Tumor heterogeneity and therapy resistance - implications for future treatments of prostate cancer

Abstract

Aim:To develop new therapies for prostate cancer, disease heterogeneity must be addressed. This includes patient variation, multi-focal disease, cellular heterogeneity, genomic changes and epigenetic modification. This requires more representative models to be used in more innovative ways. Methods: This study used a panel of cell lines and primary prostate epithelial cell cultures derived from patient tissue. Several assays were used; alamar blue, colony forming assays, γH2AX and Ki67 immunofluorescence and comet assays. Ptychographic quantitative phase imaging (QPI), a label-free imaging technique, combined with Cell Analysis Toolbox software, was implemented to carry out real-time analysis of cells and to retrieve morphological, kinetic and population data. Results: A combination of radiation and Vorinostat may be more effective than radiation alone. Primary prostate cancer stem-like cells are more resistant to etoposide than more differentiated cells. Analysis of QPI images showed that cell lines and primary cells differ in their size, motility and proliferation rate. A QPI signature was developed in order to identify two subpopulations of cells within a heterogeneous primary culture. Conclusion: Use of primary prostate epithelial cultures allows assessment of therapies whilst taking into account cellular heterogeneity. Analysis of rare cell populations and embracing novel techniques may ultimately lead to identifying and overcoming treatment resistance.

Assessing the Advantages, Limitations and Potential of Human Primary Prostate Epithelial Cells as a Pre-clinical Model for Prostate Cancer Research

“…Our previous studies using this technique showed that prostate cell lines and primary prostate epithelial cells differ in their size, speed and growth rates. We also showed that the transit amplifying cells (TA) and committed basal cells (CB) found within primary cultures have different cell signatures, with the TA cells being smaller, thicker and faster than the CB cells (27).…”

“…Prostate cancer is a multifocal disease so there may be more than one tumour in each patient (26) and there is inter-patient variability. Along with this there is cellular heterogeneity within each tumour, multiple gene mutations, gene fusions and epigenetic changes (27). Finding a cellular model(s) to address all of these parameters is challenging.…”

Epigenetic Control of Gene Expression in the Normal and Malignant Human Prostate: A Rapid Response Which Promotes Therapeutic Resistance

“…Pre-treatment of the SC population with a low (non-cytotoxic) dose of Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the radio-sensitivity of the SC fraction by 20%–40%, whilst not affecting the more differentiated and radio-sensitive cells. A significant synergy with radiation after treatment with another (clinically approved) HDAC inhibitor, Vorinostat (suberanilohydroxamic acid—SAHA) was observed in multiple primary prostate epithelial cultures [102] as defined by colony forming ability.…”

Engineering Prostate Cancer from Induced Pluripotent Stem Cells—New Opportunities to Develop Preclinical Tools in Prostate and Prostate Cancer Studies

“…Prostate cancer is a biologically heterogeneous disease and its complex nature provides a significant challenge for its clinical management. The nature of prostate cancer heterogeneity is characterised by interpatient, intertumoural (multifocal disease), intratumoural, genomic and epigenetic heterogeneity, which raises considerable challenges when developing therapies [17]. Nevertheless, several genomic landscape studies of primary and metastatic prostate cancer have identified distinct molecular subtypes and potentially actionable genomic driver events [18][19][20][21][22].…”