The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment

Abstract

Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.

Keywords: cancer metabolism; cancer-associated fibroblasts; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages.

Figure 1

Metabolic relationships between cancer and non-malignant cells of the tumor microenvironment. Competition for nutrients occurs mainly between cancer and cytotoxic immune cells. In particular, cancer cells (gray) uptake high amounts of glucose to sustain elevated glycolytic rate. At the same time, glucose is required for proliferation and maintenance of inflammatory functions of cytotoxic T lymphocytes (CTL), cytotoxic activity of natural killer cells (NK), and for functioning of proinflammatory macrophages (M1). Similarly, cancer cells uptake high amounts of amino acids, which have been found as essential, among others, for CTL cytotoxic activity, as in the case of serine. Thus, competition for nutrients generally leads to immunosuppression (red lines) and reduced tumor clearance, also because the resulting impoverished extracellular milieu may induce pro-tumorigenic immune cell phenotype, as in the case of glutamine deprivation associated with regulatory T cell (Treg) development. Metabolic symbiosis most often occurs between cancer cells and the residents of the affected tissue. For example, breast cancer may uptake lactate released as waste from highly glycolytic activated cancer-associated fibroblasts (CAF), to feed tricarboxylic acid cycle (TCA) and support oxidative metabolism. On the other hand, ovarian cancer cells were shown to uptake free fatty acids (FFA) released from lipid-rich adipocytes, to generate acetyl-CoA via fatty acid (FA) oxidation. Parasite-like behavior of cancer cells has been, among others, described in pancreatic ductal adenocarcinoma which induces autophagy in pancreatic stellate cells (PSC) leading to free amino acid release. In particular, alanine is then uptaken by cancer cells to support anaplerosis and biosynthetic reactions, such as non-essential amino acid (NEAA) and lipid synthesis. Interestingly, a long-distance metabolic parasitism was reported in the context of breast cancer, where the release of mi-122 conditioned distant organs, such as lungs, to reduce their glycolytic rates and consequently, glucose uptake, leaving higher glucose concentrations available for the metastatic cell to use while nesting in the putative metastatic niche.

Figure 2

The consequences of cancer cell metabolic reprogramming on the non-malignant populations of TME. Nutrient shortage and increased amounts of cancer cell metabolic by-products modulate the phenotype of TME cell populations. Full and dashed lines indicate, respectively, stimulation and inhibition. Wavy line represents metabolite exchange between cancer-associated fibroblasts and cancer cells.

Figure 3

Targeting metabolic reprogramming in cancer. In a fast proliferating cancer cell, energy is most often produced simultaneously by both glycolysis and oxidative phosphorylation. High glucose uptake sustains increased glycolytic rates required for macromolecule biosynthesis (proteins, lipids and nucleotides), furthermore fueled by TCA cycle intermediates that can be replenished by the use of glutamine as carbon and nitrogen source. In certain cancers, the atypical accumulation of oncometabolites, such as D-2HG, may promote epigenetic remodeling. The main cellular pathway regulating metabolic reprograming is mTORC1, whose activity regulates several transcription factors to promote glycolysis and macromolecule biosynthesis. These reactions have been recognized as valid targets for cancer treatment and some of the current metabolic anti-cancer strategies are indicated in red.