One of the keys for drug discovery is to be able to target the diseased pathways/cells without affecting the healthy cell/pathways. This is particularly evident in cancer, where the challenge is to target the cancerous cells without affecting healthy cells. Three recent publications have raised the bar of this for drug discovery. These studies have identified stem cells at the heart of the tumour which appear to be the drivers for certain types of cancer that are resistant to current chemotherapy. Simultaneously providing potentially revolutionary novel targets for cancer, whilst also increasing the challenge to hit these cells without targeting the healthy cells.
To put these findings in context, for some time there has been debate as to whether stem cells sit at the heart of cancers and the role that these cells may have. Up until this point, the evidence for stem cells has mainly been from immunohistochemical staining/FACs sorting and assaying them in vitro. The problem with using these methods is whether the in vivo phenotype is being altered by in vitro culturing. However, by use of lineage tracing, three separate groups (Luis Parada at the South Western Medical School, University of Texas; Cedric Blanpain of the Free University of Brussels and Hans Clevers at the Hubrecht Institute in Utrecht) in different tumours, in the brain, gut and skin, have demonstrated in each, a subpopulation of stem cells that may propagate and spread the cancer.
Glioblastoma multiforme (GMB) is an aggressive tumour that initially responds to chemotherapy however, the cancer nearly always returns. As such GBM is considered incurable and has a median survival of 15 months. In the first of these studies Chen et al., (1) used mice bred to develop GBM, in which they labelled healthy adult neural stem cells, but not their descendants, with a genetic marker. They found all the tumours again contained at least a few labelled cells, along with the unlabelled cells. Chemotherapy with temozolomide killed the unlabelled cells, but the tumours returned. When the animals were tested again, the tumours contained unlabelled cells that came from the labelled stem cells. When they used the chemotherapeutic treatment alongside a technique to supress the labelled stem cells they found the tumours shrank back to “residual vestiges” that bore no resemblance to GBM. Hence, they identified a chemotherapeutically resistant tumour cell that behaved more like stem cells. These cells themselves do not rapidly divide; however, they give rise to rapidly dividing progeny that are susceptible to current chemotherapy.
In a similar way Schepers et al., (3) used genetically engineered mice to label healthy gut cells and stem cells in benign intestinal tumours, a precursors of cancer. These labels carried a drug-inducible marker, that, when activated, fluoresce one of four colours. They found that even though the tumours consist of many different cell types, each tumour fluoresced the same colour, suggesting they arose from one single stem cell. To double check this, the researchers added a lower dose of the drug that caused the stem cells to fluoresce a different colour. In doing so, they demonstrated the stem cells were consistently producing progeny of different cell types.
In the final study Driessens et al., (2) also used linage tracing and identified distinct proliferative cell compartments within a benign papilloma. The majority of the cells had only limited proliferative potential, however a fraction had the capacity to persist long term. The former population gave rise to a terminally differentiated cell population; however, the more persistent population had stem cell-like characteristics and produced many progeny. In addition, as the tumours became more aggressive they were also more likely to produce new stem cells and less likely to produce terminally differentiated cells.
These studies present clear evidence of the existence of cancer stem cells, explaining the re-occurrence of some cancers after successful chemotherapy, but also critically providing new lines of research for drug targeting. Clearly research will now be focussed on killing these cells to eradicate the cancer, however, targeting the stem cell’s proliferative capacity, or encouraging them to differentiate into non-dividing cells may also be as effective. Since the numbers of stem cells within the tumours appear to be so small and readily able to differentiate, isolating them to study in vitro is unlikely to be fruitful. However, the labelling and tracking the stem cells and their progeny in vivo demonstrated by these groups enable these cells to be studied in vivo and will be vital for drug discovery programmes. This will enable micro-dissection; genomic sequencing and micro-array analysis to be more easily performed on a pure population of cancer stem cells to be used for target identification/validation. In addition by enabling the tracking of these cells and their progeny in vivo the efficacy of any compounds targeted to either kill the stem cells, or prevent the production of progeny could be assed relatively easily.
The challenge of targeting a small cell population that relatively little is known about, without damaging healthy tissue-resident stem cells will be great. However, the research provides great tools to aid this process together with a new way in to provide novel therapeutic agents for cancer therapy.
1. Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG, Parada LF. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature (August 1, 2012). doi: 10.1038/nature11287.
2. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature (August 1, 2012). doi: 10.1038/nature11344.
3. Schepers a. G, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, Clevers H. Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas. Science 730, 2012.