Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer

Abstract

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.

Keywords: cancer-associated fibroblasts; glucose; hypoxia; interstitium; lactate; macrophages; metabolism.

Figure 1

Resume of some of the metabolic changes taking place in tumor cells. During tumor development, a series of metabolic changes that favor its growth occurs. Globally, proliferating tumor cells have a great appetite for glucose and amino acids, causing a relative deficit of both in the tumor interstitium. In addition, pyruvate enters the tricarboxylic acid cycle with difficulty and is mainly transformed into lactate (Warburg effect). However, having an ATP production more based on glycolysis or OXPHOS depends on tumor type, grade, and even the stage of progression of the disease. In fact, both energy-gathering systems can coexist in tumor cells, and even cancer cells can move from one energy-gathering system to another. Created using BioRender.

Figure 2

Resume of the metabolic changes taking place in tumor cells and interstitial cell subpopulations. Lactate is released into the interstitium, contributing to its acidification. The acidity and hypoxia of the interstitium and the relative deficit of glucose and amino acids induce functional changes in the various cell subpopulations of the interstitium, including myofibroblasts, endothelial cells, T lymphocytes, and macrophages, among others. All these changes mainly promote tumor growth. Upward pointing arrows indicate increased levels or activity of that molecule or pathway. The downward pointing arrows indicate the opposite. Created using BioRender.

Figure 3

Schematic representation of the coupling model or reverse Warburg effect. The coupling model proposes the integration of the various metabolic changes observed in cancer in a more functional manner. This model is based on the premise that most human tumors, such as those of the breast, stomach, and pancreas, are comprised of stroma. The Warburg effect preferentially occurs in the predominant stromal cell type, i.e., the CAFs, where it manifests as an increase in aerobic glycolysis and a hypofunctional tricarboxylic acid (TCA) cycle. This leads to a significant release of lactate and ketone bodies into the interstitium and their capture by tumor cells. Once inside the cells, these molecules feed and enhance TCA activity. Likewise, the activation of autophagy in CAFs releases a large quantity of amino acids into the interstitium, which is captured by the cells of the tumoral parenchyma for use in the anabolic synthesis of protein. Catabolic reactions, therefore, predominate in the stromal CAFs, favoring the preponderance of anabolism in the tumor cells. This is known as the reverse Warburg effect or the coupling model. Upward pointing arrows indicate increased levels or activity of that molecule or pathway. The downward pointing arrows indicate the opposite. Created using BioRender.