Breast cancer stem cells revealed.

A fundamental problem in cancer 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. The stochastic model predicts that the tumor is relatively homogeneous and the tumorigenic mechanisms (pathways, genetic programs) that underlie the malignancy are operative in all cells. Thus, studying the bulk of the cells that make up the tumor mass can identify the key properties of the tumor. The hierarchy model predicts functional heterogeneity among the cells that comprise the tumor and that the rare T-IC are different from the vast majority of the cells that make up the tumor. Therefore, tumorigenic pathways may function differentially in distinct tumor subpopulations. This model also predicts that although eradication of the non-T-IC cells may result in a remission, the disease will relapse if the T-IC cells are not eliminated. Resolution of the T-IC problem requires both purification of tumor cells into subfractions and a functional assay to detect cells with the capacity to initiate tumor growth in vivo. The stochastic model suggests that it will be impossible to predict which kind of cells become T-IC and that stochastic events will cause T-IC cells to be found in any two sorted cell fractions with equal probabilities. By contrast, the hierarchy model predicts that it should be possible to separate T-IC from non-T-IC. Research on T-IC is most advanced for the hematological malignancies. Key to these studies is the depth of understanding of normal hematopoietic development that has been gained in the past