Human Cancer Biology Regional Cell Proliferation in Microdissected Human Prostate Specimens after Heavy Water Labeling In Vivo: Correlation with Prostate Epithelial Cells Isolated from Seminal Fluid

Purpose: Prostate cancer is detected with increasing frequency but has a highly variable natural history and prognosis and active surveillance of men with low-risk prostate cancer would benefit greatly from minimally invasive methods to identify progression. We describe here two novel in vivo metrics of cell proliferation in men with prostate neoplasia. Experimental Design: Three groups of men drank heavy water, a nonradioactive, stable isotopic tracer for 14 to 28 days: (i) healthy men, (ii) men scheduled for transrectal core needle biopsy, and (iii) men scheduled for radical prostatectomy. Prostate epithelial cells (PEC) were isolated from ejaculated seminal fluid in all subjects. Histologically graded lesions were microdissected from tissue slides obtained from subjects undergoing surgery andproliferation ratesweremeasured from isolated cells viamass spectrometry. Results: Proliferation rates of seminal PEC in healthy men (0.10%–0.27%/d) were stable on repeat sampling. Rates above 0.34%/d were seen only in patients with cancer where rates increased progressively from normal tissue through benign prostate hyperplasia, prostate intraepithelial neoplasia, and tumor grades III and IV in all subjects. Seminal PEC kinetics correlated highly with the most proliferative microdissected region in each subject (r 1⁄4 0.94). Conclusions: Prostate cell proliferation can be measured in vivo from microdissected histopathology sections or noninvasively from seminal fluid where the latter reflects the most proliferative region of the gland. This approachmay allowmonitoring of progression inmenwith low-risk prostate cancer.ClinCancer Res; 18(12); 1–11. 2012 AACR.