Conclusions and future directions

The understanding of prostate stem cells is likely to progress rapidly in the next few years as these elusive cells are defined and isolated, and their properties are identified. Progress will require further characterization of molecular markers and the establishment of in vitro culture systems to maintain the cells. Stem cells can be transfected, and the effect of the transfected gene on the regenerating tissue can be monitored. Ultimately, this technology could be used to manipulate stem cells for clinical benefit; altering stem cell kinetics, stem cell number, and sensitivity to apoptosis.

It is increasingly obvious that, in defining the identity of stem cells at the molecular level, not only the ability of these cells to express different classes of molecules should be considered, but also the relative levels of expression. Integrin a2Pj is a case in point. The properties of stem cells are also likely to be influenced by their physical position in the context of the three-dimensional structure of the gland. Thus, cell-cell and cell-matrix

Fig. 2. Stem cell model of normal tissue renewal and prostate cancer. The malignant stem cell arises from transformation of the normal stem cell. The tumor is made up of cells that are arrested in their maturation and that do not die. The histology of the tumor reflects the stage of differentiation arrest. Androgen ablation results in overproduction of malignant stem cells and their progenitors, imparting the undifferentiated, not dedifferentiated, appearance to the tumor.

Fig. 2. Stem cell model of normal tissue renewal and prostate cancer. The malignant stem cell arises from transformation of the normal stem cell. The tumor is made up of cells that are arrested in their maturation and that do not die. The histology of the tumor reflects the stage of differentiation arrest. Androgen ablation results in overproduction of malignant stem cells and their progenitors, imparting the undifferentiated, not dedifferentiated, appearance to the tumor.

interactions become important in determining and maintaining stem cell populations.

It was through the investigation of aberrant cell growth that many of the genes involved in stem cell function were first identified. The antiapoptotic gene bcl-2 and the enzyme telomerase are expressed in high-grade PIN and are restricted to the basal compartment in normal prostate (48,58). Similarly, altered expression of growth factors and their receptors, such as EGFs and FGFs, have been implicated in the etiology of prostate cancer. It remains to be seen which members of these families play a part in stem cell identity and function in the prostate.

The cell fate decisions made by stem cells are likely to be controlled by the Notch pathway. Notch is expressed during development of the mouse and is elevated in prostate cancer (84). The phenotype of a conditional ablation of the Notch gene in the prostate will provide answers as to the role of Notch in prostate epithelial stem cell fate and cancer.

If the growth of solid cancers was driven by rare cancer stem cells, it would have profound implications for cancer therapy. Therapies that are specifically directed against cancer stem cells might result in more durable responses and even cures for metastatic disease.

It also remains to be seen if the stem cells of the prostate epithelium, like the neural stem cells (104), are capable of giving rise to differentiated cell lineages in heterologous tissue.

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