Resolution of Cellular Heterogeneity in Human Prostate Cancers: Implications for Diagnosis and Treatment
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Prostate cancers have a justified reputation as one of the most heterogeneous human tumours. Indeed, there are some who consider that advanced and castration-resistant prostate cancers are incurable, as a direct result of this heterogeneity. However, tumour heterogeneity can be defined in different ways. To a clinician, prostate cancer is a number of different diseases, the treatments for which remain equally heterogeneous and uncertain. To the pathologist, the histopathological appearances of the tumours are notoriously heterogeneous. Indeed, the genius of Donald Gleason in the 1960s was to devise a classification system designed to take into account the heterogeneity of the tumours both individually and in the whole prostate context. To the cell biologist, a prostate tumour consists of multiple epithelial cell types, inter-mingled with various fibroblasts, neuroendocrine cells, endothelial cells, macrophages and lymphocytes, all of which interact to influence treatment responses in a patient-specific manner. Finally, genetic analyses of prostate cancers have been compromised by the variable gene rearrangements and paucity of activating mutations observed, even in large numbers of patient tumours with consistent clinical diagnoses and/or outcomes. Research into familial susceptibility has even generated the least tractable outcome of such studies: the genetic loci are of low penetrance and are of course heterogeneous. By fractionating the tumour (and patient-matched non-malignant tissues) heterogeneity can be resolved, revealing homogeneous markers of patient outcomes.
KeywordsProstate cancer Heterogeneity Epigenetics Gene expression
The authors wish to thank all members of the York CRU in recent years for their obvious or unconscious support in the preparation of this review. The underpinning research was funded by Yorkshire Cancer Research (NJM-Y257PA), York against Cancer (JRP), Prostate Cancer UK (Innovation Award RIA15-ST2-022(FMF) and Studentship S13-016 (LKA)), Charity Soul, with the major contributions from The Freemasons of the Province of Yorkshire (North and East Ridings), The Masonic Samaritan Fund (DP) and the EU Marie Curie ProNEST Network (JKR). Finally, we wish to acknowledge the generosity of the many prostate cancer patients and their families who donated tissues under our ethical protocol for research purposes.
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