Decreased androgen-responsive growth of human prostate cancer is associated with increased genetic alterations

Genetic mechanisms involved in prostate tumor progression from the androgen -responsive to androgen-unresponsive stage are not well understood because of the tremendous heterogeneity in the tumor as well as the lack of suitabl e models. Using 165 repeat microsatellite DNA markers distributed equally o ver all of the chromosomes, we determined an association between genetic al terations and androgen-unresponsive growth in three stages of LNCaP cell mo del (C33: early, androgen-responsive; C51: mid, decreased androgen-responsi ve; and C81: late, androgen-unresponsive and increased tumorigenicity). Fur thermore, the genetic alterations were confirmed in laser microdissected no rmal and cancerous tissues from 15 clinical samples of human prostatic aden ocarcinomas using selected markers. A stem-line karyotype analysis exhibite d an identical chromosomal pattern in both C33 and C81 stage cells except f or the structural rearrangements of chromosome 3 and a gain of one copy of the Y chromosome in the androgen-unresponsive C81 stage cells. Nine microsa tellite DNA markers on seven different chromosomes (1, 4, 5, 11, 17, 18, an d 19) showed microsatellite instability (MSI) in both C51 and C81 stage cel ls. Additionally, 23 markers on 15 different chromosomes revealed NISI in C 81 cells. Chromosomal regions demonstrating allelic loss (AL) include 1q, 3 p, 5p, 8q, 9q, and 13q in C51 and C81 cells. In clinical human specimens, M SI was observed on chromosomes 1 (20%), 5 (23%), 17 (40%), and 19,(36%), wh ereas ALs were found 40% on chromosomal region 1q, 20% on 3p, 26% on 5p and 8q, and 33% on 13q. In conclusion, the LNCaP cell model showed the increas ing number of genetic changes including MSI and AL. These increased genetic alterations may be associated with the development of the androgen-unrespo nsive phenotype.