SpeakersProf Peter Andrews, Arthur Jackson Professor of Biomedical Science, University of Sheffield
GF7, Byrne House
Time: 3:30 PM - 5:00 PM
The architecture of adult tissues, particularly those that turn-over during life, may be divided into three compartments of stem cells, transit amplifying or progenitor cells and terminally differentiated cells that perform the function of that tissue. This concept evolved from studies of the haematopoietic system, the gut and the skin, but stem cell compartments have since been identified in many other tissues. In parallel with these notions about tissue renewal, the idea developed that cancer results from a dysfunction of self renewal and differentiation in the stem cell compartment. When a stem cell divides, on average precisely half of its progeny must remain as stem cells, and half must differentiate or die. If more than half retain a stem cell phenotype, there is a potential for unlimited expansion of these cells and the development of a tumour. Such a development does not mean that the capacity of stem cells to differentiate is entirely lost, merely that it is reduced and unregulated. From these ideas has come the notion that the key malignant cell in a tumour is the aberrant stem cell, and that it is this cell that must be eliminated if a cancer is to be ‘cured’. Teratocarcinomas, a subset of germ cell tumours, have long provided a paradigm for the stem cell concept of cancer, and the role of their stem cells, embryonal carcinoma (EC) cells, in their development is well known. Embryonic stem (ES) cells isolated from early embryos are the apparently ‘normal’ counterpart of tumour-derived EC cells. However, ES cells may acquire non-random karyotypic changes on prolonged culture. In human ES cells, these changes typically involve gain of genetic material from chromosomes 17, 12 and X, and resemble similar changes observed in EC cells from testicular teratocarcinomas, one of the most common cancers of young men. As a working hypothesis, we can imagine that the over expression of genes located on these chromosomes increases the probability of self renewal of pluripotent stem cells, at the expense of commitment to differentiation or apoptosis. A corollary is the proposition that these genes play a key role in regulating stem cell behaviour and their disruption may affect tumour progression, particularly in germ cell tumours, in which enhanced self renewal capacity might equate to a more aggressive tumour phenotype. A key problem is to identify the genes that contribute this type of selective overgrowth of variant stem cells in which they are over expressed. The available data suggest that only a relatively small number of genes is involved, maybe as few as five, but that these may act independently on different aspects of the control of stem cell behaviour. Identification of these genes would provide the basis for developing better techniques for ES cell culture to avoid selection pressure for over-expressing variants. It may also provide insights into the development and progression of teratocarcinomas, and provide a model for understanding other stem cell based cancers.