CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages

Abstract

Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.

Keywords: CD36; macrophage; metabolism; metastasis; tumour microenvironment.

Figure 1

Schematic presentation of the CD36 structure. CD36 harbours two transmembrane domains in a large extracellular region containing ligand-binding sites. CD36 has two cytoplasmic tails (N-terminal and C-terminal) that contains four palmitoylation sites. The C-terminus contains two ubiquitination sites. The large extracellular loop contains 10 N-linked glycosylation sites and two phosphorylation sites. CD36 also contains three disulphide bonds between extracellular cysteines. In addition, the hydrophobic pocket is involved in ligand binding and serves as a tunnel through which hydrophobic ligands are transported from the extracellular space across the phospholipid membrane bilayer. Arrowhead and numbers denote the approximate position of amino acid residues.

Figure 2

The bidirectional interaction between cancer cells and macrophages regulated by CD36 receptor in promoting metastasis. Due to hypoxic conditions, cancer cells in tumour microenvironment (TME) increase the uptake of exogenous fatty acids for survival, energy source and rapid proliferation. Depending on the type of cancer, literatures have mentioned CD36 promotes metastasis, invasion and angiogenesis by activating the downstream GSK-3β/β-catenin, O-GlcNAcylation, AKR1C2, ERK1/2 and MMP28 signalling pathways. However, the recruitment of macrophage to TME and become tumour-associated macrophages (TAMs) is significant for cancer progression. TAM tends to have a higher level of FA uptake and accumulation via CD36, which accordingly enhance the fatty acid oxidation (FAO) of TAMs to generate more energy. This phenomenon also upregulates the lipid biosynthesis to produce more nitric oxide (NO) and reactive oxygen species (ROS) and secrete high level of immunosuppressive cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α) and more. The dynamic interaction between cancer cells and TAMs constantly favouring the tumour evasion and ultimately metastasis. NADPH, nicotinamide adenine dinucleotide phosphate; TAG, triacylglycerol; VEGF, vascular endothelial growth factor; MMPs, matrix metalloproteinase; PPARγ, peroxisome proliferator- activated receptor gamma; FABP4, fatty acid-binding protein; STAT3, signal transducer and activator of transcription 3; mTORC2, mammalian target of rapamycin complex 2.