The clonal nature of most malignant tumors is well established. Experiments spanning several decades have shown, however, that as many as one million murine or human tumor cells are required to transplant a new tumor from an existing one. Two theories have been developed to account for the observation that apparently not every tumor cell is a tumor initiating cell (T-IC). The stochastic theory predicts that every tumor cell can form an entirely new tumor; however, entry into the cell cycle is a stochastic event with low probability. Alternatively, tumor cells may exist in a hierarchical state in which only a small number of cells possess tumor initiating potential. If the stochastic model is correct, then tumor cells are biologically homogeneous and genetic or epigenetic programs that allow for tumorigenesis are operative in the majority of cells that comprise a tumor. The hierarchical model, however, predicts the tumor cells possess a functional heterogeneity and that quantitatively the cells capable of tumorigenesis are a relatively minor population among the bulk of tumor cells.
Recent data from both hematologic malignancies and solid tumors have suggested that there are only minor populations of cells in each malignancy that are capable of tumor initiation. These T-ICs have the functional properties of tumor stem cells. They appear to be capable of asymmetric division and self renewal, are only a minor faction among the bulk of more differentiated cells in the tumor, and can reconstitute all the cell types in the tumor of origin.
Currently, tumor stem cells have been isolated and characterized in several hematologic malignancies and some solid tumors. One of the first tumors in which a stem cell was identified was acute myeloid leukemia (AML). In this disease, the frequency of the leukemic stem cell (LSC) was approximately 1 per million AML blasts, establishing that not every AML cell had T-IC capacity. A CD34 positive/CD38 negative cell fraction representing 0.1 to 1 percent of the tumor cells possessed all the leukemia initiating activity in the NOD/SCID transplantation model. By contrast, the major fraction of the CD34 positive/ CD38 positive cells and the majority of CD34 negative cells, which comprise most of the cells in the tumor, could not initiate leukemia. A multiple myeloma stem ceil has also been characterized. Multiple myeloma cell lines and primary patient derived cells express the cell surface marker syndecan-1 (CD138). A population of cells representing less than 5 percent of the cells in the bulk population of multiple myeloma cells was found to be CD138 negative, and possessed in vitro clonogenic potential. These cells also engrafted successfully into Non-obese Diabetic/Severe Combined Immunodeficient (NOD/SCID mice), whereas CD138 positive cells did not engraft.
Recently, a mammary carcinoma stem cell has been isolated from primary mammary carcinomas using four cell surface markers (CD44; CD24; a mammary tumor marker, and epithelial specific antigen). The tumor initiating capacity of the cells was again verified in an in viva NOD/SCID engraftment assay. The mammary tumor stem cells represented only 2 percent of the unfractionated bulk tumor cells.
Finally, a putative brain tumor stem cell has also been isolated. These cells appear to be between 0.3 to 25 percent of the cells in the brain tumors examined. They are positive for the neural stem cell marker CD133 and have a marked capacity for self renewal and differentiation. Transplantation of these putative neural tumor stem cells into the forebrains of NOD/SCID mice yields tumors phenotypically resembling the tumors from which the stem cells were isolated.
Isolation of tumor stem cells front a larger spectrum of solid tumors and characterization of markers for such cells will be important in understanding how general the role of tumor stem cells are in the pathogenesis of cancer.
In addition to isolating and characterizing tumor stem cells themselves, it is also important to identify the genes and proteins that facilitate the self renewal phenotype that characterize all stem cells. …