An NC3Rs project grant to Professor Ian Mackenzie, from Queen Mary, University of London, has led to a new in vitro method for studying cancer stem cells with the potential to replace the use of some mouse xenograft studies. He has since received further NC3Rs funding.
Principal Investigator: Ian Mackenzie, Professor of Stem Cell Science
Organisation: Queen Mary, University of London
Award: £345,092, in 2009, over 36 months
Title: New in vitro assays for studying the biology of cancer stem cells
Read more about Professor Mackenzie's research
Cancer accounts for one in four deaths
There are over 200 different types of cancer. It is predicted that one in three people will develop some form of cancer in their lifetime. Although mortality rates from cancer have been decreasing over the past three decades, it still accounts for one in four deaths. Whilst many effective treatments have been developed, these do not always stop the spread or reoccurrence of the disease. There is a continuing need for new treatments.
Cancer stem cells are ‘tumour initiators’
Recent research has shown that there is a subpopulation of cancer cells that is responsible for both the maintenance and recurrence of cancers. These ‘tumour initiating’ cells are only a small fraction of the total cancer cell population and are termed ‘cancer stem cells’ because they possess characteristics of normal stem cells in that they can self-renew and give rise to other cell types. Cancer stem cells were first found in leukaemias and have since been shown in a range of cancers including those of the breast, prostate, colon, pancreas, and brain. They have also been shown to be more resistant than other cancer cells to chemotherapy and radiotherapy.
Human cancer cells are transplanted into mice to assess if they can cause tumours
The mouse xenograft model is considered to be the ‘gold standard’ for identifying and studying cancer stem cells. Cells from human cancers are injected into the mouse to determine their ability to cause tumours. However, survival of the human cancer stem cells depends on a range of factors such as the strain of mouse and the site of implantation. Consequently, studies can be difficult to reproduce and information about the survival of the cancer stem cells and/or the efficacy of potential therapeutics cannot be directly evaluated. Such studies also use large numbers of mice and are associated with suffering because of the growth of tumours.
New in vitro methods for studying cancer stem cells
With NC3Rs funding, Professor Ian Mackenzie, Blizard Institute at Queen Mary, University of London, has established and validated new in vitro systems to replace the use of mouse xenografts for studies of cancer stem cells.
Cells from a range of cancer cell lines derived from head and neck, breast and prostate cancers have been compared with cells freshly isolated from human cancer biopsies. This has shown that the cell lines, like fresh cancer cells, contain cancer stem cells with properties of self-renewal and resistance to apoptosis. To validate this, in collaboration with Dr Dana Costea at the University of Bergen, cell lines were transplanted into NOD-SCID mice to assess their tumorigenic potential and therefore the presence of cancer stem cells. This demonstrated that patterns of tumour formation by stem cell sub-populations were consistent with those found for the transplantation of fresh tumour cells.
These findings indicate that cell lines can form the basis of in vitro assays for studying cancer stem cells and for screening therapeutics. Such in vitro models also have other advantages over the mouse xenograft model – they allow individual cells to be studied directly and, since they are quick and easy to set up, they can be scaled up as high throughput assays – this is the next objective of the NC3Rs grant that Professor Mackenzie and his team are working on.
The potential to replace the use of thousands of mice used in xenograft studies
There is now considerable worldwide interest in the biology of cancer stem cells and, in particular, in their roles as novel and necessary targets for drug therapies. In the last three years there have been over 500 publications reporting the use of the mouse xenograft model to study the properties of cancer stem cells.
A typical xenograft study uses over 50 mice and therefore the adoption of in vitro assays has the potential to replace the use of thousands of animals. Moreover, with the need to test both existing and new therapeutic drugs for their effectiveness in cancer stem cell elimination, there is the potential for even greater replacement by demonstrating that in vitro systems provide effective stem cell assays.
This case study was published in a review of our research portfolio in September 2011.