Molecular pathways: trafficking of metabolic resources in the tumor microenvironment

Abstract

A model of tumor metabolism is proposed that describes how the complementary metabolic functions of the local stroma and the tumor cells contribute to cancer progression. Cancer cells alter the metabolism of cancer-associated fibroblasts to obtain lactate and amino acids, which are utilized for energy production, rapid growth, and resistance to chemotherapy drugs. Cancer cells use glutamine supplied by cancer-associated fibroblasts to replenish tricarboxylic acid cycle intermediates and as a nitrogen source for nucleotide synthesis. Moreover, adipocytes in the microenvironment attract cancer cells through the secretion of inflammatory cytokines and proteases. The cancer cells then induce metabolic changes in the adipocytes to acquire free fatty acids that are oxidized by cancer cells to generate energy for proliferation. Increasing knowledge about the metabolic symbiosis within the tumor has led to novel therapeutic strategies designed to restrict metabolic adaptation, including inhibiting lactate transporters and repurposing antidiabetic drugs (thiazolidinediones, metformin).

Figure 1

Metabolic adaptations in the tumor microenvironment and therapeutic strategies. Stromal cells form a complex metabolic hub in their interactions with cancer cells. Cancer-associated fibroblasts (CAFs) are metabolically activated by signals (in the form of cytokines or oxidative stress) from cancer cells, resulting in the release of energy rich metabolic intermediates such as lactate and amino acids. These metabolites are then taken up via specific transporters to generate ATP. Oxygen availability also dictates metabolic heterogeneity since cancer cells in hypoxic areas use anaerobic glycolysis to generate lactate which is subsequently taken up by normoxic cancer cells and used for ATP production. Cancer-associated adipocytes (CAAs) also undergo metabolic alterations induced by cancer cells including heighted activity of hormone sensitive lipases (HSL) which produces free fatty acids (FFA), that once released by CAAs, are taken up by cancer cells. Intracellular FFA are chaperoned by fatty acid binding proteins such as FABP4. FA are oxidized in mitochondria to generate ATP. This complex relationship between cancer cells and stromal cells favors cancer growth/migration/invasion and metastasis. However it also provides multiple therapeutic targets. Some of the promising strategies include targeting pyruvate dehydrogenase kinase in CAFs with dichloroacetate (DCA), inhibiting lactate transporters with AZD3965, promoting breakdown of non-essential amino acid asparagine with L-Asparaginase, preventing induction of the CAA phenotype with thiazolidinediones (TZDs), and targeting the FABP4 protein to block use of FFAs as a source of energy. The diabetes drug metformin may also be used to reduce oxidative stress in CAFs and inhibit uptake of FFA in cancer cells. HIF-1α: hypoxia inducible factor 1a, TGF-β: transforming growth factor β, PDK: pyruvate dehydrogenase kinase, SLC6A4: glutamine transporter, MCT: monocarboxylate transporter, TCA: tricarboxylic acid cycle, AMPK: AMP-activated protein kinase, OXPHOS: oxidative phosphorylation.