Effects of metabolic cancer therapy on tumor microenvironment

Abstract

Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly – clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

ALDOB represents a potential prognostic biomarker for patients with clear cell renal cell carcinoma

“…The TME refers to the cellular environment in which the tumor exists ( 56 ). Numerous studies have confirmed that TME plays an important role in tumor development, adaptation, and pathogenesis ( 57 - 59 ).…”

Metabolomics at the tumor microenvironment interface: Decoding cellular conversations

“…114 Asparagine is one non-essential amino acid that can be targeted by the enzymeLasparaginase to decrease blood asparagine levels. 114 Currently,L-asparaginase is clinically approved for the treatment of some lymphomas and is undergoing clinical trials for solid tumors and other cancers. Currently, L-asparaginase is critical for achieving a high cure rate in pediatric acute lymphoblastic leukemia and is because the lymphoblasts lack asparagine synthase.…”

“…Additionally, other cells, such as endothelial cells and immune cells, use extracellular asparagine, the depletion of asparagine can have complex outcomes, including impaired immune response. 114,115 To overcome these issues, research is being conducted to develop novel drug combinations and L-asparaginase formulations. 115 The physiological function of tissue and disease is closely related to the spatial and temporal distribution of metabolites, and, understanding this, will allow a deeper understanding of disease state and phenotype.…”

“…It is known that cancer cells can become dependent on both essential and non‐essential amino acids. In some cancers enzymes involved in asparagine biosynthesis are downregulated, which makes them dependent on exogenous asparagine 114 . Asparagine is one non‐essential amino acid that can be targeted by the enzyme l ‐asparaginase to decrease blood asparagine levels 114 .…”

“…In some cancers enzymes involved in asparagine biosynthesis are downregulated, which makes them dependent on exogenous asparagine 114 . Asparagine is one non‐essential amino acid that can be targeted by the enzyme l ‐asparaginase to decrease blood asparagine levels 114 . Currently, l ‐asparaginase is clinically approved for the treatment of some lymphomas and is undergoing clinical trials for solid tumors and other cancers.…”