Abstract
Hormone-refractory prostate cancer, a heterogeneous disease, has varying degrees of androgen sensitivity. To understand the physiological changes in the hormone-refractory state, the present study used a lineage-derived androgen receptor (AR)-positive, androgen-insensitive prostate cancer cell line and evaluated the tumorigenic phenotype, focusing on tumor-stromal interactions in vivo. First, tumorigenic differences of cancer cells alone were examined in an androgen-insensitive AR-positive LNCaP subline, AIDL, compared with those of the androgen-sensitive AR-positive parental LNCaP and the androgen-insensitive AR-negative PC-3 cells transplanted into subcutaneous, sub-renal and prostatic orthotopic graft sites. Next, cancer cells were recombined with rat urogenital sinus mesenchyme (rUGM) to simulate the tumor-stromal microenvironment. Tumors of AIDL and LNCaP without stromal components both formed well-defined globular tumors and contained large blood-filled areas, with no significant difference in tumor growth or histopathology regardless of the cell line's androgen sensitivity or graft site. In contrast, tumors of AIDL and LNCaP recombined with rUGM both showed reduction of blood-filled areas in the tumors and increased tumor growth compared with cancer cells alone. Tumors of AIDL + rUGM recombinants were approximately three times as large as those of LNCaP + rUGM recombinants, whereas tumors of AIDL and LNCaP without rUGM were not different in size. In addition to the tumor size, cell proliferation (Ki-67 labeling index) in tumors of AIDL + rUGM recombinants was significantly higher than that in tumors of LNCaP + rUGM recombinants. Immunoreactivities of AR, E-cadherin and beta-catenin were decreased in AIDL + rUGM recombinants relative to AIDL alone and LNCaP + rUGM recombinants. These results demonstrated that tumorigenic features of androgen-insensitive AR-positive prostate cancer cells could be significantly influenced by rUGM. Therefore, this in vivo recombination model with rUGM may be useful in developing new treatment strategies.