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Review
. 2020 Jul 20;54(2):183-195.
doi: 10.1016/j.devcel.2020.06.018. Epub 2020 Jul 7.

Cancer Cells Don't Live Alone: Metabolic Communication within Tumor Microenvironments

Fuming Li  1 , M Celeste Simon  2
Affiliations
Review

Cancer Cells Don't Live Alone: Metabolic Communication within Tumor Microenvironments

Fuming Li et al. Dev Cell. .

Abstract

Solid tumors reside in harsh tumor microenvironments (TMEs) together with various stromal cell types. During tumor progression and metastasis, both tumor and stromal cells undergo rapid metabolic adaptations. Tumor cells metabolically coordinate or compete with their "neighbors" to maintain biosynthetic and bioenergetic demands while escaping immunosurveillance or therapeutic interventions. Here, we provide an update on metabolic communication between tumor cells and heterogeneous stromal components in primary and metastatic TMEs and discuss emerging strategies to target metabolic communications for improved cancer treatments.

Keywords: antitumor immunity; combination therapy; immunomodulation; metabolic communication; metabolic symbiosis; metabolism; metastasis; nutrient competition; signaling molecule; stromal cells; tumor microenvironment.

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Conflict of interest statement

Declaration of Interests

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Metabolic Heterogeneity and Symbiosis among Solid Tumor Compartments.
Vascular integrity and proximity to vasculature create oxygen and nutrient gradients leading to intratumoral metabolic heterogeneity. In hypoxic regions, cancer cells increase glucose uptake and preferentially convert it to lactate; lactate is exported through MCT4, and then imported through MCT1 by cancer cells in more oxygenated regions. In addition to glucose and lactate, oxygenated cancer cells also use alternative fuels for oxidative metabolism, and potentially provide amino acids (AAs) and lipids to hypoxic cancer cells.
Figure 2
Figure 2. Tumor-Stroma Metabolic Communications in the TME.
Heterogenous stromal cell populations metabolically cooperate with cancer cells directly or indirectly in the tumor microenvironment. Ovarian cancer-associated fibroblasts (CAFs) provide cysteine (Cys) and reduced GSH to withstand oxidative stress. Ovarian CAFs also provide cancer cells with glutamine (Gln) and utilize cancer cell-derived glutamate (Glu) to regenerate Gln. Pancreatic CAFs provide cancer cells with alanine (Ala) through autophagy, with lysophosphatidylcholines (LPCs) to support phosphatidylcholine synthesis, and indirectly with collagen-derived proline (Pro) to support survival under nutrient limitation. Similarly, breast CAFs supply cancer cells with autophagy-derived dipeptides. Prostate and pancreatic CAF-derived exosomes provide nutrient cargo to cancer cells. Mesenchymal stem cells (MSCs) shuttle mitochondria and/or mitochondrial DNA into leukemia, lung and breast cancer cells, and consume cystine to provide leukemic cells with Cys. Tumor cell-derived Lactate (Lac) stimulates CD4+ T cell differentiation into regulatory T cells (Tregs), promotes tumor-associated macrophage (TAM) polarization, but inhibits natural killer (NK) cells and effector T cells (Teffs). Similarly, tumor cell-derived kynurenine (kyu) facilitates Tregs differentiation but limits function of Teffs. Murine sarcoma-derived retinoid acid (RA) promotes intratumoral monocyte differentiation toward TAMs. TAMs promote tumor growth partly by providing metabolites such as polyamines. Adipocytes provide ovarian and breast cancer cells with fatty acids (FAs), pancreatic cancer cells with Gln, and engage in an arginine (Arg) cycling pathway using citrulline (Cit) to produce nitric oxide (NO).
Figure 3
Figure 3. Nutrient Competition between Cancer Cells and Immune Cells.
Increased glucose (Glu), arginine (Arg), tryptophan (Trp), serine (Ser) and methionine (Met) uptake and catabolism by cancer cells directly limits their availability to effector T cells (Teffs). Tryptophan (Trp) catabolism by cancer cells and tumor-associated macrophages (TAMs) produces immunosuppressive kynurenine (kyu) to facilitate Tregs differentiation. Glucose (Glu) catabolism by cancer cells produces lactate (Lac) to promote macrophage polarization into TAMs.
Figure 4
Figure 4. Emerging Functions of Lactate in Regulating Signal Transduction and Gene Expression.
(1) Hypoxia-induced lactate binds to NRDG3 and prevents it from pVHL-dependent degradation; stabilized NDRG3 protein binds c-Raf to mediate activation of the Raf-ERK pathway. (2) Binding to lactate interrupts MAVS mitochondrial localization, RIG-I and MAVS interaction, subsequent MAVS aggregation, and attenuates downstream TBK1-IRF3 signaling. (3) Lactate accumulation produces lactyl-coA for histone lactylation that contributes to target gene expression in macrophages.
Figure 5
Figure 5. Organ-Specific Metabolic Communication in Metastatic TME.
Brain metastases use acetate, glutamine, branched-chain amino acids (BCAAs) and polyunsaturated fatty acids (FAs) from astrocytes to fuel growth. In addition to glucose, liver metastases produce creatine kinase, brain-type B (CKB) to phosphorylate hepatocyte-derived creatine, and then import phosphocreatine for energy metabolism. Lung metastases preferentially metabolize pyruvate to create a collagen-rich niche which potentially provides proline (Pro) for metastatic growth. Lung metastases also release miR-122-containing exosomes to limit glucose access to fibroblasts. Bone metastases release serine (Ser) and lactate (Lac) to promote osteoclast differentiation and create an osteolytic niche for tumor growth. Adipocytes within the omentum potentially provide fatty acids (FAs) to fuel metastatic growth. Bile acids (BAs) accumulation in the lymph node facilitates metastatic tumor growth by activating the YAP-fatty acid oxidization (FAO) axis.
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