I was one of the invited speakers of this summer school and I lectured on various topics including the involvement of stem cells in cancer diseases, resistance and in particular I also focussed on pancreatic cancer. One topic regarding stem cells is that stem cells and cancer cells show quite some similarities. In fact, some of the stem cells like, for example embryonic stem cells themselves, have tumorigenic activity and for human embryonic stem cells this is actually one of the assays to prove that those cells you are assaying are indeed human embryonic stem cells. So it has been long recognised that stem cells and cancer cells have features which are highly similar.
The most recent data now even suggests that stem cells, our normal stem cells in some of our organs, are in fact the cell of origin of cancer. So, as we all know, cancer is an accumulation of different genetic lesions, different mutations which accumulate in certain cells and it turns out that probably many of the starting seeds of cancer is actually in our own stem cells. So this is caused if a stem cell is hit by a mutation, a stem cell is long lived and it can produce billions of progenitor cells, of progeny, for the rest of the life of the organism. Now if one stem cell is hit by a mutation it generates billions of cells which also have inherited that single mutation. So, basically one physical event, namely the initiation of the mutation, actually is billion-fold amplified if you hit a stem cell. If, for example, a differentiated cell is hit by a mutation which maybe lives only another week actually it dies off and with its death also the mutation is gone. So the system actually always clears mutated cells. However it cannot clear these cells if the mutation happens in a stem cell.
Could this make stem cell transplants problematic?
Not necessarily, however is there a relationship between resistance and stem cells or cancer stem cells. If you imagine or you know that our standard chemotherapy has typically three main side effects which affect highly regenerative tissues: it involves the skin – we lose the hair, it involves the gastrointestinal mucosa where we get diarrhoea and it infects the bone marrow so the haematopoietic system where we become anaemic if we are long treated with chemotherapy. Now what happens if you… chemotherapy kills typically fast dividing cells. Stem cells are typically not fast dividing and some of them are even in a deep dormancy phase. So now if you stop the chemotherapy what happens to these organs? Does the hair come back? Yes. So the gastrointestinal problems stop and the bone marrow starts working again. Why is that? That is because our normal stem cells are actually not affected by the chemotherapy. They cannot be affected because if they would be affected such drugs would be selected out because they would be too toxic. However, if basically our stem cells are the seed for the tumour, obviously these cells which are hit by the first, second, third mutation which are derived from stem cells, they obviously also are resistant to chemotherapy. This actually has founded the idea of the cancer stem cell which survives in response to therapies and often these cells are very rare. However, if you stop the therapy these cells have the clonal capacity to regenerate an organ and if they are mutated regenerate the cancer and this nicely explains why we often see relapses and metastases after initially actually a therapy which worked quite nicely to reduce the main tumour mass but these typically fail to also eliminate cancer stem cells.
Are drugs being developed to target stem cells?
Yes, there is quite some effort to target or identify markers or signalling pathways which would specifically target cancer stem cells. Or a second approach is that it turns out that like normal stem cells also cancer stem cells can be in an at least transient state of deep dormancy where they are totally insensitive to chemotherapy but also to targeted therapies. So one could imagine to activate such cells first and we know, for example in the blood system, we can activate them with interferons with LPS, mimicking viral or bacterial infection. They can be activated and after they are activated they are super-sensitive to certain therapies. So one could imagine, and that’s actually done in several labs, a two-stage targeting procedure with first activation of the cancer stem cells and then followed by a drug which actually kills these cells.
What makes this meeting unique?
It’s like all summer schools, it’s highly motivated students so they have a good mix of students who are more research oriented and some which are more clinical oriented. This interaction is absolutely critical. So the basic and the more fundamental research and mechanistically driven research actually has entered really the field with respect to clinical translation and that’s where we have to go. So we have to develop new therapies, new concepts to really target this extremely complex disease of cancer.
What is the take-home message?
Tumours are extremely heterogeneous and the more we know about the tumours actually the more complex things get. Which on the one hand is frustrating but on the other hand it’s clear that we will be able to cure cancer only if we approach it from different angles, so basically using different technologies to eliminate tumours. That involves targeted therapies, that involves probably chemotherapy, it involves drugs which kill cancer stem cells as well as immunotherapy. If we can come up with such a complex treatment strategy I’m convinced that in ten years we can cure more cancers than we can do today.
