Science overview 2006/7

The conversion of a normal cell to a cancer cell is a long and complex process that involves the accumulation of many genetic modifications. Cells have elaborate controls that prevent genetic changes, however many of these are lost during tumour development. The objectives of the research in the Institute are: 1) to understand how cells respond to agents that damage the genetic material of cells (i.e. DNA) and to resolve how these responses are altered in tumour cells, 2) to exploit the alterations of cellular response to these DNA damaging agents to produce more effective targeted therapies, and 3) to establish how inherited alterations of the cellular response determine individual risk of developing cancer or how individuals respond to therapy.

The most notable discovery this year comes from Angie Cox’s laboratory. Her research aims to understand the effect of common inherited alterations (polymorpisms) of DNA damage response genes in cancer risk and response to therapy. In the previous year she reported a novel common polymorphism that reduced the risk of breast cancer. This work has been followed up by an international consortium of laboratories that tested the effect of this alteration in populations around the world. This study revealed that the polymorphism discovered by Dr. Cox’s group is the only such marker identified thus far that reliably predicts an individual’s risk to this form of cancer. This comprehensive study has now been published in Nature Genetics. Further work in Dr. Cox’s laboratory is directed at identifying other such genes that confer risk to breast, prostate or colon cancer and to understand the mechanisms underlying this enhanced risk.

Jim Catto’s group published a series of papers reporting the relationship of genes silenced during the development of bladder cancer to the risk of progression. Many genes are turned off during the development of tumours and these changes in “programming” are thought to have a huge influence on this process. However not all the genes reprogrammed in this way affect tumour development and work in Dr. Catto’s lab is aimed at identifying those that most accurately predict progression risk.

There is increasing evidence that the control of DNA synthesis is lost as one of the earliest events in tumour development. Two research projects in the Institute over the last year have shed light onto basic mechanisms controlling DNA replication. A paper published in Nature by an international collaboration including Thomas Helleday reported that activated oncogenes eliminate important controls of DNA replication in early tumour cells. However this inappropriate DNA synthesis triggers yet another barrier to tumour development that must be broken down for tumours to form. Cyril Sanders’ group has published a series of papers describing how a DNA helicase is regulated during the initiation of DNA synthesis in a model virus system. These earliest initiation points are crucial for DNA synthesis and control of this process may offer new opportunities to stop tumour cell growth.

Aside from work being undertaken at the Institute other Sheffield researchers are undertaking exciting new projects supported by the YCR. Hypoxic areas are a hallmark feature of tumours but are difficult to access and thus treat by conventional therapies due to poor vascular supply; Prof Claire Lewis and her colleagues are developing novel strategies for targeting gene therapies specifically to these sites. They are also investigating the crucial role of tumour-associated macrophages in driving tumour angiogenesis and metastasis. A problem with potential cancer vaccines is their low innunogenicity; Andy Heath’s team is working on overcoming this by using conjugates of a monoclonal antibody CD40 to enhance immune anti-tumour responses. Colby Eaton and others are working with a self protective protein (osteoprotegrin) produced by tumour cells, to see how it affects survival in prostate cancer. Prof Nicola Brown’s team is majoring on studies to understand how proteins such as vascular endothelial growth factor and tissue factor modulate tumour angiogenesis. They are also exploring the influence of cell death mechanisms on tumour immunity. Jim Catto and colleagues are investigating another protein called Crumbs 2 as a putative new screening marker for tumour progression, and on the basic science front Prof Peter Andrews team is taking a novel approach to identifying key genes that may influence the progression of germ cell tumours by studying the regulation of pluripotency in malignant tem cells. Dr Karen Sisley and Prof Ian Rennie are investigating whether the aqueous and vitreous humors of the eye influence the growth, invasion and metastatic behaviours of a rare but aggressive eye tumour, uveal melanoma.

The main clinical research base (the Cancer Research Centre at Weston Park Hospital) under Prof Rob Coleman’s leadership continues its major involvement in clinical trails and bone oncology research.

We were delighted to be selected in a bid headed up by Prof Penella Woll, against strong competition and after detailed peer review, for Experimental Cancer Medicine Centre (in Development) status. We will receive funding for 5 years from the Department of Health and Cancer Research UK in a programme designed to underpin translational research in Sheffield and particularly the bone oncology programme. Yorkshire Cancer Research have enthusiastically indicated that they too would like to support this initiative.

Link to

YCR science overview 2002/3
YCR science overview 2003/4
YCR science overview 2004/5
YCR scienc overview 2005/6

Programme of research 2001/2
Programme of research 2002/3
Programme of research 2003/4
Programme of research 2004/5
Programme of research 2005/6
Programme of research 2006/7

Publications 2001/2
Publications 2002/3
Publications 2003/4
Publications 2004/5
Publications 2005/6
Publications 2006/7

Reports 2001/2
Reports 2002/3
Reports 2003/4
Reports 2004/5
Reports 2005/6
Reports 2006/7

Institute for Cancer Studies own site