Tumor is a multifactorial disease whose occurrence and progression require metabolic reprogramming of tumor cells. Tumor cells autonomously alter their flux through various metabolic pathways to meet increased bioenergetic and biosynthetic demands and to alleviate the oxidative stress required for tumor cell proliferation and survival. With the development and application of technology, researchers have made remarkable progress in the field of tumor metabolism, not only revealing the heterogeneity and plasticity of tumors but also discovering new metabolic pathways that maintain tumor growth.
Historical Perspective: The Warburg Effect
Tumor metabolism originated from Otto Warburg's research, who was awarded the 1931 Nobel Prize in Physiology or Medicine for his discovery of the mitochondrial respiratory chain Complex IV. Warburg observed that even under aerobic conditions, cancer tissue slices produced large amounts of lactate from glucose compared to normal tissues, a phenomenon known as aerobic glycolysis or the Warburg effect. In the 1990s, it was discovered that lactate dehydrogenase A (LDHA), involved in glycolysis, is a transcriptional target of the oncogene MYC and is essential for the increased glycolysis and tumorigenicity of cancer cells, providing a molecular basis for the Warburg effect. In addition, dysregulation of pathways such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor (HIF) was also found to be necessary for cancer cell survival and growth, increasing glycolysis through upregulation of glucose transporters and glycolytic enzymes.
Recent Advances: Shifting Focus to TCA Cycle and Beyond
At the beginning of this century, much research focused on why the Warburg effect benefits tumor growth. One explanation is that by increasing glycolysis, intermediates can enter side pathways for biosynthesis, providing nucleotides, lipids, and amino acids necessary for cell proliferation. However, in the past decade, the tricarboxylic acid (TCA) cycle has regained significance as a central metabolic hub promoting tumor growth. Particularly, engineered electron transport chain (ETC) gene mutations in tumor cells maintain intact TCA cycle function while disrupting ATP generation via oxidative phosphorylation. This indicates that ATP generated from glycolysis can sustain primary tumor growth. Additionally, pyruvate carboxylase (PC), catalyzing the production of oxaloacetate from pyruvate, has been shown to be essential for both primary and metastatic tumor growth. Oxaloacetate generated can limit tumor growth by depleting aspartate and glutamine. This reveals that glycolysis and the TCA cycle can maintain tumor growth through the biosynthesis of metabolites.
One consequence of oxidative metabolism is the production of reactive oxygen species (ROS), which can promote tumorigenesis but need to be tightly controlled to levels that do not induce cell death, i.e., redox balance. Metabolites, in addition to their biosynthetic roles, can also act as signaling molecules to promote tumor growth by regulating gene expression (i.e., oncometabolites). In recent years, the field has expanded from studying central carbon pathways of glycolysis and the TCA cycle to various branching metabolic pathways necessary for tumor growth, progression, and metastasis.
Fig.1 Biology of ROS in cancer cells (Martínez-Reyes I., Chandel N. S. 2021).
The tumor microenvironment (TME) plays a critical role in tumor progression, with metabolic crosstalk between tumor cells, stromal cells, and immune cells. Immune cells, particularly T cells, undergo metabolic reprogramming upon activation, shifting from oxidative phosphorylation to glycolysis, which supports their proliferation and effector functions. Conversely, tumors can induce an immunosuppressive microenvironment by competing for nutrients and producing metabolic byproducts like adenosine, which inhibits T cell function. Understanding these dynamic interactions between tumor cells and immune cells and how they influence therapeutic responses remains an open question in the field.
In short, tumor metabolism is a complex and rapidly evolving field with profound implications for cancer biology and therapy. Advances in our understanding of the metabolic rewiring of cancer cells, the TME, and immune cells offer opportunities for targeted therapies and precision medicine. However, many questions remain unanswered, and further research is needed to uncover the intricacies of cancer metabolism and its role in cancer progression.
References
- Martínez-Reyes I.; Chandel N. S. Cancer metabolism: looking forward. Nature Reviews Cancer. 2021, 21(10):669-80.
- Dejure F. R.; Eilers M. MYC and tumor metabolism: chicken and egg. The EMBO Journal. 2017, 1;36(23):3409-20.
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