Abstract
Simple SummaryTumors exhibit metabolic changes that differentiate them from the normal tissues from which they derive. These metabolic changes favor tumor growth, are primarily induced by cancer cells, and produce metabolic and functional changes in the surrounding stromal cells. There is a close functional connection between the metabolic changes in tumor cells and those that appear in the surrounding stroma. A better understanding of intratumoral metabolic interactions may help identify new vulnerabilities that will facilitate new, more individualized treatment strategies against cancer. We review the metabolic changes described in tumor and stromal cells and their functional changes and then consider, in depth, the metabolic interactions between the cells of the two compartments. Although these changes are generic, we illustrate them mainly with reference to examples in breast cancer.Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer.
Highlights
The most critical activator of cancer-associated fibroblasts (CAFs) is the oxidative stress produced by reactive oxygen species (ROS) derived from the relative hypoxia of the tissue, arising from its hypovascularization and from the decrease in glutathione synthesis derived from the deficit of its amino acid components
As the coupling model suggests, in breast cancer, the metabolic reprogramming in CAFs with low caveolin levels is associated with increased catabolism and the production of lactate, glucose, and ketones that are released into the interstitium, where they serve as nutrients for breast cancer tumor cells
Cancer cells induce metabolic and functional changes in the surrounding stroma cells that favor tumor growth and are associated with tumor progression and prognosis. Stromal cell subpopulations such as CAFs, tumor-associated macrophage (TAM), or tumor-infiltrating lymphocytes (TILs) are associated with prognosis in breast cancer and other tumors
Summary
Amino acids are the second carbon source for proliferating tumor cells, providing energy and making up most of the biomass of proliferating tumor cells [35]. Serine is necessary for synthesizing nucleotides and cysteine, like glutamine, to synthesize glutathione [44] For this reason, tumor cells have developed different strategies to ensure the supply of amino acids by, for example, overexpressing different transporters or by the uptake of amino acids by micropinocytosis of extracellular proteins [8,45]. Increased synthesis of fatty acids is achieved by augmented FAS expression by the FASN gene, which is notably overexpressed in breast cancer. Some stop proliferating due to the relative lack of nutrients and enter G0 This is the case for quiescent cancer stem cells, which, in G0, are relatively insensitive to glucose deprivation [87], and preferentially use lactate as an energy source, favoring their long-term survival [88,89,90,91]. Lactate functions as a signaling metabolite, favoring angiogenesis in breast cancer [97]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
