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Scientists reveal how indestructible cancer cells survive

Worldwide Cancer Research scientists have identified a protein ‘switch’ mechanism which allows cancer cells to survive with no blood or energy supply. The findings, published this week, provide important clues that might help researchers understand the resistance to drugs that ‘starve’ tumours and also how cancer cells manage to survive in the centre of the tumour mass, where barely any blood vessels can reach.

Fighting to survive

The main goal of a tumour cell, above all, is to survive. To do this, it is equipped with skills that healthy cells do not have, including the ability to continue growing when glucose levels are very low. This could be one of the reasons widely-used anti-angiogenic agents often fail to eliminate cancer, no matter how much they starve it by hindering the development of the blood vessels that provide nutrients and glucose. Now, a group of CNIO researchers have identified one of the key biochemical mechanisms that allow cancer cells to survive without glucose.

In particular, they have discovered a group of proteins that actually act as a switch: when food -glucose- is available, tumour cells use a particular biochemical path to survive and continue to proliferate; when there is no glucose, the switch triggers a different path to achieve the same goal, namely the survival of the tumour cells.

Whatever it takes

As explained by Dr Nabil Djouder, researcher at the CNIO and author of the paper published this week in Cancer Cell,

"Tumour cells are very smart; when one door that seemed essential for their growth and proliferation closes, they open new ones that allow them to adapt to any stress and survive. This is why they develop highly sophisticated mechanisms and learn to survive, and why it is so difficult to cure cancer."

For years researchers have been wondering how tumour cells manage to survive in the in the centre of a tumour mass, where barely any blood vessels can reach, and this research answers an important part of the puzzle. The discovery also helps address the urgent need to understand the resistance to anti-angiogenic agents, one of the most widely-used anticancer drugs, whose effectiveness is based on preventing the growth of the blood vessels that supply the tumour, thus starving the cancer cells of nutrients.

Now for the scientific bit…..

Everything that happens in a cell is based on a series of biochemical reactions. In a very simplified metaphor, it is like a circuit with numerous switches that connect or disconnect. Dr Djouder and his team have identified the system of switches that allows cells to detect whether or not there is glucose, and then to decide, what biochemical path they must follow in order to survive.

The sophisticated system is composed of three proteins: URI (which acts as the switch), OGT and c-Myc. c-Myc is a well-known oncogene, meaning it is a cancer causing gene and it encourages cell proliferation and survival. However, Dr Djouder’s group discovered that c-Myc protein levels play a pivotal role for cancer cell survival when glucose levels are low.

The sequence of events

Here is what happens:

  • URI is the boss at the top and controls OGT activity.
  • OGT is middle management, reporting to URI. It senses and uses glucose to control c-Myc levels.
  • When glucose is present, OGT uses it to stabilize c-MYC levels, which in turn carries out its role as an oncogene.
  • When cells face a glucose shortage, the boss URI turns down OGT activity which reduces its use of glucose, leading to c-Myc being destroyed.
  • The result is that in the absence of glucose, the survival of the cell depends on URI which has oncogenic activities.

“Our findings suggest an important glucose-sensing mechanism in which URI acts as a regulator, controlling OGT activity and therefore c-MYC levels, and allowing cancer cells to tolerate severe nutritional stress situations”, says Dr Djouder.

“This mechanism can be of general importance in tumorigenesis and may explain how cancer cells exposed to glucose deficiency can proliferate instead of regressing”.

What next?

This is early-stage research and far from having any clinical applications but it opens up exciting lines of further investigation. An obvious strategy would be to hijack the action of URI but URI is a protein whose functions are not yet sufficiently known and it must first be confirmed that it doesn’t have a key role in healthy cells. This is something that Dr Djouder and his group at the CNIO fully intend to investigate with the remaining time on their Worldwide Cancer Research grant.

Additional information:

This study was funded by grants from the Spanish Ministry of Economy and Competitiveness and Worldwide Cancer Research.

Written by CNIO Communications Team and edited by Dr Lara Bennett at Worldwide Cancer Research.

Image kindly provided by Dr Alexander Bird.

Reference article:

Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. Stefan Burén, Ana L. Gomes, Ana Teijeiro, Mohamad-Ali Fawal, Mahmut Yilmaz, Krishna S. Tummala, Manuel Perez, Manuel Rodriguez-Justo, Ramón Campos-Olivas, Diego Megías y Nabil Djouder. Cancer Cell (2016). DOI: http://dx.doi.org/10.1016/j.ccell.2016.06.023

Science Communication Manager at Worldwide Cancer Research

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