“Warburg-effect-related metabolic changes in cancer generate measurable biomarkers, including glucose and lactate, that can be used in cancer diagnostic strategies.”

The avid consumption of glucose with concomitant lactate production by malignant cells, even under aerobic conditions, is called the Warburg effect, or aerobic glycolysis. As most invasive tumours display the Warburg effect, this has proven of great clinical importance in detecting malignancies with 18-fluorine 2-deoxyglucose positron emission tomography (FDG-PET) scans.

Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways. In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.

In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria. This process, known as the Warburg Effect, has been studied extensively. The common feature of this altered metabolism is increased glucose uptake and fermentation of glucose to lactate.

Warburg later hypothesised that mitochondrial dysfunction caused by irreversible mitochondrial damage underlies aerobic glycolysis , and this altered glycolytic feature of cancer cells is the basis of fluorine-18 fluoro-2-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) [3]. Although the Warburg effect is not applicable to all human cancers, it is a widely accepted concept that is used to understand tumour metabolism. 18F-FDG PET/CT is a well-established imaging modality that has been widely used for staging, restaging, treatment-response assessment, and the prediction of prognosis in breast cancer .

Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. He observed that cancer cells had higher glucose uptake in comparison to non-transformed cells, and instead of using it primarily to produce ATP by mitochondrial respiration and oxidative phosphorylation (OXPHOS), they mainly metabolized glucose via pyruvate to lactate by LDH regardless of the presence of oxygen.

Lactate-producing ('lactagenic') cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. Significance of Warburg’s discovery is still apparent in the common cancer diagnostic test using ^18^F-deoxyglucose positron emission tomography (^18^F-FDG-PET).

Note that the traditional “Warburg Effect” describes tumors relying heavily on glucose uptake (via GLUTs) with subsequent lactate exportation (via MCT4s) in normoxia. Warburg et al. (2) measured arteriovenous (a–v) differences across tumor beds in rat tumor models. He showed that the vein always had more lactate and less glucose than the artery feeding the tumor, suggesting a net lactate output in presumably normoxic tumor beds.

Elevated lactate levels in tumors due to the Warburg effect can be measured non-invasively using magnetic resonance spectroscopy (MRS) and serve as biomarkers for cancer diagnosis and monitoring treatment response.

Nearly 100 years ago, Otto Warburg undertook a study of tumor metabolism, and discovered increased lactate caused by increased glycolysis in cancer cells.

Nearly a century ago, Otto Warburg discovered that tumors consume tremendous amounts of glucose relative to most non-transformed tissues, and that the majority of glucose consumed by tumors is fermented to lactate, rather than oxidized in pathways that require respiration. This phenotype is referred to as “aerobic glycolysis,” because unlike carbohydrate fermentation in response to oxygen limitation, aerobic glycolysis involves high levels of fermentation even when oxygen is abundant. Aerobic glycolysis a hallmark of proliferative metabolism found across many kingdoms of life, but is frequently associated with cancer cells, and is known as the Warburg effect in this context.

Note that the traditional “Warburg Effect” describes tumors relying heavily on glucose uptake (via GLUTs) with subsequent lactate exportation (via MCT4s) in aerobic conditions.

Our findings show that lactic acidosis diminishes Warburg effect in tumor cells, but this change does not necessarily promote a shift to OXPHOS. All tumor cells consumed glucose and produced lactate during the exponential and stationary phases.

The elevated levels of lactate can further support the proliferation of tumor-infiltrating regulatory T cells (Tregs) and enhance Treg-mediated immunosuppression.

These findings suggest that high lactate and histone lactylation levels in macrophages may contribute to the formation of tumors and their immunosuppressive microenvironment.

The Warburg effect is an abnormal tendency of tumors to produce lactate in an environment with normal oxygen levels. By showing that cultivated tumor tissues exhibit high rates of glucose uptake and lactate release even in the presence of oxygen, Otto Heinrich Warburg initially characterized this effect in 1924. According to a research, axillary veins from chicken wings with sarcomas exhibited lower glucose levels and greater lactate levels than those from limbs without tumors.

The Warburg effect, also known as aerobic glycolysis, is defined as the propensity of cancer cells to take up high levels of glucose and to convert it to lactate even in the presence of oxygen. These metabolic changes produce measurable biomarkers that can be used in diagnostic strategies.

18F-FDG PET imaging exploits the Warburg effect, where cancer cells show increased glucose uptake and metabolism, serving as a standard diagnostic tool for many cancers including lung, lymphoma, and colorectal cancer, with high sensitivity and specificity as per NCCN guidelines and numerous clinical studies.

The Warburg effect, proposed by Otto Warburg famously suggests that in growing tumors; there is rapid glucose uptake, reduced glucose oxidation and increased lactate production even in the presence of oxygen.