Metabolic Interactions in the Tumor Microenvironment

Abstract

Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies.

Keywords: cancer-associated fibroblasts; crosstalk; hypoxia; immune; stroma.

Figure 1

Features of the tumor microenvironment that contribute to metabolic heterogeneity. Intrinsic and extrinsic variables influence the metabolic properties of a tumor. Cell intrinsic variables include the genetic, epigenetic and metabolic programs active in each cell type. Extrinsic variables include interactions among the heterogenous cellular populations, nutrient availability, waste and pH gradients, oxygen (O₂) tension, extracellular matrix (ECM) deposition, physical and oxidative pressures. CAF, cancer associated fibroblast; TAM, tumor associated macrophage.

Figure 2

The multifaceted roles of lactate in tumor metabolism. (A) Cross-feeding and crosstalk mechanisms. Glucose-derived lactate has been reported to (i) originate in hypoxic cancer cells and feed cancer cells within the same tumor that are in proximity to the vasculature; (ii) originate in cancer associated fibroblasts (CAF) and feed cancer cells; (iii) originate in cancer cells and feed mesenchymal stem cells (MSC) and CAFs; (iv) polarize macrophages toward an alternative polarized M2 / tumor associated macrophage (TAM) fate; and (v) inhibit anti-tumor T cells. Lactate is released through the MCT4 transporter and taken-in by the MCT1 transporter. (B) Intracellular metabolic and signaling functions. Metabolism of intracellular lactate regulates nitrogen and redox balance, bioenergetics, and biosynthesis. In addition, lactate can participate is signaling via direct binding to N-myc downstream-regulated gene 3 (NDRG3) and activation of a hypoxia inducible factor 1α (HIF1α)-dependent angiogenic program. aKG, alpha-ketoglutarate; Glu, glutamate; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, nicotinamide adenine dinucleotide reduced.

Figure 3

Heterocellular nutrient competition in the tumor microenvironment. Glucose avid cancer cells impair anti-tumor T effector (Teff) cell effector function by limiting glucose availability. Tryptophan (Trp) avidity and metabolism by cancer cells and tumor associated macrophages (TAM) reduces tryptophan availability in the tumor microenvironment. This directly impairs anti-tumor Teff cells, and indirectly supports pro-tumor regulatory T cells (Treg) via release of the tryptophan metabolite kynurenine (Kyn). Similarly, arginine avidity and metabolism in TAMs depletes arginine in the tumor microenvironment and impairs anti-tumor T cell activity.

Figure 4

Heterocellular nutrient symbiosis in the tumor microenvironment. Tumor-associated stromal cell populations engage in cooperative metabolic processes with cancer cells in the tumor microenvironment. Ovarian cancer associated fibroblasts (CAF) have been reported to provide cysteine (Cys) and reduced glutathione (GSH) to combat oxidative stress, a process blocked by T effector (Teff) cells. Ovarian CAFs also provide the cancer cells with glutamine (Gln) and utilize cancer cell-derived lactate (Lac) and glutamate (Glu) to regenerate Gln. In pancreatic cancer, CAFs provide the cancer cells with alanine (Ala) in an autophagy dependent manner. Similarly, breast CAFs provide the cancer cells with autophagy-derived dipeptides. CAF-derived exosomes are another means of nutrient transfer and provide nutrient cargo to prostate and pancreatic cancer cells. Cells of the adipocyte lineage have been reported to provide pancreatic cancer cells with Gln, ovarian and breast cancer cells with fatty acids, and to engage in an arginine (Arg) cycling pathway by way of citrulline (Cit) to activate nitric oxide (NO) production and subsequently glycolysis in the cancer cells. Mesenchymal stem cells have been reported to shuttle mitochondria and/or mitochondrial DNA in leukemia, lung and breast cancer, and to consume the cysteine (Cys) dimer cystine and provide leukemic cells with chemoprotective Cys.