university of york
Science oveview 2006/7
The YCR Cancer Research Unit
Since 1991 we have set out to increase understanding of the molecular basis of human prostate cancer. An increasing male population over the age of 50 has seen prostate cancer incidence rise and, if detected late, the prognosis is uniformly poor. Even optimised treatments often fail to significantly change by more than a few months the life expectancy of the unfortunate patients. We still do not know what causes prostate cancer.
So, just why is this? Prostate cancer has a reputation of being a heterogeneous disease composed of many different cell types, which is difficult to diagnose precisely. Through the efforts of Dr Anne Collins in developing a method to select and culture a particularly virulent population of cells from prostate cancer, now known as cancer stem cells, we have begun to understand some of the scientific reasons behind not only the variability of the disease, but also its ability to resist most common therapies, using agents which have been proven successful in other cancer types.
So where do these cancer stem cells come from? Originally, we believe they derive from the normal prostate tissue stem cell. These are long lived cells which give rise to the others which make up the "business end" of the prostate, ie the secretion of proteins which allow sperm to flow freely and, therefore, promote fertility. When they go wrong they begin to lose control of their growth and also the pre-programming control which allows them to produce daughter cells.
Our results indicate that the cancer stem cell has much in common with its normal counterpart, but has many distinctive differences. Firstly, very small numbers of purified cancer stem cells are required to start a new cancer, relative to the bulk population of a tumour which has a very low cancer inducing potential. Current therapies are targeting this bulk population, which is logical since they are the most common cells in the tumour, but the data generated in York for prostate cancer and elsewhere in the world for breast, lung, colon cancers and various types of leukaemia, indicates that, in combination with destruction of the tumour mass it may well be important, in order to achieve a cure, to target the very small and very different cancer stem cell population.
We now have a catalogue of genes from prostate cancer stem cells which has revealed some clues to their nature and to their origin. For example, they express many genes associated with inflammation, a feature which has been implicated in the induction of many cancers, particularly including prostate cancer for almost 20 years. We also know that they have stopped communicating with their nearest neighbours.
Therefore, with the start of a new funding period from YCR in 2007, emphasis will switch from discovering the cells which are the source of prostate cancer, and their incredible variability, to this ever present population of cancer stem cells. We will try to understand how these various genes affect the behaviour of the cancer cells, ie how does it grow within the prostate, does it move outwith the prostate, and if it does, why does it grow in the bone rather than many other sites in the body?
In addition to the substantial funding from Yorkshire Cancer Research further support has been obtained over the last twelve months from the National Cancer Research Institute, the US Department of Defense and the European Union through their framework programmes of research.
The expression catalogue also tells us much about the ability of prostate cancers to develop resistance to therapy. While most of the bulk of the tumour is exquisitely sensitive to drugs which block the androgen receptor, for example, and drugs which inhibit the rapid cell growth which is characteristic of most cancers, the cancer stem cell appears to be resistant to radiation therapy as well as chemotherapy. It will be a hard nut to crack when it comes to ultimate curative therapies.
To be able to kill cancer stem cells, you have to see them. Since our best estimates for the number of cancer stem cells within any tumour is fewer than 1 in 1,000, this poses real difficulties in monitoring their responses to therapy. Last year we began a new project to specifically label the cancer stem cells using a stripped down version of the virus that causes AIDS. After 12 to 18 months work we now have a number of cancer stem cells which fluoresce red, allowing us for the first time to be able to track their progress.
Colony of Cancer Stem Cells from Prostate Cancer expressing a Red Fluorescent Protein
(Image courtesy of Stefanie Hager, YCR Cancer Research Unit, University of York)
The greatest challenge, however, remains finding ways to kill these inherently resistant cells. Although we have still to prove it, the chances are high that they exist deep within the tumour mass in a "niche" which is designed to protect them and to preserve their stem cell characteristics. As a result of a long term collaboration between ourselves and the University of Sheffield, funded by YCR and also supported by the UK National Cancer Research Institute, we have now demonstrated that macrophages "armed" by infection with a therapeutic virus can penetrate deep into prostate tumours to the very area where the cancer stem cells are likely to reside deep within the tumour. Although at a very early stage, this offers some hope in the quest for stem cell specific gene therapies to complement a new generation of drugs to target the cancer stem cell population.
YCR p53 Research Group
Exploring new avenues that may enable selective killing of cancer cells. In the YCR P53 Research Laboratory at York we are developing new methods to study how cancer cells differ from normal non-cancer cells. Such differences affect the way cancer cells grow and divide in the body. They also indicate conditions that are essential for cancer cell survival but which are non-essential for normal cells. Thus our research aims to identify novel targets for selective killing of cancer cells without adversely affecting healthy cells in the body. Most conventional anti-cancer therapies damage both cancerous and normal tissues and this is what causes the unwanted side effects of anti-cancer treatment. At York we aim to identify new anti-cancer targets that will allow selective anti-cancer therapy without damaging the whole body or normal tissue close to the cancer site. For our experiments we employ cells lines derived from human tissues of normal and of cancerous origin. Importantly, our experiments include cancer cell lines that are also employed in the NIH (National Institutes of Health, USA) screening panel of cell lines for evaluation of new anti-cancer agents developed world-wide.
The Post Doctoral Scientists involved in this research are Dr. Shafiq Ahmed, Dr. Simon Allison, Dr. Jack Ford, Dr. Ming Jiang and Dr. Lorna Warnock. The smooth running of the lab is managed by our excellent technicians Sally Raines and Julie Mercer.
Over the past year we have presented our work at numerous international and national meetings and at invited international and national seminars. Cian Lynch (a PhD research student) presented his work in poster form at the 2006 P53 Workshop held in New York, USA. These workshops are held once every two years and provide a forum for around 200 top ranking International Scientists to discuss their work on P53. Exactly what is p53 and why is it so important? P53 is the body's natural defence against cancer. It is a protein and is inherited through the p53 gene. If the p53 gene is damaged (or mutated) the effect is transmitted to the p53 protein which loses its ability to protect against further genetic damage and cancer. Carcinogens in cigarette smoke damage the p53 gene and this is the major cause of lung cancer. Sun-bathing and exposure to ultraviolet light (UV) also damages p53 and causes skin cancer. Over half all cancers can be traced back to damage of the p53 gene. Usually such damage is acquired during our life-time. However, some very unfortunate individuals inherit a damaged p53 gene from their parents. This means that every cell in their body is carrying mutant abnormal p53. The result is that such individuals develop cancer at a very early age. Why loss of only one (of the two) p53 genes should have such a devastating effect is unknown and has puzzled scientists for many years since the remaining normal gene should be sufficient to fulfil the role of p53 as a tumour suppressor. Cian Lynch has been investigating this phenomenon and has discovered that loss of one p53 gene unexpectedly causes a four-fold reduction in expression of the remaining normal (wild type) p53 gene. This reduction takes p53 below the threshold required for its anti-cancer protective functions.
As always international communication and collaboration between scientists is hugely important. In one collaboration, involving laboratories in York, London, Sweden and the USA we have finally completed a project started 10 years ago in the YCR Research Lab here at York. This project aimed to resolve the molecular structure of the p53 protein in its normal state. Such information is vital for the development of therapeutic agents designed to restore function to damaged p53. Using a technique called cryo-electron microscopy, and freezing purified p53 protein in liquid ethane, we obtained a revolutionary structure for p53 which appears as a skewed cube assembled from four p53 molecules. Future studies aim to analyse the effects of common mutations on p53's structure and hopefully identify ways in which p53 can be restored to its normal functional state.
In April 2006 Jo Milner initiated and co-organised an international workshop funded by the European Molecular Biology Organization; other co-organisers were Julian Hiscox and Carlos Rubbi, and Julie Wainwright did a wonderful job of managing all on-site accommodation and organisation at York. Award of EMBO Workshop funding is highly competitive and prestigious. The actual meeting was a great success and was written up in the journal EMBO Reports (What is new in the nucleolus? Workshop on the Nucleolus: New Perspectives. Matthews D.A. & Olson M.O.J. EMBO Reports 7: 870 - 873. 2006).
Jo Milner also presented our YCR funded research at numerous international meetings and seminars, and was honoured to be included as one of five international speakers at the celebration meeting to mark the opening of a major new Research Centre at the Heinrich-Pette Research Institute, Hamburg, Germany.
Whilst our research progresses into the future, our past research continues to attract pharmaceutical companies interested in taking our laboratory-based discoveries forward towards the cancer clinic. This is particularly rewarding and underscores the importance of our YCR-funded research for the development of novel anti-cancer therapies and for patient benefit.
Link to
YCR science overview 2002/3
YCR science overview 2003/4
YCR science overview 2004/5
YCR science 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
Programme of research 2007/8
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
Reports 2007/8
YCR Cancer Research Unit
Professor Norman Maitland's site
Professor Jo Milner's site (p53 Research Group).
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