Not enough oxygen in tumor tissues

The identification of this phase transition provides an explanation for the disappointing results obtained during tests aimed at inhibiting mTor activity in order to prevent the progression of tumors. “Oxygen pressure is greatly reduced in most solid tumors and if these tumors have an oxygen pressure of between 1.5 and 2%, the mTor inhibitors are not effective”, stresses Françoise Remacle.

In order to identify this phase transition, researchers used an advanced technology called “microchips”, which was developed by James Heath. This technique makes it possible to analyse the molecular signalling of mTor for single cells. “In chambers with a volume in the order of a nanoliter you can measure the concentration of proteins which are secreted in a single cell”, explains Françoise Remacle. “Based on data gathered for 1000 chambers par example, we can then construct a histogram of the measured concentrations. It is very important to be able to characterize the signalling pathways and understand the fluctuations in the response to an external change such as oxygen pressure in this case”, she continues. From this, the scientists created a covariance matrix which makes it possible to describe the interactions between the different proteins measured. “Having made these measurements at different oxygen pressures, we were able to identify an oxygen pressure for which this matrix has a nil eigenvalue and this is the point at which there is a phase transition”, indicates Françoise Remacle. Moreover, this matrix also supplies information about the involvement of proteins analysed in different signalling pathways.

Results confirmed by tests on two models

These analyses based on concepts and methods of physical chemistry have made it possible to understand at which point mTor activity “ switches ” from one signalling pathway to another and at what values of oxygen pressure this protein cannot be inhibited. “ The results we obtained were confirmed by tests carried out on two types of tumor cell models: a GBM cell culture (GlioBlastoma Multiform, a type of brain cancer) and a neurosphere cell culture from a GBM tumor originating from a transplant on humans”, continues Françoise Remacle.

This discovery could have implications for hopes placed in the use of mTor as a therapeutic target in the fight against cancer. The hypoxia observed in many solid tumors is linked to vascularization and tissue density. “I do not believe that we can adjust the oxygen pressure in a tumor in order to attempt to improve the mTor response to inhibitors”, explains Françoise Remacle. “There are other promising proteins which have been identified as targets for halting the progression of tumors.  It would perhaps be necessary to decide to target these other proteins”, she concludes.