BioFiles Volume 7, Number 4 — Cancer Metabolism

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Cancer MetabolismTable of Contents

 


Introduction

Mark Frei
Linda Stephenson, Ph.D.

It has been over 80 years since Otto Warburg published his seminal observations that cancer cells utilize glycolysis over oxidative phosphorylation and secrete high levels of lactic acid. Warburg hypothesized that cancer was caused by mitochondrial defects that forced the cell to rely on glycolysis for energy.1-5 The inability to determine the mechanisms that led to this metabolic switch, the advent of molecular biology, and the discovery of oncogenes and tumor suppressors shifted interest away from metabolism towards a focus on unraveling the genetic lesions that promote oncogenesis. Interest in cancer metabolism has been renewed due to the many recent discoveries that have begun to elucidate the role many common oncogenes and tumor suppressors play in the reprogramming of metabolic pathways during oncogenesis. Since these pathways are used by multiple types of tumors, targeting these pathways may offer potential therapeutic targets against a wide variety of cancer cells.

While the increased dependence on glycolysis is a common feature of many cancer cells, other pathways are also commonly reprogrammed during oncogenesis. For example, many cancer cells use glutamine inefficiently and cellular uptake of glutamine in many cancer cells is often far in excess of what is required for biosynthetic needs.6 Tumor cells also upregulate the pathways contributing to nucleotide, protein, and fatty acid synthesis.3,4 A key challenge for researchers will be unraveling and elucidating the multiple mechanisms by which tumor cell metabolism is reprogrammed.

Oncogenesis is typically a multistep phenomenon in which the cell gradually acquires mutations and epigenetic changes that promote increased malignancy. In terms of metabolism, these adaptations include not only the metabolic reprogramming due to alterations in oncogenic signaling pathways or loss of tumor suppressors, but also to alterations that occur as a result of changes in the tumor microenvironement. For example, increased hypoxia and acidification are cellular stressors that can alter metabolic reprogramming to favor tumor progression and may result in differences in the metabolic profiles of cells even within the same tumor.7 Additionally, metabolic reprogramming is also influenced by the tissue origin of the tumor.8 Understanding how these individual pathways interact will allow for more targeted combinatorial therapies, and the potential to identify and exploit unique synthetic lethalities within an individual tumor.

References

  1. Cairns, R. A. et al. Regulation of Cancer Cell Metabolism. Nature Reviews Cancer, 11, 85-95 (2011)
  2. DeBerardinis, et al. The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Cell Metabolism, 7, 11-20 (2008)
  3. Jones, R.G. and Thompson, C.B. Tumor Suppressors and Cell Metabolism: a Recipe for Cancer Growth. Genes & Development, 23, 537-548 (2009)
  4. Kroemer, G. and Pouyssegur, J. Tumor Cell Metabolism: Cancer’s Achilles’ Heel. Cancer Cell, 13, 472-482 (2008)
  5. Shaw, R. and Cantley, L.C. Decoding Key nodes in the metabolism of cancer cells: sugar & spice and all things nice. F100Reports Biology. 4:2 (2012)
  6. DeBerardinis, R.J. et al. Beyond Aerobic Glycolysis: Transformed Cells Can Engage in Glutamine Metabolism That Exceeds the Requirements For Protein and Nucleotide Synthesis. Proc. Natl. Acad. Sci USA, 104, 19345-19350 (2007)
  7. Kim, J.W. et al. Effects of Hypoxia on Tumor Metabolism. Cancer and Metastasis Rev. 26, 291-298 (2007)
  8. Yuneva, M. O. et al. The Metabolic Profile of Tumors Depends on Both the Responsible Genetic Lesion and Tissue Type. Cell Metabolism, 15, 157-170 (2012)

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