Daria Martin, Schering Stiftung Projektraum


Oncogenes meet metabolism - from deregulated genes to a broader understanding of tumour physiology

Dr. Dominik Mumberg, Apoptosis & Signal Transduction Research, Bayer Schering Pharma AG, Berlin, Germany
Dr. T. Steger-Hartmann, Laboratory Diagnostics, Genetics & Ecotoxicology, Bayer Schering Pharma AG, Berlin, Germany
Guido Kroemer, Institut Gustave Roussy, France, Research Director INSERM
Hector Keun, Imperial College, London

Berlin, November 14-16, 2007

Internationally renowned scientists met for the fourth time this year at the invitation of the Ernst Schering Foundation. Around 50 researchers from France, Switzerland, the US, the UK, and Germany convened at the Harnack-House of the Max Planck Society from the 14th to the 16th of November 2007 to exchange their latest findings in the field of oncogenes and metabolism. A more appropriate venue for this meeting could not have been found, since Otto Warburg discovered the phenomenon of "Anaerobic glycolysis" in this very building in Berlin-Dahlem. Anaerobic glycolysis, also known as Warburg effect, describes the change of tumor cell metabolism to convert glucose to lactate under normal oxygen conditions. Although Warburg made his discovery in the 1920s, thereby establishing the link between cancer and changes in the metabolic phenotype, to this day the complex metabolic pathways in healthy and diseased cells such as tumor cells have not been fully understood.

The convention of experts from oncology, toxicology and researchers from applied clinical sciences as well as those that study metabolism using a systems approach aimed at fostering scientific exchange and interaction between the different disciplines.
Professor Guido Kroemer, Director of the Institute Gustave Roussy from Villejuif in France and co-organiser of the symposium, summarized the seven hallmarks of cancer cells that allow tumors to grow in such uninhibited ways in his opening lecture: induction of genetic instability, abnormal expression of genes, abnormal signal transduction and avoidance of apoptosis (programmed cell death), abnormal cell-to-cell communication, invasion and metastasis, induction of angiogenesis (spontaneous blood-vessel formation), and immune evasion.

In particular, abnormal gene expression and the effects on tumor cell metabolism were the main topics of this symposium. Kroemer, an Austrian scientist, who has lived and worked in France for the past 16 years, focuses his research on the role of mitochondria in apoptosis. Mitochondria, which are also referred to as the "cellular power plants" are responsible for the conversion of glucose to ATP, the universal source of chemical energy. Kroemer was able to demonstrate, how cancer cells can avoid apoptosis by blocking the tumor suppressor signal p53 interaction with the mitochondria.

With the inhibition of apoptosis, tumor cells have managed to switch of one of the body´s major control mechanism to eliminate abnormal cells. Another strategy tumors use is fast growth. However, this often leads to the physiologically unfavourable situation of nutrient depletion and hypoxia (lack of oxygen), the reason for this being the lack of vascularisation of the tumor. But tumors have found yet another way around this problem: On the one hand they induce angiogenesis themselves, on the other hand they can use autophagy. Autophagy is a process involving the degradation of a cell's own damaged components to protect it against toxic metabolites. Eileen White, Professor at Rutgers University in Piscataway, New Jersey, US, presented research from her lab that demonstrated how autophagy actually promotes tumor growth. "It is a paradox, really", says Prof. White. "How can it be that a situation of nutrient depletion and physiological stress enhances tumor growth?" She goes on to answer her own question: "One of the main purposes of autophagy is the prevention of dangerous DNA-double strand breaks. During autophagy the cell limits its metabolic turnover to an absolute minimum thus essentially going into "hibernation". In this state, the cell can endure periods of nutrient shortage until vascularisation of the tumor will deliver new nutrients and oxygen", explains White. However if the escape route of autophagy is not available to tumor cells, they might be driven into death by necrosis, if apoptosis is blocked too. Blocking autophagy might therefore be a starting point, for the development of new anti-cancer drugs, thinks the Professor from New Jersey.

The altered metabolism is a characteristic of tumor cells which was already discovered by Otto Warburg. Another feature is a high growth rate. It requires however a significant energy supply, mainly by sugars, a trait that is already being exploited clinically in PET imaging, a technique for tumor detection and localization with the help of labelled glucose. However, it is not only the high energy demand that is typical for tumor cells, it has also been found that a change in their metabolism results in a different metabolic profile.

It is precisely this trait that Dr. Sybille Mazurek from the Institute of Biochemistry and Endocrinology from the University of Giessen, Germany makes use of in her research on pyruvate kinase M2PK. M2PK is an enzyme of the glycolysis pathway. The pyruvate kinase M2PK transforms phosphoenolpyruvate (PEP) to pyruvate. Under normal physiological conditions the enzyme occurs in a tetrameric isoform. Mazurek was now able to show that tumor cells mainly contain the M2PK enzyme in a dimeric isoform, which has a significantly reduced affinity to the substrate PEP. "Tumor-M2PK is not working properly", explains Dr. Mazurek. "The result is that substrates like fructose-6-phosphate and fructose-1.6-bisphosphate start to accumulate. The cells then divert these substrates towards other metabolic pathways like nucleogenesis – the generation of phospholipids and nucleic acids." These cellular building blocks are of great importance to maintain the high growth rate of tumor cells. Sybille Mazurek and her team from Giessen University see tumor-M2PK mainly as an excellent tumor-bio-marker. The altered form of tumor-MPK can easily be detected in simple assays like i.e. stool samples of patients with colorectal cancer.

There are, of course, other metabolic pathways that are typically altered in tumor cells as well. Some of these were discussed by Professor Lewis Cantley from Harvard Medical School in Boston, Massachusetts, USA. He presented his latest finding in the field of phosphoinositide-3-kinase, an enzyme that is involved in signal transduction at the cell membrane. Dr. Jacques Pouysségur from the Institute of Signaling, Development Biology & Cancer Research in Nice, France, spoke on signal transduction pathways in cells under hypoxic stress (oxygen deprivation).

In recent years modern analytical methods like nuclear magnetic resonance spectroscopy (NMR) and the possibilities to process huge amounts of data have lead to the ability to analyze broad spectra of metabolites as well as to characterize metabolic changes within a cell or organism – a technique called metabonomics. Metabonomics is applied in various fields such as research into the metabolism of healthy and diseased cells, investigation of the changes in cell metabolism before and after treatment with a certain drug, as well as the study of differences in the metabolome of entire ethnic groups.

During the Dahlem symposium Professor John R. Griffiths from St. George´s Hospital Medical School in London, UK, introduced a study that monitored the efficacy of cancer treatment using metabonomics. The results of this investigation led Griffiths to the conclusion that the often quoted "magic bullet" to combat typical cancer genes might be highly overrated. "Our studies show that cancer cells are extremely flexible. Once you block one metabolic pathway by knocking out one gene, the cells will quickly find a way around it", says Prof. Griffiths. "What we need isn´t a magic bullet, we need a magic shotgun. We need to knock out as many pathways as possible at the same time in order to really get a grip on cancer cells."However this "magic shotgun" is not yet in sight. What is possible already, is the monitoring of therapy response. Griffiths research shows conclusively that after only one round of anti-cancer treatment patients clearly stratify into groups of responders and non-responders. Thus patients that do not react to a certain type of treatment can be singled out for special therapy, thereby saving precious time and optimizing treatment costs as well.

In some places metabonomics is already being employed for the early detection of certain types of cancer like ovarian cancer. Kunle Odunsi, Professor at Roswell Park Cancer Institute in Buffalo, New York, USA, is able to clearly distinguish healthy women from patients suffering from ovarian cancer using NMR analysis of blood serum. Furthermore patients with early stage cancer can be separated from those with advanced stage disease. Prof. Odunsi is driving attempts to translate his findings into an early detection test programme because, "Ovarian cancer is one of the most common causes for cancer death in women in western cultures. However most women only become aware of their disease when the cancer has progressed to advanced stages. The chances of survival are rather low. However, early stage patients have a much better chance, we can cure more than 90 percent of these women. A simple test using serum samples thus might be able to save many women's lives" , explains Odunsi.

Future prospects of what healthcare might look like in a few years time were illustrated by Professor Elaine Holmes of Imperial College in London, UK and Dr. Sunil Kochhar from Nestlé Research Centre in Lausanne, Switzerland. Prof. Holmes' lab applies clinical metabonomics to gain metabolic signatures of entire ethnic groups like Americans, Chinese, Japanese, and Europeans. This is ever more important, many of the experts of the symposium agree, since it seems more and more clear that individual lifestyle, genetic background as well as the general conditions of life go hand in hand to determine, whether and how a person is going to respond to a certain type of therapy.
Ways of preventing people from falling sick in the first place and how to achieve that with certain nutritional supplements are the proclaimed aim at Nestlé Research Centre. Dr. Sunil Kochhar spoke on attempts to help groups of consumers at risk for certain diseases like Irritable Bowel Syndrome (IBS) to higher quality of life, by supplementing their diet with i.e. probiotics. Thus they hope to prevent or at least delay the onset of severe diseases.

"I was fascinated by the amount of cross-discipline dialogue that I came across during this symposium", says Dr. Dominik Mumberg, head of Apoptosis and Translational Oncology Research of Bayer Schering Pharma and co-organisor of the symposium. "It would be great if we could all meet again in three years at this very same place and see, what kind of co-operations were started today and what has come of them." His colleges and co-organisers Dr. Thomas Steger-Hartmann, head of Laboratory Diagnostics, Genetic and Ecotoxicology at Bayer Schering Pharma and Dr. Guido Kroemer were also very pleased with the amount of scientific exchange, interesting discussions and new impulses for oncology research.

The results of the symposium will be published by the Springer publishing house and will be available in bookstores. The series "Scientific Symposia" by the Schering Foundation will be continued from the 9th to the 11th of April 2008 with a workshop on "The ubiquitin system in health and disease" in Berlin, Germany.


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