Afundamental problem in can-cer research is identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumor-initiating cell (T-IC) function and are capable of maintaining tumor growth.

A remarkable series of transplant experiments from the 1950s, which reflect the state of human experimentation of a bygone era, demonstrated that autologous injection of tumor cells into the thigh could only be initiated if 106 tumor cells were injected (1). Subcutaneous injection of human tumor samples into mice gave similar results. Two theories were developed to explain why not every cell within a tumor was capable of regenerating the tumor (2). The stochastic theory predicts that every cell within the tumor is potentially tumor-initiating but entry into the cell cycle is governed by low probability stochastic events. By contrast, the hierarchy theory proposes that the tumor is functionally heterogeneous and only a limited number of cells are capable of initiating the tumor. However, cells of this class all initiate tumors at high frequency. Although each theory predicts that a limited number of cells within a tumor will initiate tumorigenic growth, the underlying biological mechanisms are radically different.