22nd European Association for Cancer Research, Barcelona, 8th July 2012
Circulating metastasis-initiating cells in breast cancer
Professor Andreas Trumpp – German Cancer Research Centre (DKFZ), Heidelberg. Germany
There are probably several different types of cancer stem cells and we know that tumours are very heterogeneous and are, in many instances, hierarchically organised in a way, so like a pyramid and on top of that pyramid you have what we call the cancer stem cell. It’s more malignant, it has the capacity to re-initiate the tumour, it’s often more resistant to chemotherapy, to radiation therapy, even to targeted therapy and can also initiate metastasis, which is the main problem clinically. So most patients die of metastases, not of the primary tumour, and we feel that often there is not enough emphasis on studying really the metastatic process rather than the primary tumour.
What is your lab working on?
We work on pancreatic cancer but also on breast cancer and today, here in Barcelona, I talked about a project to identify metastasis-initiating cells which circulate in the blood of breast cancer patients. That there are epithelial tumour cells circulating in the body through the blood system has been recognised for quite some time but there was no real biological or functional assay to identify which cell, indeed, can initiate metastasis. That was the focus of that project and so we started a study with a total of 600 breast cancer patients where we took blood for all of these and followed first the number of circulating tumour cells but then did functional assays. So we purified these, we identified a number of markers or receptors which are present on these cells which make them particularly malignant and also stem cell like and by transplanting these into immunocompromised mice, they were able to form bone metastases and these metastases looked extremely similar to the metastases you found then in the patients. We identified a number of markers and receptors which not only explain why these cells are so highly malignant and have stem cell characteristics, but we may use these markers to better diagnose incoming breast cancer patients into a high-risk or low-risk group. Last, but not least, some of these receptors, there are already inhibitors in the pipelines of several pharmaceutical companies and so maybe some of these inhibitors could be used to prevent or even target breast cancer metastases.
The patients we have so far analysed are breast cancers in progress, so they either have local reoccurrence, they relapsed or they became metastatic. Now the data we have, we now go back to patients who are at M0, so don’t have metastases yet. But nevertheless we identified, for example, one receptor called CD47 which, if expressed already in the primary tumour, the prognosis of these patients is much worse, they only survive half as long as the ones who have CD47 not in the primary tumour. This receptor, from our data, looks like it’s switched on at the moment metastasis starts. So it may also be used to better stage the patients, also the molecular level. If you are negative you can be almost certain that there are no local or distant metastases, if you are positive then there’s a worry that already the disease has spread.
Can the marker be targeted?
There are instances for them in the group from Irving Weissman and colleagues, they work already, for several years now, on CD47 and they work on a targeting strategy for CD47. It actually is a ligand which blocks macrophages or other phagocytic cells to eat up the tumour so it’s also called a ‘don’t eat me’ signal. It prevents the inate immune system from recognising these tumour cells and phagocytosis them so if they express high level then this is not happening. It’s a strategy of the tumour cells to escape the immune system in the blood.
What is the difference between circulating stem cells and circulating endothelial cells?
The significant heterogeneity already in the primary tumour, as I mentioned, the primary tumour is already hierarchically organised and cells from the top of the hierarchy and the middle of the hierarchy or the bottom of the hierarchy, they can all enter the bloodstream. So far they are just measured independent of the knowledge of where they come from. Now it looks like only the ones from the top of the hierarchy, only these can restart a tumour whereas the other ones cannot. So if you want to make better prognosis or better diagnostics, we should only measure the ones from the top of the hierarchy with stem cell characteristics and not all the tumour cells. From our studies, we would predict that the percentage of tumour of metastasis initiating cells in the blood ranges between 1-50%. So in some patients it may be a very small number of these cells are really the bad ones, only 1%, so we should try to measure only these and not the 99% which are not doing anything anyway.
