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Dr. Donald Coffey

Donald Coffey

Morphology of Prostate Cancer (PIN)


The Catherine Iola and J. Smith Michael
Distinguished Professor of Urology
The Johns Hopkins University School of Medicine

Professor of Oncology
The Johns Hopkins University School of Medicine

Professor of Pharmacology and Molecular Sciences
The Johns Hopkins University School of Medicine

Professor of Pathology
The Johns Hopkins University School of Medicine

Principal Professional Staff, The Johns Hopkins
Applied Physics Laboratory


Ph.D., Biochemistry, Johns Hopkins University, Baltimore, MD

Research Summary

For the past year, we have worked on a stem-cell model to explain why benign prostatic hyperplasia never develops on to form prostate adenocarcinomas. The general concept in oncology is that a series of multiple hits develop in the genome from a benign to a premalignant phase and finally with an accumulated genomic damage to form cancer. This is certainly not the simple case in prostate cancer, where no form of benign disease exists as a premalignant lesion and indeed only prostatic intraepithelial neoplasia (PIN) has been proposed to be a premalignant lesion. In this regard, we have carried out a series of studies on human prostate tissues to determine the stem-cell dynamics and the morphological changes associated with these early (PIN) lesions. We have used a series of stem-cell markers to show that the basal cells are the normal stem-cell component that matures into large secretory epithelial cells. We have been able to show that the basal cells undergo hyperplasia in BPH, and that in the human prostate, practically all of the proliferating cells reside within this compartment. We had earlier proposed a two-cell type of basal-cell unit in which one was a transient proliferating cell capable of rapid expansion under androgen stimulation. We can now identify these two types of epithelial cells. In contrast, in the cancer process, replication components move from the basal cells up into the secretory epithelial layers. This places these replication cells at high risk for cancer because these cells are not capable of inducing glutathione-s-transferase to protect their genome during replication. Therefore, the cells are replicating under unsafe conditions and permit genomic damage and thus carcinogenesis. Since these epithelial cells expand, cancer is characterized by the loss of the basal cell layer as they are diluted out. This is one of the hallmarks of prostate cancer diagnosis.


Dr. William G. Nelson, in our group, has reported earlier that the CpG islands in the promoter region of glutathione-s-transferase pi are all hypermethylated and that this repression is the most common genomic change associated with prostate cancer. We have used this in relation to stem-cell markers and replication indices to show that this enzyme is absent in the replicating cells in the preneoplastic lesions. In BPH, the replicating basal cells do have glutathione-s-transferase induction and are capable of protecting themselves against oxidative damage. Oxidative damage has been reported to be characteristic of the DNA from prostate cancer but not from BPH or normal tissues. The newly replicated and damaged prostate cells that occur as cancer also have activated telomerase to make them immortal. We had earlier shown that telomerase was an androgen-deregulated gene and during castration telomerase levels had been induced. This induction of telomerase with the absence of androgen is turned off with the readministration of androgen. In cancer, telomerase is on with or without androgens.

In summary, our major work has shown that the stem-cell model and the migration of these components into the upper epithelial compartment with the loss of genomic protection results in cancer, whereas in the benign disease, the replication is retained in the basal compartment that is protected. This is a major new model for understanding prostate cancer and will be a major focus of our future work. This work is being carried out in close collaboration with Dr. Angelo DeMarzo of the Department of Pathology and Dr. Nelson.

Journal Citations

Coffey, D.S.; Getzenberg, R.H.; DeWeese, T.L. Hyperthermic biology and cancer therapies: a hypothesis for the "Lance Armstrong effect". Jama. 2006 Jul 26;296(4):445-448.

Isaacs, J.T. Prostate stem cells and benign prostatic hyperplasia. Prostate. 2008 Jun 15;68(9):1025-1034.

Jubala, C.M.; Lamerato-Kozicki, A.R.; Borakove, M.; Lang, J.; Gardner, L.A.; Coffey, D.; Helm, K.M.; Schaack, J.; Baier, M.; Cutter, G.R.; Bellgrau, D.; Modiano, J.F. MHC-dependent desensitization of intrinsic anti-self reactivity. Cancer Immunol Immunother. 2009 Feb;58(2):171-185.

Kamat, A.A.; Coffey, D.; Merritt, W.M.; Nugent, E.; Urbauer, D.; Lin, Y.G.; Edwards, C.; Broaddus, R.; Coleman, R.L.; Sood, A.K. EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer. 2009 Jun 15;115(12):2684-2692.

Kelloff, G.J.; Choyke, P.; Coffey, D.S. Challenges in clinical prostate cancer: role of imaging. AJR Am J Roentgenol. 2009 Jun;192(6):1455-1470.


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