BERKELEY, CA (UroToday.com) - Castrate-resistant prostate cancer (CRPC) is the second leading cause of cancer death in men in the developed world. In the United States alone, approximately 30 000 men die annually from CRPC. While androgen deprivation therapy can be effective during the early stages of disease, nearly all prostate cancer (PCa) patients develop CRPC. Once this occurs, the PCa continuum typically leads to a fatal outcome. Although several new therapies have been introduced recently for CRPC treatment, the median survival time of men with CRPC remains only 30-36 months. The ongoing challenge is to identify new therapeutic regimens and rational targets to improve PCa patient survival.
Recent studies from our group[1, 2] and others have demonstrated that human cells and tissue release large quantities of extracellular vesicles (EVs). EVs contain a cargo of a unique array of proteins and RNAs, and can transfer these molecules to neighboring cells, altering their activities, gene expression profiles, and the expression of transferred RNAs. Successful CRPC therapy requires selective targeting of prostate cancer (PCa) cells for delivery of agents that either kill CRPC cells or reduce their tumorigenic/metastatic phenotype in a clinically meaningful manner. EVs derived from human mesenchymal stem cells (hMSC) have been shown to reverse chemo-resistance, inhibit tumor xenograft growth,[3] and induce PCa phenotype shifting.[2] hMSC EVs are physiologically well-tolerated and, therefore, have the potential to be utilized as a therapeutic delivery platform. Based on the research regarding the role of EVs in affecting the phenotype in CRPC, we propose the following working hypothesis: EVs isolated from hMSCs can induce epigenetic changes in recipient cells resulting in the inhibition of the PCa phenotype and improve the therapeutic response of patients with CRPC.
To date, the use of hMSC EVs for PCa therapy has not been explored. Given the rapid advances and emerging technologies from the EV field (e.g., exRNA communication), there is great potential for novel application(s) to PCa therapeutic development. Other, more specific facets of future hMSC EV research will address the goals of identifying biomarkers and therapeutic targets for PCa treatment, as well as the overarching challenge of developing effective treatments for CRPC. The impact of this research will provide critical insight into a new therapeutic approach to abrogate the resistance for PCa, and, if successful, will be applicable to other types of cancer. These studies will allow for the timely analysis of hMSC EVs with the goal of performing Phase 1 clinical trials with hMSC-derived EVs for the treatment of CRPC patients. The long-term impact of these studies will lead to new therapeutic strategies for CRPC, with the long-term goal of a cure for this intractable cancer.
References:
- Renzulli, J.F., Del Tatto, M., Dooner, G., Goldstein, L., Dooner, M., Colvin, G., Chatterjee, D. and Quesenberry, P. Microvesicle Induction of Prostate Specific Gene Expression in Normal Human Bone Marrow Cells. J. Urol. 2010: 184, 2165-2171. PMID: 20850816
- Panagopoulos, K., Cross-Knorr, S., Dillard, C., Pantazatos, D., Del Tatto, M., Mills, D., Renzulli, J., Goldstein, L., Quesenberry, P. and Chatterjee, D. Reversal of chemosensitivity and induction of cell malignancy of a non-malignant prostate cancer cell line upon extracellular vesicle exposure. Mol. Cancer. 2013 Oct 8;12(1):118. PMID: 24103426
- Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, Camussi G. Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev. 2013 Mar 1;22(5):758-71. doi: 10.1089/scd.2012.0304. PMID: 23034046
Written by:
Devasis Chatterjee,a Joseph F. Renzulli II,b and Peter J. Quesenberrya as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Departments of Medicinea and Urology,b Rhode Islanda and Miriamb Hospitals, Providence, RI USA
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