demonstrated, melanoma cancer stem cells show higher intracellular neutral lipids, higher lipogenesis activation, and lower autophagic flux [24]. This evidence indicates a complex molecular apparatus that allows melanoma cells to finely regulate fatty acid storage and mobilization depending on the metabolic environment and their differentiation level.

FABP4 and FABP2 have recently been reported to have a significant association with cancer progression in patients with colorectal cancer [16] and several studies demonstrate that obesity and high fat intake are risk factors in colorectal cancer [13,25-28]. On the other hand, several studies highlight the obesity paradox in melanoma, reporting significantly lower mortality in overweight patients undergoing treatment for melanoma [29], although a recent publication indicated that some caution is warranted [30]. Patients with melanoma or colorectal cancer appear to respond in opposite ways to high dietary fat intake or fat metabolism and may therefore be useful models to investigate how lipid-related gene expression may differentially regulate cancer initiation. For this reason, this study investigated lipid-related gene expression in patients with melanoma or colorectal cancer. Many genes have been identified as lipid modulators, although this field still remains poorly investigated. Genes controlling dyslipidemia in mice were recently reported [31], as well as other molecules that interfere with lipid storage [32,33], while a complete list of lipid-related genes in humans is currently lacking. In this work we investigated the expression of 8 genes (FABPs and other lipid-related genes) in melanoma and colorectal cancer biopsies, hypothesizing that differences in melanoma and colorectal cancer gene expression may partly explain the different role dietary fat plays in melanoma (ie, protective) and colorectal cancer (ie, detrimental). A significant reduction of the genes for scavenger receptors CD36 and MARCO (which are able to bind lipoproteins) and FABP4 and FABP7 translocases (which are able to bind and cell-internalize fatty acids) was found in melanoma biopsies compared to healthy controls, according to 2 independent databases, IST Online and GEO. We hypothesize that this reduced expression may lead to a reduced uptake of lipids and reduced cellular internalization. CD36 and FABP4 were also validated in a third database, Oncomine, using the DNA-TCGA data set. These genes showed no difference in control expression data compared to data from patients with colorectal cancer, for whom high fat dietary intake represents a negative prognostic factor. Therefore, we believe that the reduced gene expression observed in melanoma (571 patients and 484 controls, in 3 independent databases) might contribute to counteracting the detrimental effects of high fat intake.

More extensive analyses are ongoing in other cancers and on a larger list of relevant lipid-related genes; nevertheless, the results from this study may reveal some of the molecular mechanisms responsible for the obesity paradox observed in melanoma.