Cancer Metabolism: Partners in the Warburg effect

  1. Joshua D Rabinowitz  Is a corresponding author
  2. Hilary A Coller
  1. Princeton University, United States
  2. University of California, Los Angeles, United States
  3. David Geffen School of Medicine, United States

In 1918 Albert Einstein convinced Otto Warburg to leave the German infantry and fulfill his patriotic requirements in the first World War by performing research instead (Koppenol et al., 2011). Back in the lab at the Kaiser Wilhelm Institute, Warburg discovered that thin slices of tumors produced lactate much more rapidly than normal tissue. This rapid fermentation of glucose by tumors, even in the presence of ample oxygen, was the first biochemical trait assigned to cancer and is known as the Warburg effect.

When oxygen is present, most human cells rely on a process called oxidative phosphorylation inside mitochondria to convert lactate into carbon dioxide and usable energy. Warburg proposed that the rapid glucose fermentation and associated lactate secretion by the cancer cells was due to mitochondrial dysfunction. However, subsequent studies have shown that most cancer cells do have working mitochondria and, moreover, depend heavily upon them to produce energy (Zu and Guppy, 2004Moreno-Sánchez et al., 2007). Instead of causing mitochondrial dysfunction, it was found that the mutations that cause cancer also promote the breakdown of glucose in a process called glycolysis. The most striking example involves the PI3K-Akt signaling pathway, which both transduces the signal from the hormone insulin to drive glucose uptake, and is one of the most frequently mutated pathways in cancer. One way this pathway can be activated is by the loss of a tumor suppressing enzyme called PTEN (Shaw and Cantley, 2006). The observation of oncogene-driven glucose uptake seemed to neatly explain the Warburg effect.

Over the past few decades, evidence has steadily accumulated that cancer cells also hijack surrounding cells (Cirri and Chiarugi, 2012). For example, cancer cells secrete growth factors to promote the formation of new blood vessels (Orimo et al., 2005), which are required to supply tumors with nutrients. Moreover, they co-opt surrounding connective tissue cells, including fibroblasts, which exchange signals with the cancer cells in a manner that ultimately drives tumor growth and likely helps to suppress immune responses to the tumor (Cirri and Chiarugi, 2012). However, both the mechanism of this exchange and its role in tumor growth remain poorly understood.

Fibroblasts may exchange both signaling molecules and metabolic fuels with the cancer cells, either by secreting individual molecules (e.g. lactate; Martinez-Outschoorn et al., 2014) or by releasing membrane-bound vesicles known as exosomes (Castellana et al., 2009). For example, recent work has shown that the spread of cancer in the brain is promoted by the exosomes that are released by a particular type of brain cell. These exosomes contain small RNA molecules known as microRNAs that can silence the gene that encodes the PTEN enzyme, whose loss drives an increase in glycolysis (Zhang et al., 2015).

Now, in eLife, Deepak Nagrath at Rice University and colleagues – including Hongyun Zhao as first author – show that cancer-associated fibroblasts release exosomes that both deliver nutrients to cancer cells and inhibit oxidative phosphorylation (Zhao et al., 2016; Figure 1). Zhao et al. use isotope-labelled carbon compounds to provide compelling evidence that exosomes from fibroblasts can supply an amino acid called glutamine and other nutrients to cancer cells. A shortage of glutamine can limit the growth of pancreatic and perhaps other cancers (Kamphorst et al., 2015). Importantly, although the exosomes contribute modest amounts of nutrients, they can protect cancer cells from starvation, hinting at one potential role for such metabolic exchange in tumors.

More striking and surprising is the role of the exosomes in causing the Warburg effect. Adding exosomes to prostate or pancreatic cancer cells both promotes glycolysis and blocks oxidative metabolism. It is likely that the increase in glycolysis is caused by the reduction in oxidative phosphorylation so, in this respect, the exosomes trigger glycolysis in the way initially envisioned by Warburg. These results call for a re-examination of the contributions of both processes to energy generation in cancer cells that are still associated with their neighbors.

Such re-examination is particularly important given that oxidative phosphorylation is reduced so dramatically in cancer cells, with oxygen consumption lowered by up to 80% within 24 hours of receiving exosomes from fibroblasts. Zhao et al. – who are based at Rice University, Baylor College of Medicine, the University of Texas MD Anderson Cancer Center and Stanford University – propose that the exosomes may deliver microRNAs that silence oxidative metabolism genes, but this is hard to reconcile with the timing. Since the proteins involved in oxidative phosphorylation are generally long-lived, even complete inhibition of their production seems unlikely to produce such drastic effects so quickly. Nor can the decreased oxidative phosphorylation be explained by the delivery of nutrients by exosomes, because increasing the access to such nutrients would be expected to promote, not inhibit, the use of oxygen. Thus, understanding how the exosomes inhibit oxidative phosphorylation is a key challenge going forward. Such work holds the potential to illuminate not only the Warburg effect, but also the regulation of oxidative phosphorylation in cells more generally.

Fibroblasts supply nutrients to cancer cells and inhibit oxidative phosphorylation in cancer cells.

Fibroblasts (pink cells) associate with epithelial cancer cells (blue cells) and release exosomes (circles) that transfer nutrients to epithelial cancer cells (orange lines). In addition, they inhibit mitochondrial oxidative phosphorylation in the cancer cells (black blunt arrows), perhaps via microRNAs that silence particular genes.

References

    1. Zu XL
    2. Guppy M
    (2004) Cancer metabolism: Facts, fantasy, and fiction
    Biochemical and Biophysical Research Communications 313:459–465.
    https://doi.org/10.1016/j.bbrc.2003.11.136

Article and author information

Author details

  1. Joshua D Rabinowitz

    Department of Chemistry and the Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
    For correspondence
    joshr@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Hilary A Coller

    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    2. Department of Biological Chemistry, David Geffen School of Medicine, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0992-6494

Publication history

  1. Version of Record published: April 13, 2016 (version 1)

Copyright

© 2016, Rabinowitz et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,752
    Page views
  • 762
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Joshua D Rabinowitz
  2. Hilary A Coller
(2016)
Cancer Metabolism: Partners in the Warburg effect
eLife 5:e15938.
https://doi.org/10.7554/eLife.15938
  1. Further reading

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Liangyu Zhang, Weston T Stauffer ... Abby F Dernburg
    Research Article

    Meiotic chromosome segregation relies on synapsis and crossover recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in 'homolog engagement' is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans, recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break induction. Inactivation of CHK-2 terminates double-strand break formation and enables crossover designation and cell cycle progression. These findings illuminate how meiotic cells ensure crossover formation and accurate chromosome segregation.

    1. Cell Biology
    2. Physics of Living Systems
    Christa Ringers, Stephan Bialonski ... Nathalie Jurisch-Yaksi
    Research Article

    Motile cilia are hair-like cell extensions that beat periodically to generate fluid flow along various epithelial tissues within the body. In dense multiciliated carpets, cilia were shown to exhibit a remarkable coordination of their beat in the form of traveling metachronal waves, a phenomenon which supposedly enhances fluid transport. Yet, how cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine experiments, novel analysis tools, and theory to address this knowledge gap. To investigate collective dynamics of cilia, we studied zebrafish multiciliated epithelia in the nose and the brain. We focused mainly on the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Even though synchronization is local only, we observed global patterns of traveling metachronal waves across the zebrafish multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right nose, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions, cilia colliding with each other, and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment coincide and generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.