Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment

Abstract

Obesity is a leading contributing factor to cancer development worldwide. Epidemiological evidence suggests that diet affects cancer risk and also substantially alters therapeutic outcome. Therefore, studying the impact of diet in the development and treatment of cancer should be a clinical priority. In this Review, we set out the evidence supporting the role of lipid metabolism in shaping the tumor microenvironment (TME) and cancer cell phenotype. We will discuss how dietary lipids can impact phenotype thereby affecting disease trajectory and treatment response. Finally, we will posit potential strategies on how this knowledge can be exploited to increase treatment efficacy and patient survival. Obesity and the Tumor Microenvironment Excess caloric intake leads to obesity and is a major risk factor for diabetes, cardiovascular disease, stroke, and incidence of cancer worldwide. Indeed, high body fat is associated with an increased likelihood of developing multiple hematological malignancies, and breast, esophageal, renal, colon, pancreatic, and endometrial cancers [1]. Prospective analysis of 900 000 cancer-free adults in the US showed that men and women with the highest body mass index (BMI) had a 52% and 62% increased risk, respectively, of dying from cancer than their normal weight counterparts [2]. Increased body weight and fat tissue results in altered hormone levels, such as increased estrogen and insulin, which play major roles in cancer development and can result in systemic metabolic changes; that is, hyperglycemia (see Glossary; due to insulin resistance) or elevated levels of circulating lipids. Obesity also promotes tissue inflammation and vascular dysfunction [3]. However, there is limited understanding of the direct impact that diet has on cells within the TME. For example, it is not well known if elevated blood glucose levels promote the proliferation of cancer cells or if increased lipid availability in the TME promotes cancer cells to use these lipids as an energy source or substrates for membrane synthesis. Epidemiological evidence suggests that diet substantially alters treatment outcome in cancer patients; that is, meta-analyses show that breast cancer recurrence is 30% higher in obese women compared to their normal-weight counterparts [4]. Therefore, a better understanding of the effect of diet, in particular the carbohydrate-and fat-rich western diet, on nutrient availability within the TME and its impact on signaling pathways that determine drug sensitivity is essential for the development of novel anticancer therapies. In this Review, we discuss lipid metabolism within the context of the TME and explore how diet can impact cancer phenotype, disease trajectory, and treatment response.

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…Dietary lipids also can affect lipid metabolism and have a role in shaping the tumor micro-environment, as well as cancer progression and treatment [151,152]. High-fat diet-induced obesity and type 2 diabetes mellitus are considered as risk factors for many cancer types, including pancreatic and breast cancers [153,154].…”

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

“…Their content can be used for energy and acetyl-CoA production through fatty acid oxidation in the mitochondria. The carbon source for de novo lipogenesis in cancer cells is represented by glucose, glutamine and acetate (adapted from [ 46 ]). CEs, cholesteryl esters; FABPs, fatty acid-binding protein; GLUT1, glucose transporter 1; G6P, glucose-6-phosphate; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; NADPH, nicotinamide adenine dinucleotide phosphate—reduced form; NADP + , nicotinamide adenine dinucleotide phosphate—oxidized form; MCTs, monocarboxylate transporter; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; SLC1A5, solute carrier family 1 member 5; TCA, tricarboxylic acid cycle.…”

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

“…The sterol regulatory elementbinding proteins (SREBPs) are transcription factors that coordinate and regulate the synthesis of lipids. They act in response to upstream signaling networks and to the intracellular nutrient status, to regulate the expression of enzymes involved in cholesterol and fatty acid (FA) synthesis and uptake (5).…”