Every single cell has to eat to generate energy and work properly. Simple. Yes, simple and complicated at the same time. All the processes involved in cell growth and division are very important and are tightly regulated. Imagine that each cell of our body decided to grow and divide without any control… it would be a chaos. Actually, there are several mechanisms in our cells that sense if something goes wrong and can even trigger their auto-destruction. In this way, the defects that have been produced won’t be passed on to the next generation of cells. However, it looks like cancer cells escape this control and have an uncontrolled division. Are cancer cells cleverer than the normal ones? How do they manage to escape these controls? Cancer cells usually modify their behaviour in different ways to avoid being recognised as abnormal cells and destroyed.

A clear example of this change in behaviour is the energy production in cancer cells. In regular conditions and in the presence of oxygen, cells get energy (as ATP, an energy molecule) from glucose through different processes. The first one is called glycolysis.  This process doesn’t happen in any specific cellular compartment, but in its cytoplasm. The result of the glycolysis is a compound called pyruvate, which in the presence of oxygen, will be transformed by the Krebs Cycle to produce a high amount of ATP. The Krebs Cycle takes place inside the mitochondrias, the energy factories of the cell. However, when there is not enough oxygen, the pyruvate is transformed into lactate, through the anaerobic oxidation, in the cytoplasm with the production of a very low amount of ATP. All these processes are very well regulated and the cell can sense when there is something wrong in the mitochondria. If this happens the cell will activate an auto-destruction mechanism called apoptosis to avoid bigger problems.

During the 30’s Otto Warburg suggested a theory to explain some of the escape mechanisms of the cancer cells. He proposed a model in which the cancer cell would “switch off” its mitochondria and get the energy in the cytoplasm, even in the presence of oxygen, through an aerobic glycolysis. This theory, called the Warburg Effect, has been accepted for many years but how it happens exactly is not known yet. However, Professor Michael Lisanti’s group (where Stephanos Pavlides, who has helped with his knowledge to this article, works) has done several studies that are in contradiction with this theory. Cancer cells produce free radicals and, due to this, they live surrounded by oxidative stress. Researchers in Lisanti’s group were studying normal cells, called fibroblasts, that surround breast cancer ones. When they put together these normal fibroblasts and the cancer cells from breast cancer they saw that the oxidative stress produced by the cancer cells was affecting the normal cells as well. The free radicals, produced by the cancer cells, produced a process called autophagy, by which the cell “eats” its own components, in the fibroblasts. When this happens, pyruvate and lactate (the energetic molecules) are produced by the fibroblasts and taken by the cancer cells. In this way the fibroblasts are feeding the cancer cells promoting their growth and “switching their mitochondria back on”. If the mitochondria of the cancer cells are again on and there is no problem in them, the cells will escape the mitochondrial dependent auto-destruction (apoptosis). These researchers have called “The Reverse Warburg Effect” to the fact that the aerobic glycolysis doesn’t happen in the cancer cells but in the fibroblasts. In addition, the autophagy in fibroblasts produces more free radicals that will amplify the effect of the ones produced by the cancer cells promoting a higher amount of DNA damage in the cells. This damage is one of the reasons for genomic instability, one of the processes that can transform a normal cell into a cancerous one. In conclusion, cancer cells effect on fibroblasts behaviour promotes cancer cells feeding by the fibroblasts (producing the energetic compounds through autophagy), the fibroblasts help on the cancer cells evolution (producing DNA damage and genomic instability) and the protection against the apoptotic cell death (promoting the switch back on of the mitochondria in the cancer cells).

These conclusions came from previous studies in several labs where researchers discovered that low levels of a protein, called caveolin1 or Cav1, were related to aggressive and poor prognostic breast cancers. At the beginning they didn’t know exactly why this happened. However they saw that in tumors with very little Cav1 there was a high amount of proteins involved in glycolysis, meaning that these cells had a high autophagic activity. This happened in the cells surrounding the tumors (fibroblasts) and not in the proper cancer cells. Actually, the amount of Cav1 in the fibroblasts predicts cancer recurrence, metastasis and tamoxifen (common drug used to treat breast cancer) resistance of breast and pancreatic cancers, among others.

As you can see, this is a complicated but promising subject. Actually this effect can explain several facts related to the treatment of different cancers. One kind of treatment that has been tried, without success, is the therapy focused on inhibiting the formation of new blood vessels, or antiangiogenic therapy. Antiangiogenic drugs produce an oxygen decrease, or hypoxia, around the cancer promoting oxidative stress and autophagy. These conditions are ideal for cancer cells to grow and divide because they are fed by the nutrients produced by the surrounding fibroblast through autophagy.   

On the other hand, there have been some studies using drugs that block autophagy, preventing the fibroblasts digestion and subsequent release of nutrients for the cancer cells to use. Malaria drug chloroquine uses this mechanism and it would be very interesting to study its effect on cancer. In addition, drugs that supress mitochondria’s ability to use lactate and other glycolytic products could help block the energy supply of the cancer cells. Actually, one of these drugs used in diabetes treatment, metformin, has an effect on cancer cells. Diabetic patients who are taking metformin have less risk of having cancer. However, this hasn’t been scientifically proven.

In short, studying the processes of energy production and consumption, or metabolism, in cancer cells and their surrounding cells is a very promising research field, as well as the study of drugs already used for other diseases and their effect on cancer. This opens a new line of future cancer treatments that hopefully will have positive results and help decrease the mortality produced by this group of diseases called “cancer”.

References:

1: Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, Pasanisi P, Pilotti S. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2012 Jun 4. doi: 10.1038/onc.2012.181. [Epub ahead of print] PubMed PMID: 22665053.

2: Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Philp NJ, Pestell RG, Lisanti MP. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle. 2012 Apr 1;11(7):1445-54. Epub 2012 Apr 1. PubMed PMID: 22395432; PubMed Central PMCID: PMC3350881.

3: Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, Sneddon S, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 2012 Mar 15;11(6):1108-17. Epub 2012 Mar 15. PubMed PMID: 22313602; PubMed Central PMCID: PMC3335917.

4: Maycotte P, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy. 2012 Feb 1;8(2):200-12. Epub 2012 Feb 1. PubMed PMID: 22252008; PubMed Central PMCID: PMC3336076.

5: Ahn JH, Ahn SK, Lee M. The role of autophagy in cytotoxicity induced by new oncogenic B-Raf inhibitor UI-152 in v-Ha-ras transformed fibroblasts. Biochem Biophys Res Commun. 2012 Jan 13;417(2):857-63. Epub 2011 Dec 21. PubMed PMID: 22206679.

6: Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, Pavlides S, Ertel A, Sotgia F, Lisanti MP. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle. 2011 Jun 1;10(11):1794-809. Epub 2011 Jun 1. PubMed PMID: 21521946; PubMed Central PMCID: PMC3142463.

7: Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz AK, Vander Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F, Flomenberg N, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle. 2010 May 15;9(10):1960-71. Epub 2010 May 15. PubMed PMID: 20495363.

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