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Frame et al. J Cancer Metastasis Treat 2017;3:302-14 Journal of
DOI: 10.20517/2394-4722.2017.34
Cancer Metastasis and Treatment

www.jcmtjournal.com
Topic: How does the prostate cancer microenvironment affect Topic: Open Access
the metastatic process and/or treatment outcome?

Tumor heterogeneity and therapy resistance -

implications for future treatments of

prostate cancer

Fiona M. Frame , Amanda R. Noble , Sandra Klein , Hannah F. Walker , Rakesh Suman , Richard Kasprowicz ,
3
3
1
1
1
2
Vin M. Mann , Matt S. Simms , Norman J. Maitland 1
4,5
1
1 Cancer Research Unit, Department of Biology, University of York, Heslington, North Yorkshire YO10 5DD, UK.
2 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3 Phase Focus Limited, Electric Works, Sheffield Digital Campus, Sheffield S1 2BJ, UK.
4 Department of Urology, Castle Hill Hospital (Hull and East Yorkshire Hospitals NHS Trust), Cottingham HU16 5JQ, UK.
5 Hull York Medical School, University of Hull, Hull HU6 7RX, UK.
Correspondence to: Prof. Norman J. Maitland, Cancer Research Unit, Department of Biology, University of York, Heslington, North Yorkshire
YO10 5DD, UK. E-mail: n.j.maitland@york.ac.uk
How to cite this article: Frame FM, Noble AR, Klein S, Walker HF, Suman R, Kasprowicz R, Mann VM, Simms MS, Maitland NJ. Tumor heterogeneity
and therapy resistance - implications for future treatments of prostate cancer. J Cancer Metastasis Treat 2017;3:302-14.
ABSTRACT
Article history: Aim: To develop new therapies for prostate cancer, disease heterogeneity must be addressed.
Received: 22 May 2017 This includes patient variation, multi-focal disease, cellular heterogeneity, genomic changes
First Decision: 9 Jun 2017 and epigenetic modification. This requires more representative models to be used in more
Revised: 22 Jun 2017 innovative ways. Methods: This study used a panel of cell lines and primary prostate
Accepted: 14 Aug 2017 epithelial cell cultures derived from patient tissue. Several assays were used; alamar
Published: 6 Dec 2017 blue, colony forming assays, γH2AX and Ki67 immunofluorescence and comet assays.
Ptychographic quantitative phase imaging (QPI), a label-free imaging technique, combined
Key words: with Cell Analysis Toolbox software, was implemented to carry out real-time analysis of
Prostate, cells and to retrieve morphological, kinetic and population data. Results: A combination of
ptychography, radiation and Vorinostat may be more effective than radiation alone. Primary prostate cancer
live-cell imaging, stem-like cells are more resistant to etoposide than more differentiated cells. Analysis of QPI
primary cells, images showed that cell lines and primary cells differ in their size, motility and proliferation
quantitative phase imaging
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.

INTRODUCTION two sides of the same coin; because there is tumor
heterogeneity, therapy resistance is inevitable. There
Tumor heterogeneity and therapy resistance are are many different kinds of heterogeneity [Figure 1],

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