Discovery of mechanism that prevents cells from transforming into cancer cells

MRC scientists have discovered a mechanism that prevents cells from transforming into cancer cells. As cells age they enter a state called senescence, a kind of suspended animation that allows a cell to keep functioning but prevents it from changing. This state can also be triggered by what's called an 'insult' to the cell, for example a signal from a cancer-initiating gene.

In research published in Cell, the team details a number of genes, receptors and signalling molecules the cell uses to preserve itself. They reveal how some of these signalling molecules are secreted by senescent cells to reinforce the message to halt growth.

Dr Jesus Gil of the MRC Clinical Sciences Centre at Imperial College London who led the research explains:

''Previous studies have shown that senescent cells accumulate in lesions that can become malignant so it is important to learn how cells reach this stage and how they behave afterwards. Understanding how cells control their growth as they age provides an insight into how cells self-regulate to prevent cancer arising.''

Cells that are in a senescent state don't grow or divide but do remain metabolically active. The process begins in response to cell stress and helps protect the cell from the risk of succumbing to control of genes that initiate cancerous changes or being affected by damage to DNA.

Dr Gil's team set out to identify the genes that control senescence. They analysed small regions of RNA (mirror image of DNA that translates code in DNA to build proteins) to find those that extend the lifespan of cells. The small RNAs are a useful tool to identify specific genes.

Dr Gil said:

''The process of senescence begins in response to cell stress, the cell stops itself from replicating any further to prevent it from passing on the damage so senescence protects the cells from transforming into cancer cells. By looking for evidence of the mechanism that extends the life of cells we have been able to identify a self-amplifying process in which stressed or aging cells reinforce the message to stop growing.''

The search for snippets of RNA led to identification of a gene called CXCR2 and revealed that the self-amplifying network of signals revolves around molecules that bind to a CXCR2 receptor on the surface of the cell. When the action of the CXCR2 gene was 'knocked down' the cells were found to grow for longer.

This research has shown that the signalling molecules, or chemokines as they are known, that bind to CXCR2 are secreted by the same senescent cells. Commenting on the significance of this discovery Dr Gil concludes:

''Many of these secreted factors or their receptors could be targeted by drugs so understanding their role in preventing the development of cancer could lead us to new therapeutic approaches.''

Original research paper: Chemokine signalling via the CXCR2 Receptor Reinforces Senescence, Jesus Gil et al is published in Cell.

A second paper, from a research group led by Dr Daniel Peeper of NKI in Amsterdam, will be published in the same edition of Cell. It focuses on a second cytokine secreted by senescent cells, interleukin 6 (IL-6). A review of both papers is published in the 13 June 2008 edition.

http://www.mrc.ac.uk

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