A breakthrough study in the journal Nature provides the first evidence for genetic diversity of cancer propagating cells within individual patients.  The study in Acute Lymphoblastic Leukaemia (ALL) patients, say UK investigators from the Institute of Cancer Research (Sutton), John Radcliff Hospital (Oxford), University College (London) and Newcastle University, provides important insights into the reasons why some cancers can prove notoriously resistant to treatment.

Cancer stem cells have been widely regarded as the “bull’s eye” for drugs to target. However, the latest findings suggest there is no single bull’s eye, but instead multiple moving targets that are responsible for reducing the effectiveness of targeted treatments.

Using multiplexing fluorescence insitu hybridization probes, Mel Greaves and colleagues showed that up to eight genetic abnormalities could be detected in single cells.  From their work a genetic picture of subclones could be drawn up leading to the development of a composite picture of subclonal architecture.

The investigators believe that in the early stages of the disease the original cancer stem cells produce distinct “subclones” of themselves , with each of these sub-clones containing different combinations of genetic mutations and will go on to develop further sub-clones independently of each other. “Our data suggest dynamic patterns of subclonal development that are nonlinear with a variable branching architecture,” write the authors.   While some sub-clones will be destroyed by drugs, other branches may be resistant to treatment and become dominant, driving the cancer forward.

Furthermore, investigators showed that when leukaemia subclones were serially transplanted into mice, they also revealed the same “branching” patterns. Clonal architecture is dynamic and is subject to change in the lead-up to diagnosis and relapse, add the authors.

Drugs, say the investigators, are more likely to be effective for longer if they target properties shared by all cancer stem cells in each patients. In future research, the authors say, it will be important to assess if the genetic diversity of propagating cells holds true for other types of leukaemias and for cancer in general.

Reference

K Anderson, C Lutz, F van Delft et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2010 . Doi: 10.1038/nature09650.