Different Tumor Microenvironments Lead to Different Metabolic Phenotypes.

The beginning of the twenty-first century offered new advances in cancer research, including new knowledge about the tumor microenvironment (TME). Because TMEs provide the niches in which cancer cells, fibroblasts, lymphocytes, and immune cells reside, they play a crucial role in cancer cell development, differentiation, survival, and proliferation. Throughout cancer progression, the TME constantly evolves, causing cancer cells to adapt to the new conditions. The heterogeneity of cancer, evidenced by diverse proliferation rates, cellular structures, metabolisms, and gene expressions, presents challenges for cancer treatment despite the advances in research. This chapter discusses how different TMEs lead to specific metabolic adaptations that drive cancer progression.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.

Different Tumor Microenvironments Lead to Different Metabolic Phenotypes.

KEY POINTS: The beginning of the twenty-first century offered new advances in cancer research, including the expansion of the knowledge about the tumor microenvironment (TME). Because TMEs provide the niches in which cancer cells, fibroblast, lymphocyte, and immune cells reside, they play a key role in cancer cell development, differentiation, survival, and proliferation. Throughout cancer progression, the TME constantly evolves, causing cancer cells to adapt to the new conditions. The heterogeneity of cancer, evidenced by diverse proliferation rates, cellular structure, metabolism, and gene expression, presents challenges for cancer treatments despite the advances in research. This chapter discusses how different tumor microenvironments lead to specific metabolic adaptations which drive cancer progression.