Cellular metabolism plays a critical role in cancer development.
Disruptions in normal metabolic processes can lead to the onset of various cancers, as cancerous cells often reprogram their metabolism to fuel uncontrolled growth and survival. These altered metabolic pathways not only support the cancerous state but can also drive its progression.
The good news is that these very metabolic changes present an opportunity—by targeting the unique metabolic features of cancer cells, researchers are exploring new therapeutic strategies to treat cancer more effectively.
Cancer Risk and Metabolism
While the uncontrolled proliferation of cells is a well-established hallmark of cancer, growing research now highlights the significant role of metabolic dysfunction in cancer development. Emerging studies have shown that metabolic disorders and abnormalities can not only support tumor growth but also actively contribute to the onset of various types of cancer.
The Warburg Effect and Cancer Cell Metabolism
Otto Warburg was the first to demonstrate that the metabolism of tumor cells differs significantly from that of normal cells. His pioneering research revealed a fundamental difference in how cancerous and healthy cells generate energy. In normal cells, pyruvate—produced during glycolysis—is primarily oxidized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. However, in tumor cells, most pyruvate is instead converted into lactic acid, even in the presence of oxygen. This phenomenon is known as aerobic glycolysis, or the Warburg effect.
Cancer cells bypass the usual regulatory mechanisms that control glycolysis in several ways. For example, phosphofructokinase (PFK)—a key glycolytic enzyme—becomes less sensitive to inhibition by ATP in cancerous cells. As a result, high intracellular ATP levels no longer suppress glucose breakdown, allowing glycolysis to continue unchecked. Additionally, cancer cells may increase levels of fructose-2,6-bisphosphate, which further enhances glycolysis by activating PFK.
Beyond glycolysis, cancerous cells undergo a variety of metabolic changes, including:
Increased citrate production
Elevated intra- and extracellular lactate levels
Enhanced uptake and metabolism of glucose and glutamine
These metabolic alterations are not merely a byproduct of cancer but actively contribute to tumor growth and survival. For instance, elevated glucose consumption and lactate production are hallmarks of aggressive tumor behavior. This is particularly evident in individuals with type 2 diabetes, where high blood glucose levels are associated with an increased risk of developing cancers such as pancreatic, liver, colorectal, gastrointestinal tract, and breast cancer.
Targeting Tumor Metabolism: A Promising Avenue for Breast Cancer Detection and Therapy
Recent advances in quantitative tandem mass spectrometry (MS/MS) have enabled researchers to analyze blood and tissue samples from breast cancer patients with unprecedented precision. Through this technique, a distinct metabolic phenotype has been identified that correlates with increased breast cancer risk. These metabolic signatures align with known congenital metabolic disorders observed in certain breast cancer subtypes. Remarkably, this method allows for the identification of breast cancer type with up to 95% accuracy, positioning quantitative MS/MS as a powerful tool for early detection and personalized diagnostics.
The Role of Glycolysis in Tumor Progression
Experimental studies using xenograft models have shown that suppressing the expression of key glucose metabolism regulators—such as GLUT2, lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase (PDK)—can significantly reduce tumorigenicity. Conversely, knocking down the β-catalytic subunit of mitochondrial H⁺-ATP synthase accelerates glycolysis, resulting in a more aggressive, tumor-promoting phenotype. These findings underscore the central role of the glycolytic pathway—commonly referred to as the Warburg effect—in tumor development.
Metabolism as a Therapeutic Target in Cancer
Traditional oncogene-targeted therapies, while effective initially, often fail to prevent recurrence due to cancer’s adaptive nature. In contrast, metabolic reprogramming is a hallmark shared across many tumor types, making metabolism-based therapies a potentially more universal and durable strategy. Importantly, resistance to metabolic therapies is less common than resistance to gene-targeted treatments.
Several therapeutic approaches aimed at reducing glycolytic flux in tumor cells are currently under investigation:
Low-carbohydrate diets to reduce extracellular glucose availability
Lonidamine, which inhibits the conversion of glucose to hexose
PKM2 activators/inhibitors, which help regulate intracellular pyruvate levels
Additionally, targeting glutaminolysis, another key metabolic pathway in cancer cells, offers further therapeutic promise. This can be done by:
Inhibiting glutamine transporters (e.g., SLC1A5) through retinoblastoma protein regulation
Suppressing glutaminase (GLS) activity, which converts glutamine to glutamate
Targeting regulatory pathways such as c-Myc, NF-κB, and MAPK/ERK, all of which influence GLS expression and activity
By impeding glycolysis and shifting pyruvate metabolism toward oxidative phosphorylation, tumor growth can be slowed and lactate accumulation reduced—a strategy validated across multiple preclinical studies.
Challenges and Considerations
Despite their potential, metabolic-based cancer therapies are not without limitations. One of the primary concerns is non-specific toxicity, as healthy cells—especially immune and neuronal cells—also depend heavily on glucose metabolism. This can lead to weakened immune responses and neuropathic side effects, highlighting the need for targeted delivery methods or combination strategies that minimize harm to healthy tissues.
Conclusion:
The growing understanding of tumor metabolism not only enhances diagnostic accuracy through tools like MS/MS but also opens up new therapeutic possibilities. By precisely targeting the altered metabolic pathways in cancer cells, we may be able to develop more effective, less resistant-prone treatment options, paving the way for a new era in oncology.