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Induction of Prostate Specific Antigen Gene Expression in Co-cultured Normal Human Bone Marrow Cells
Joseph F. Renzulli II, MD, Gerri Dooner, MA, Anthony Mega, MD, Lisa Goldstein, MD, Gerald Colvin, DO, Peter Quesenberry, MD.
Brown University, Providence, RI, USA.

Induction of Prostate Specific Antigen Gene Expression in Co-cultured Normal Human Bone Marrow Cells
Purpose: Transfer of genetic material from cancer cells has been recently demonstrated by way of microvesicles. Cell specific phenotypes can be induced in normal cells by the transfer of material within the microvesicles leading to epigenetic changes. We report the expression of prostate specific antigen (PSA) genes in normal human marrow cells co-cultured with human prostate cancer cells.
Materials and Methods: Prostate tissue was harvested from surgical specimens of five patients with biopsy proven prostatic adenocarcinoma following elective radical prostatectomy. Histologic evaluation of the harvested tissue confirmed prostatic adenocarcinoma in four patients. One patient specimen demonstrated only normal prostate tissue in the harvested sample and was utilized as a control sample. The tissue was co-cultured with human marrow cells across a 0.4uM polysterene membrane for 7 days. Target cells were harvested and total RNA was extracted and cDNA was reverse transcribed from the RNA in our translational research labarotory. Real Time RT-PCR was performed and fold differences in expression of select prostate specific genes were analyzed (PCA3, STEAP, PART, ACPP, TMPRSS2, ERG, PSCA, ETV1, PSA).
Results: Four specimens with histologically confirmed prostatic adenocarcinoma and one specimen with normal prostate tissue (patient 1) were evaluated. Patient 2 and 3 had pathologic Gleason 9, patient 4 had pathologic Gleason 6 and patient 5 had pathologic Gleason 7 adenocarcinoma. The relative gene expression for the control specimen (patient 1) relative to the marrow control (not co-cultured with prostate tissue) was non-detectable. The relative gene expression for the remaining four patients were as follows; patient 2 (>1000 fold), patient 3 (>1000 fold), patient 4 (2-10 fold), and patient 5 (100-1000 fold).
Conclusions: Prostate cancer cells co-cultured with human bone marrow cells induce expression of prostate specific genes after 7 days. The higher pathologic Gleason grade tumors resulted in greater gene expression in the whole marrow cells. The proposed mechanism of transfer of the epigenetic material is via microvesicles. This mechanism of genetic transfer between cells may present several options for novel therapeutic agents such as antibodies to block microvesicle release from cancer cells or agents which may block naïve cells from accepting the microvesicles.


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