targeting them may be more effective. Another debate is over the origin of CSCs - whether from dysregulation of normal stem cells or from a more specialized population that acquired the ability to self-renew (which is related to the issue of stem cell plasticity). Confounding this debate is the discovery that many cancer cells demonstrate a phenotypic plasticity under therapeutic challenge, altering their transcriptomes to a more stem-like state to escape destruction. Evidence The first conclusive evidence for CSCs came in 1997. Bonnet and Dick isolated a subpopulation of leukemia cells that expressed surface marker CD34, but not CD38. The authors established that the CD34+/CD38− subpopulation is capable of initiating tumors in NOD/SCID mice that were histologically similar to the donor. The first evidence of a solid tumor cancer stem-like cell followed in 2002 with the discovery of a clonogenic, sphere-forming cell isolated and characterized from adult human brain gliomas. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Cancer stem cells isolated from adult human gliomas were shown to induce tumours that resembled the parent tumour when grafted into intracranial nude mouse models. In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their efficacy. Tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this was explained by poor methodology (i.e., the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the CSC paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000. Further evidence comes from histology. Many tumors are heterogeneous and contain multiple cell types native to the host organ. Tumour heterogeneity is commonly retained by tumor metastases. This suggests that the cell that produced them had the capacity to generate multiple cell types, a classical hallmark of stem cells. The existence of leukemia stem cells prompted research into other cancers. CSCs have recently been identified in several solid tumors, including: Brain Breast Colon Ovary Pancreas Prostate Melanoma Multiple Myeloma Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) Mechanistic and mathematical models