Abstract
A successful prostate cancer must be capable of changing its phenotype in response to a variety of microenvironmental influences, such as adaptation to treatment or successful proliferation at a particular metastatic site. New cell phenotypes emerge by selection from the large, genotypically heterogeneous pool of candidate cells present within any tumor mass, including a distinct stem cell-like population. In such a multicellular model of human prostate cancer, flexible responses are primarily governed not only by de novo mutations but appear to be dominated by a combination of epigenetic controls, whose application results in treatment resistance and tumor relapse. Detailed studies of these individual cell populations have resulted in an epigenetic model for epithelial cell differentiation, which is also instructive in explaining the reported high and inevitable relapse rates of human prostate cancers to a multitude of treatment types.
Highlights
Prostate Cancer Is a Heterogeneous Disease Governed by Episodic Genomic RearrangementsHuman prostate cancer has a deserved reputation for being amongst the most heterogeneous of human tumors [1]
The effects of heterogeneity have been previously discussed in some detail [1], but the many different cell types in a “tumor” include variable proportions of stromal cells which we and others have shown to play a significant etiological role in the gene expression within the epithelial component of the cancer [6,7,8], and minor cell populations, as a result of lymphocytic or macrophage infiltration, the proportion of which is variable within the tumors, and has been shown to influence/treatment responses and patient outcomes [9]
A second historical limitation of these high resolution studies has been the need for relatively large amounts of DNA to carry out reproducible sequencing in the absence of G+C bias introduced by the need for PCR amplification at a sufficient depth of read to pick out rare populations, limiting the starting materials to an analysis of larger tumors: imposing a selection for growth and often greater heterogeneity [15]
Summary
Prostate Cancer Is a Heterogeneous Disease Governed by Episodic Genomic Rearrangements. Fewer than 50% percent of cancers show a positive response to standard of care treatment such as docetaxel, despite all tumors containing replicating cells which microtubule poisons such as Docetaxel should be able to affect [2] Whilst such heterogeneity is generally accepted, it is rarely reflected in molecular studies of the cancers, either at the phenotypic or genotypic levels [3,4,5]. Major transcriptional effectors of the stem cell state identified in promoter analyses of differentially regulated genes matched to their known expression levels in prostate epithelial stem cells. The factors which control both normal and aberrant differentiation in prostate epithelium were unknown
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