No conflicts of interest were declared.
Clonal architecture of human prostatic epithelium in benign and malignant conditions†
Article first published online: 24 AUG 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 225, Issue 2, pages 172–180, October 2011
How to Cite
Gaisa, N. T., Graham, T. A., McDonald, S. A., Poulsom, R., Heidenreich, A., Jakse, G., Knuechel, R. and Wright, N. A. (2011), Clonal architecture of human prostatic epithelium in benign and malignant conditions. J. Pathol., 225: 172–180. doi: 10.1002/path.2959
- Issue published online: 6 SEP 2011
- Article first published online: 24 AUG 2011
- Accepted manuscript online: 1 JUL 2011 08:53AM EST
- Manuscript Accepted: 27 JUN 2011
- Manuscript Revised: 24 JUN 2011
- Manuscript Received: 3 JUN 2011
- stem cells;
- prostate cancer
The location of stem cells in the epithelium of the prostatic acinus remains uncertain, as does the cellular origin of prostatic neoplasia. Here, we apply lineage tracing to visualize the clonal progeny of stem cells in benign and malignant human prostates and understand the clonal architecture of this epithelium. Cells deficient for the mitochondrially-encoded enzyme cytochrome c oxidase (CCO) were identified in 27 frozen prostatectomy specimens using dual colour enzyme histochemistry and individual CCO-normal and -deficient cell areas were laser-capture microdissected. PCR-sequencing of the entire mitochondrial genome (mtDNA) of cells from CCO-deficient areas found to share mtDNA mutations not present in adjacent CCO-normal cells, thus proving a clonal origin. Immunohistochemistry was performed to visualize the three cell lineages normally present in the prostatic epithelium. Entire CCO-deficient acini, and part-deficient acini were found. Deficient patches spanned either basal or luminal cells, but sometimes also both epithelial cell types in normal, hyperplastic or atrophic epithelium, and prostatic intraepithelial neoplasia (PIN). Patches comprising both PIN and invasive cancer were observed. Each cell area within a CCO-deficient patch contained an identical mtDNA mutation, defining the patch as a clonal unit. CCO-deficient patches in benign epithelium contained basal, luminal and endocrine cells, demonstrating multilineage differentiation and therefore the presence of a stem cell. Our results demonstrate that the normal, atrophic, hypertrophic and atypical (PIN) epithelium of human prostate contains stem cell-derived clonal units that actively replenish the epithelium during ageing. These deficient areas usually included the basal compartment indicating the basal layer as the location of the stem cell. Importantly, single clonal units comprised both PIN and invasive cancer, supporting PIN as the pre-invasive lesion for prostate cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.