Tuesday, January 30, 2018

Scientific Publication in Medical Biology - Team Hypoxia and tumor metabolism

Glycolysis or "Warburg effect" is not necessary for tumor growth revealing high plasticity of tumor metabolism

The vast majority of tumors ferment glucose into lactic acid. This fermentation is even taking place in the presence of oxygen, called 'Warburg effect', to the credit of the Nobel Prize in Medicine, Otto Warburg. As this fermentation is week in energy-generating (ATP), the cancer cell compensates for this low yield by a very high glucose consumption associated with a secretion of two equivalents of lactic acid in the tumor microenvironment. It is this metabolic characteristic (avidity for glucose) that has been exploited for many years in the clinic to accurately diagnose tumors and metastases by radiolabeling with the 18FDG glucose analogue in PET-Scan (Figure). This glycolytic phenotype kind of cancers 'glucose-addiction' has stimulated the search for specific inhibitors blocking the glycolytic metabolism of various key steps of glycolysis. The tumor growth inhibiting effects for many molecules are excellent in vitro and in mice. However, to date, no molecule has been able to 'enter' the clinic due to their high toxicity.

 

 

 

 

 

 

 

 

 

 

 

The accelerated development of genetic techniques (CRISPR-Cas9) to accurately invalidate, activate or repair the gene of its choice is revolutionizing our knowledge of biology. In the article published at Oncotarget we inactivated the gene coding for glucose-6-phosphate isomerase (GPI, 3rd step of glycolysis) in 2 tumor cell lines (melanoma, colon cancer). The consequence of this inactivation is a complete stop of the glycolysis measured by total suppression of the secretion of lactic acid. On the other hand, the minimal impact of this suppression of the "Warburg effect" on the growth of the 2 tumor models surprised us. In fact, both in vitro and in vivo, the growth rate of tumors is only reduced by a factor of 2. 
These cells derive their energy from oxidative phosphorylation and are dependent on oxygen for their survival.These results highlight the metabolic plasticity of cancers demonstrating that the Warburg effect cannot represent, contrary to popular belief, an anti-cancer target.
A therapeutic approach, targeting the oxidative stress of cancers and completing the results presented above will be the subject of another news, end of February.

Monique Cunha de Padua, Brazilian student in Thesis (1st author of the article) and Dr Jacques Pouysségur, Team leader "Tumor Hypoxia and Metabolism", Centre Scientifique de Monaco

 

For more information, visit www.centrescientifique.mc or contact:

- Dr. Milica VuceticPost-doctoral Fellow of the 'Tumor Hypoxia and metabolism', Medical Biology Department, Centre Scientifique de Monaco (milica@centrescientifique.mc), granted by GEMLUC.

- Dr. Jacques Pouysségur, Team Leader of the 'Tumor Hypoxia and metabolism', Medical Biology Department, Centre Scientifique de Monaco (Jpouyssegur@centrescientifique.mc).

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