Cell of origin role in cancer stem cell and GBM phenotype
Dr Luis Parada - Memorial Sloan Kettering Cancer Centre, New York, USA
We work under the hypothesis that many forms of solid tumours grow in a hierarchical fashion which is to say that at the apex there is a so-called cancer stem cell that is responsible for the propagation of the tumour, would be then, by definition, responsible for re-emergence of the tumour following chemo and radiotherapy. So we believe that it’s identifying and isolating this cell that is most important at targeting the real tumour because, in fact, most of the current therapies are aimed at dealing with cells that proliferate and they also kill normal cells that proliferate. Here, what we believe is that, in fact, the proliferating cells are actually the by-product of the cancer stem cell and that the cancer stem cell is really the important one that we must understand and target effectively.
The interesting concept here is that, in fact, a corollary of our hypothesis is that, in fact, most cells in an organ are not capable of giving rise to a tumour but that there are exactly specific constraints on the type of cell that it can actually give origin to a tumour, we refer to that as the cell of origin, the cancer or tumour cell of origin, and we believe that in most cases this is either an organ stem cell, an adult organ stem cell, or its immediate progenitor. At least experimentally, using mouse models which is what we do, we’ve shown that, in fact, in the brain only stem cells and progenitors can give rise to a brain tumour called glioblastoma and that, in fact, the more differentiated cells in the brain are incapable of giving rise to these tumours. So this adheres to our hypothesis and now we’ve devised tools, at least in mouse models, where we can prospectively identify the cell of origin and we can also identify the cancer stem cell. So our hope is that through the isolation and study of these cells we can then translate our information to human glioblastoma and to patients.
Tell me about your talk on neurofibromatosis-1
Sure, so neurofibromatosis type 1 is the most prevalent genetically inherited disease of the nervous system. People with NF1, as it’s commonly called, can suffer a panoply of different kinds of ethologies ranging from intellectual deficits to autism to structural abnormalities in their bones but, most importantly and most prevalent, is presence of tumours in their nervous system, in both the central nervous system, brain and spinal cord, but also in the peripheral nervous system. So they suffer from tumours called neurofibromas and other tumours called malignant peripheral nerve sheath tumours, both of which are completely recalcitrant to all known cancer therapies. So what we’ve been able to do is to successfully model these tumours by virtue of exactly the same mutations in human patients using our genetically engineered mice and we’ve devised strategies to better understand how these tumours arise, what their constraints are and do they have cancer stem cells. Happily the answer to the latter question is yes and we’re now able to identify these cancer stem cells. So I’ve put together leaders in the field of neurofibromatosis for the symposium tomorrow and they’re going to be discussing the most recent advances in terms of therapies for patients, the very first therapies that are actually making a difference in the clinic.
It’s an amalgamation of a rather new idea about how solid tumours grow. Some would call them still controversial ideas but we feel that we are making experimental headway and really demonstrating that this is an important new way of looking at how tumours grow and at realising that there is a quiescent component to the tumour which is the one that we really must target.
Do you have any advice for clinicians?
Yes, I think that by virtue of isolating the properties of the cancer stem cells there will be new therapies that will either unmask them and cause them to enter the cell cycle so that they become responsive to therapy or, alternatively, completely novel therapies that target the stem cells and not normal cells.
What is your take home message?
I would just say that this is an extremely exciting time to be a cancer researcher with the coming together of the wealth of genomic information coupled with the biology, and I can’t emphasise that enough. The biology of the tumours, where they come from, how they grow and their natural history is a fundamentally important component of cancer biology that is not trumped by knowing the panoply of mutations in a tumour. So I think that I would caution the young researchers in the field to never forget about the biology, the cell of origin and the natural history of a tumour.