Reverse Warburg Effect and Breast Cancer Biomarkers

I have written before about Michael Lisanti’s ‘reverse Warburg effect’ theory, and interviewed one of Lisanti’s collaborators in the UK, Dr Anthony Howell of the Christie Cancer Centre in Manchester. Briefly, the theory states that tumour cells ‘cannibalise’ surrounding tissues by creating highly oxidative conditions which force non-cancerous cells into metabolic states that produce nutrients that the tumour cells feed on. This is in contrast to the ‘classical’ Warburg theory, which states that it is the tumour cells which switch metabolic states.

This new theory radically over-turns the conventional view of tumour metabolism and makes a number of predictions which have direct clinical relevance. It also suggests that the traditional explanation of the Warburg effect is due in part to the in vitro models of cancer that have been used – in other words it’s due in part to scientists having the wrong models of cancer to play with. In the test tube isolated cancer cells do exhibit the ‘classical’ Warburg effect as they adapt to those conditions, but in real tumours the conditions are different and evolutionary pressures leads to this ‘reverse Warburg effect’.

While all of this might be of academic interest to the research scientist, does it have any relevance to the patient or the clinician? And the answer is that yes it does, in two distinct ways. The first is the new theory makes some specific predictions on how tumours behave and on how they interact with the surrounding tissues. In particular the theory suggests some new biomarkers that can be used to identify patients at high risk of early breast cancer recurrence, metastasis, drug and hormone resistance and decreased survival. Secondly, and linked to the first point, the new theory suggests some interesting new avenues to explore for treatment.

In a new paper, Lisanti and his team examined tumour samples from 180 triple negative breast cancer patients looking for specific markers related to his theory. The results of tissue analysis showed that having high levels of MCT4 (a marker of hypoxia, oxidative stress and aerobic glycolysis) in the tumour stroma (the cells that surround the tumour) was highly related to a decreased overall survival rate. This is a significant finding, being able to identify those patients at highest risk is vitally important.


Furthermore, based on the theory and supported by these and other results, there are suggestions that interfering with the reverse Warburg effect can have direct therapeutic benefits. In this latest paper, Lisanti and colleagues list a number of existing drugs that should be explored, including the anti-oxidant N-Acetyl-Cysteine (NAC), the anti-diabetes drug Metformin (and there is already lots of evidence for the anti-cancer effect of this) and Hydroxy-Chloroquine.

This latest paper adds to the growing number of studies that support the new theory, and which are pointing more and more to direct therapeutic benefits.

What we need to see now, as a matter of priority, are the clinical trials necessary to prove that the theory is correct and that the proposed therapies show benefit to patients.

The new paper, fortunately available on open access, is available here: http://www.landesbioscience.com/journals/cc/article/19530/