Deregulating Cellular Energetics

Cancer cells must adjust their metabolism accordingly to enable their uncontrolled growth.

Glucose enters cells through glucose transporters that are protein channels that selectively facilitate glucose molecules to enter the cell. Since cancer cells actively produce more cell surface glucose transporters, more glucose enters the cell, where it is broken down by aerobic glycolysis into lactic acid. ATP and metabolic precursors are then rapidly produced through various metabolic pathways.

Typically, these pathways are tightly controlled, requiring specific enzymes for processing the molecules from each step to the next. Cancer cells are dependent on these enzymes that control these pathways, and that are often over-expressed or mutated in cancer cells. Chemotherapy strategies target these dependencies.

Cancer cells exhibit a phenotype that reflects their metabolic needs.

Proliferation, associated with carcinogenesis, involves oncogenes, proto-oncogenes, and mutated tumor-suppressor genes. Rapid proliferation correlates to the cells’ metabolic phenotype. To maintain rapid growth, cancer cells will reprogram their metabolic phenotype, switching between glycolytic and aerobic phenotypes.

Cancer cells change their substrate preference as they alter their metabolic phenotypes. For example, cancer cells may increase glutamine metabolism, alter lipid metabolism, or shift the balance between anabolic and catabolic processes. There is increasing evidence of the interactions amongst genes, substrates, and phenotypes.

Seahorse XF technology and assays bring unique value to investigate the mechanisms behind the hallmarks of cancer and altered cell metabolism.

Researchers are using Seahorse XF technology and XF stress tests to explore these metabolic changes, and the effect of metabolic therapies to increase their understanding of cancer. The Seahorse XF Cell Mito Stress Test measures the key parameters of respiration: basal respiration, proton leak, ATP-linked respiration, maximal respiration, and spare respiratory capacity. The Seahorse XF Glycolysis Stress Test measures the key parameters of glycolytic function: glycolysis, glycolytic capacity, and glycolytic reserve.

A recent Nature paper (Russell et al, 2017) investigated metabolic profiles to compare 2D cultures with cancer spheroids, and micro-slices from tumors with normal organs using the Searhorse Extracellular Flux Analyser. They subsequently reported that metabolic profiling of complex microtissues is necessary to understand the effects of metabolic co-operation and that this method can be used as a reproducible, early and sensitive measure of drug toxicity.

In 1924 Otto Warburg first discovered that cancer cells generated a large proportion of their ATP by metabolizing glucose via aerobic glycolysis (as opposed to mostly through oxidative phosphorylation (OXPHOS) in normal cells). Initially, it was thought that this Warburg effect was a cause of cancer, but it was later established that this shift to glycolytic metabolism was an effect of cancer cell transformation. Genetic changes and epigenetic modifications in cancer cells alter the regulation of cellular metabolic pathways. These distinct metabolic circuits could provide viable cancer therapeutic targets.

The results of the genetic and epigenetic mutations on the altered regulation of metabolic pathways in cancer cells are increased bioenergy production and an altered redox balance, all of which promotes cell proliferation and survival.  Furthermore, microenvironments within large tumors can dynamically alter metabolic pathways creating heterogeneous populations of cells.

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