Does prostate cancer co-opt the developmental program?
The hypothesis that cancer is a caricature of normal development and tissue renewal was originally based on descriptive studies of normal tissues and cancers. The concepts that arose from these studies were that both normal tissues and tumors are sustained by a self-renewing population of stem cells that initially gives rise to undifferentiated and highly proliferative progeny. Eventually, derivatives of these proliferating cells become growth quiescent and express differentiation markers characteristic of the organs within which they reside. A major difference between normal tissues and tumors is the impairment of differentiation in tumors such that undifferentiated, mitotically active cells accumulate in tumors. An important feature of the model is the idea that the biology of the undifferentiated and proliferating cell populations in tumors is governed by the same pathways that regulate normal development and tissue renewal. At the time these ideas were formulated, we lacked sufficient understanding of the molecular and cellular basis of prostate development and cancer progression to evaluate the validity of these ideas for understanding prostate cancer. Research in recent years has validated the prediction that cells with stem cell-like properties are a critical source of new cells both during prostate development and during prostate cancer progression. It is also the case that many of the genes that regulate prostatic development re-appear during prostate cancer progression. A closer examination of the best understood of these developmental regulatory pathways, the androgen-signaling pathway, reveals important differences between normal development and tumors. This pathway is co-opted in prostate cancer by genetic and epigenetic changes that alter the molecular details of how signaling is initiated and alter the transcriptional outcome of signaling by silencing key targets of androgen signaling and fusing androgen-responsive promoters to new genes to create new targets for androgen signaling. Future research is needed to understand if other developmental regulatory pathways are altered during prostate progression in a manner analogous to the androgen signaling pathway.
Marker
Paul C
PC
School of Pharmacy, Paul P. Carbone Comprehensive Cancer Center, Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Ave, Madison, WI 53705, USA. marker@wisc.edu