Targeting Glucose Metabolism

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

Glucose Metabolism

To execute progression and metastasis, cancer cells undergo metabolic evolution to maximize nutrient utilization for bioenergetic and biosynthetic demands, survive harsh tumor microenvironment (TME), and escape immunosurveillance. The aberrant glucose metabolism is a major kind of metabolic reprogramming in cancer. A majority of human tumors exhibit significantly higher glucose flux compared with adjacent normal tissues, and the glucose metabolism is characterized by increased aerobic glycolysis in the tumorous tissues, known as the Warburg effect. In fact, significant metabolic heterogeneity exists among the cells in a tumor. In reverse Warburg effect, cancer-associated fibroblasts (CAFs) also metabolize glucose through anaerobic glycolysis and export lactate, which is then taken up and utilized by oxidative cancer cells. Moreover, impaired immune function due to metabolic competition between cancer and immune cells is one of the critical factors of an immunosuppressive TME.

Fig. Abnormal glucose metabolism and tumors. (Wu, 2020)

Functions of Glucose Metabolism in TME

Tumor cell survival under aberrant metabolism of glucose is a vital step not only for the process of tumorigenesis but also to reshape TME. Nutrient competition and depletion of glucose in the TME by cancer cells have been proposed as a metabolic mechanism of immunosuppression.

When there is a lack of glucose in the TME, the function of most immune cells will be defective. In tumors, T cell activation and proliferation could be impaired by metabolic disruption. The activation of NK cells depends on glycolysis and oxidative phosphorylation to supply energy. The lack of nutrition, especially glucose, in the TME affects the metabolism of NK cells and their tumoricidal effect.
Tumor glycolysis contributes to the acidic TME through the release of lactate. The acidic environment is more toxic to adjacent tissue compared with the cancer cells themselves. Acidic TME promotes the growth and survival of tumor cells but also the recruitment of inflammatory cells that are re-educated in the TME to favor tumor spread and metastasis. In addition, lactic acid can downmodulate the function of cells from the lymphoid origin, then contributing to tumor escape from immune attack.

Targeting Glucose Metabolism

The imbalance between glucose metabolism and cancer cell growth in TME is closely related to the occurrence and progression of cancer. Uptake and use of glucose can be controlled by a multitude of factors including enzymes (GLUT and hexokinase), mitochondrial defects, hypoxia-inducible factor, MYC, PI3K/Akt/mTOR, p53/TIGAR/PFKB3. Compared to conventional cytotoxic therapy, modulation of particular targets with altered glycolytic metabolism would reduce treatment toxicity. Targeting glucose metabolism becomes an attractive target to restore anti-tumor immunity and develop anticancer therapy.

Fig.2 Therapeutic targeting cell metabolism in the TME. (Kouidhi, 2018)

Targeting glycolytic enzymes

Several enzymes in the glycolytic pathway have been targeted, some showing tumoricidal effects in vitro and in vivo. Unfortunately, there has been little clinical success given that glycolysis is crucial to the glucose metabolism of normal cells as well.

Glycolytic inhibitors

2-DG competitively inhibits hexokinase through product inhibition due to the accumulation of 2-DG-6-phosphate (2-DG-6-P), which is not metabolized further causing the metabolic block. Numerous preclinical studies have demonstrated anti-proliferative effects of 2-DG but clinical success has been limited.

AMPK activation

The AMPK pathway plays an important role in the TME. AMPK activation is thought to reduce tumor burden in part by slowing tumor growth, while concurrently supporting the expansion and survival of tumor-infiltrating lymphocytes in the TME. AMPK activity must be balanced, however, as excessive AMPK may inhibit effector T cell responses.

Targeting immune checkpoints

As PD-1 signaling inhibits glycolysis in T cells and PD-L1 in cancer cells stimulates aerobic glycolysis, this reciprocal glucose uptake associated with the PD-1-PD-L1 axis can be applied to metabolic modulation with immune checkpoint inhibitors as a new strategy for cancer immunotherapy.

Creative Biolabs provides high-quality services and helps you save precious time to focus on analyzing data and making project plan. With the help of our professional scientists, we are committed to developing services in targeting tumor metabolism.

References

Wu, F.; et al. Emerging landscapes of tumor immunity and metabolism. Frontiers in Oncology. 2020, 10: 2117.
Kouidhi, S.; et al. Targeting tumor metabolism: a new challenge to improve immunotherapy. Frontiers in immunology. 2018, 9: 353.