Abstract 3053: Epigenetic control of cell phenotypes in the stem cell compartments of human prostate and prostate cancer: Implications for enhancement of prostate cancer therapies
Authors: Maitland Norman J. , Pellacani Davide , Rane Jayant K. , Frame Fiona M. , Collins Anne T. 
Published: May 2015

There is increasing evidence that the phenotype of heterogeneous prostate tumors can be determined to some extent by reversible (non-mutagenic/epigenetic) genetic mechanisms. In the complex microenvironment of a developing cancer, this is an excellent survival strategy. The target cell (and molecular targets) for primary therapeutic intervention in prostate cancer is frequently determined by hormone responsiveness. We have shown that, in cells fractionated from human cancers (relative to cell lines or multiply passaged xenografts), the human prostate cancer-inducing cell (TIC) is a primitive, more basal-like cell with stem cell characteristics and limited hormone sensitivity.

The TICs, and indeed normal tissue stem cells, have proven remarkably resistant to both radiotherapy and chemotherapy, as a result of their unique stem cell-like chromatin configuration, which can be ‘unlocked’ using common epigenetic control disruptors (e.g. HDAC inhibition), resulting in differentiation and the enhancement of therapeutic efficacy. This result prompted us to explore the nature of epigenetic control in multiple cellular fractions of both basal and luminal cells purified from established prostate cell lines, primary tumor cultures, primary xenografts of prostate cancer and small directed biopsies of freshly biopsied prostate tumor tissues.

The data indicate a remarkable difference between multiple ‘standard’ cell line models of prostate cancer and cell types from near-patient models. Chromatin status in terms of histone modification, genomic methylation patterns, microRNA expression are all cell-type specific, in contrast to the variable data reported in extracts of unfractionated human tumor biopsies, reflecting tissue heterogeneity. The TIC fraction has retained (or acquired) the bivalent chromatin of embryonic stem cells in a fully undifferentiated state. Dominant epigenetic signals are associated with cellular differentiation and maintenance of the proliferating luminal phenotype, which can mask underlying changes responsible for tumor induction, stem cell maintenance and metastatic capability. Therapeutic targeting of the former simply shrinks tumors without affecting metastatic induction and patient survival. Unlinked clusters of coregulated genes define the differentiation process, and contain novel molecular targets such as stem cell maintenance genes, which could render all cells in a cancer susceptible to current therapies as part of a combination treatment strategy.

The lower concentrations of stem cell modifying agents (e.g. retinoic acid and HDAC inhibitors), when used as phenotype modifiers rather than toxins, in combination with more established (cytotoxic) therapies, are more likely to be well tolerated in patients, compared to the toxic clinical doses of current ‘differentiating’ agents.

Citation Format: Norman J. Maitland, Davide Pellacani, Jayant K. Rane, Fiona M. Frame, Anne T. Collins. Epigenetic control of cell phenotypes in the stem cell compartments of human prostate and prostate cancer: Implications for enhancement of prostate cancer therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3053. doi:10.1158/1538-7445.AM2014-3053