Characterisation of primitive stem cell-like canince cancer cells : identification of therapeutic targets through genomics

Previously we demonstrated tumour-initiating cells (stem cells) in tumour tissue dogs. In this study we refined the methodology and markers for cancer stem cell identification in this species. Further, we then characterised these cells at the transcriptional level to identify key pathways involved in tumorogenesis in this species and potential mechanisms involved in drug and radiation resistance. We identified a number of key molecular targets that are currently being explored as both biomarkers of disease and therapeutic benefit.

Cancer is a disease driven by a small number of tumour "stem cells" that give rise to the bulk population of cancer cells. Significantly, these cells are highly resistant to radiotherapy and chemotherapy and therefore survive conventional treatments. In this study we refined techniques to identify these cells. Further, we used complex molecular techniques to identify the differences between these cells and "normal" cancer cells at the genetic level. From this we were able to identify a short-list of genes that are critical to cancer stem cell survival and offer the potential for targeting in cancer in the dog.

We refined and characterised a number of markers and techniques for purifying cancer stem cells in dogs.
We characterised these cells in terms of their resistance to radiation and chemotherapy. From this we identified major differences in DNA damage pathways in these cells which contribute to survival of the cancer.
We used array technology to analyse the transcriptional profile of cancer stem cells versus "normal" cancer cells and mesenchymal stem cells. From this we have identified a short list of candidate genes that have the potential to be targeted therapeutically.
We identified one specific gene that is massively up-regulated in cancer stem cells in bone cancer in dogs and is of major significance therapeutically. This has implications for the management of cancer in dogs, and also could have an impact on human medicine, specifically the treatment of osteosarcoma in children.