In the latest of my posts on better aging, I’m going to discuss the topic of starving cancer cells. (You can find the rest of the articles here: 1, 2, 3, 4, 5, 6, 7.) Biologists have known for nearly a century that some types of cancer cells consume significantly more glucose than normal cells. Healthy cells burn most of a sugar molecule in their mitochondria in order to make energy, which is why mitochondria are often referred to as cellular “power plants.” 

Cancer cells, however, function quite differently. They rely heavily upon another energy-producing process in the metabolism of sugar called glycolysis. This produces energy faster, but also extracts much less of it from the sugar molecule. Cancer’s preference for glycolysis has been dubbed the “Warburg effect,” after German physiologist, and Nobel Prize winner, Otto Warburg, who was the first to demonstrate it experimentally.

It has never been entirely clear why the difference exists. Cancer cells presumably need a considerable amount of energy in order to grow and proliferate throughout the body. How do they do it?

A new paper in the journal Cell Metabolism attempts to address this question. In doing so, authors Craig Thompson and Natasha Pavlova launch a novel explanation for the origin of cancer itself.

 

From one cell to many

One of the great fundamental challenges of biology is how multicellular organisms evolved, and how these clusters of cells manage to function together harmoniously. Dr. Thompson has argued that the cells that make up multicellular organisms operate in a fundamentally different way than their single-celled counterparts. This union of cells works because the individual cells in the group operate according to certain “rules,” which ensure that they share nutritional resources and only take up nutrients in response to growth signals. In contrast, single-celled organisms are able to consume nutrients continuously, without regard for cells around them, and can reproduce relatively freely.

Due to the effects of mutations, cancer cells essentially become “antisocial” – they are able to deviate from the rules, without regard for how it affects the wellbeing of the whole. Instead of behaving cooperatively, as part of a larger organism, a cancer cell feeds and reproduces itself without inhibition. The authors liken the nutrient uptake of cancer cells to yeast blooming in a vat of sugar. Cancer cells behave more like a single-celled organism, governed by its own interests, rather than as a part of a greater cellular “community.” This metabolic shift results in aberrant tissue growth, detrimental to the whole organism. It is this altered metabolism of nutrients, according to the authors, that is cancer’s true cause.

To support this theory, the authors observe in the article that many oncogenes (genes that have been associated with cancer) exhibit direct effects on cell metabolism, giving individual cells extraordinary power to regulate the uptake and utilization of nutrients in the environment. For example, some oncogenes increase glucose consumption (AKT and RAS) while others increase the uptake of amino acids (MYC and Rb). This metabolic reprogramming is critical to cancer cell growth and spreading.

Glucose is not the only driver of cancer cell growth. Certain forms of cancers have also been shown to rely heavily upon glutamine as a source of fuel. Cancer cells have evolved a number of different ways of acquiring the amino acid from host tissues. In fact, it appears that cancer cells may derive energy by literally consuming cellular signals. Zhao and colleagues came upon this discovery when investigating the role of exosomes, which are tiny pouches of proteins and nucleic acids that transmit information between cells. The team was surprised to find that not only were the cancer cells receiving these signals from other cells, they were using them as a source of energy, consuming amino acids directly from the exosomes. This is another example of how remarkably resourceful cancer cells can be – drawing in glucose and amino acids from the environment as building blocks for tumors.

 

Therapeutic relevance: starving cancer

Why should all of this matter to us? Recognizing the fundamental importance of metabolic alterations could have major implications for cancer treatment. In their article, Thompson and Pavlova identify six distinct areas of cell-metabolite interaction, all of which become dysregulated in cancer cell metabolism. Any of these could emerge as potential therapeutic targets.

For example, drugs that are known to affect cell-signaling pathways but that have not traditionally been associated with cancer treatment, such as metformin, may prove to be effective cancer-suppressing therapies. Metformin is commonly prescribed for diabetes due to its effects on metabolic and intracellular-signaling pathways. It inhibits glucose production from the liver, and reduces levels of insulin in the bloodstream. This reduction in insulin stimulation results in less activation of insulin receptors. In turn, this leads to the downregulation of certain signaling pathways that are associated with cell growth and proliferation – and which are commonly used by cancer cells. To recall a line from a previous post on aging, I wrote: “there are more than 200 ongoing clinical trials studying the effect of metformin in preventing and even treating cancers.”

Similarly, with respect to exosomes, it is also likely that drugs that interfere with the uptake of their signals could emerge as a novel treatment. Indeed, in their study, Zhao and his team exposed cancer cell cultures to several agents that disrupt the transmission of exosomes and found that metabolic activity in the cancer cells declined precipitously. Several of the drugs that they applied – which included heparin and chloroquine – are already in use for other conditions. We will, of course, need to see clinical trials with human participants before we can say whether or not any of these drugs are truly effective as chemotherapeutics, but it sure is nice to have new promising agents.

Furthermore, as we continue to better understand how cancer cells acquire access to and utilize nutrients, we may also be better able to understand dietary therapies that have been investigated for treatment or prevention of cancer. For example, adherence to a ketogenic diet may help “starve” cancer cells by depriving them of glucose for energy. Taking this information together, a low glutamine ketogenic diet might prove to be quite useful to certain types of cancers.  

The Warburg model may also shed light on why many nutritional supplement interventions, which initially seemed so promising, have ultimately proved to be disappointing (or even outright harmful). In the next blog post on this subject, we will discuss one such example.

 

References

1. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. 2009. Science 324(5930):1029–33.
2. Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. 2016. Cell Metabolism 23(1):27-47.
3. Sedwick, C. Craig Thompson: The method to cancer’s madness. 2010. Journal of Cell Biology 191(4):696-697.
4. Hajjar J, Habra MA, Naing A. Metformin: an old drug with new potential. 2013. Expert Opinion in Investigational Drugs 22(12):1511–1517.
5. Zhao H, Yang L, Baddour J, Achreja A, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. 2016. ELife pii: e10250.