Prostate cancer frequently metastasizes to the bone, and the interaction between cancer cells and bone microenvironment has proven to be crucial in the establishment of new metastases. Bone marrow mesenchymal stem cells (BM-MSCs) secrete various cytokines that can regulate the behaviour of neighbouring cell. However, little is known about the role of BM-MSCs in influencing the migration and the invasion of prostate cancer cells. We hypothesize that the stromal cell-derived factor-1α released by BM-MSCs may play a pivotal role in these processes. To study the interaction between factors secreted by BM-MSCs and prostate cancer cells we established an in vitro model of transwell co-culture of BM-MSCs and prostate cancer cells DU145. Using this model, we have shown that BM-MSCs produce soluble factors which increase the motility of prostate cancer cells DU145. Neutralization of stromal cell-derived factor-1α (SDF1α) via a blocking antibody significantly limits the chemoattractive effect of bone marrow MSCs. Moreover, soluble factors produced by BM-MSCs greatly activate prosurvival kinases, namely AKT and ERK 1/2. We provide further evidence that SDF1α is involved in the interaction between prostate cancer cells and BM-MSCs. Such interaction may play an important role in the migration and the invasion of prostate cancer cells within bone.

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We studied the effects of zoledronic acid (ZA) and leuprorelin acetate (LA) separately and combined on a human cell line derived from a bone metastasis of prostatic adenocarcinoma (PC3). In particular, we focused on the effects that drugs given singularly or in association may play on tumor evolution and metastatization. Cell proliferation, 2D-and 3D-migration were studied in basal conditions and under attractive stimuli exerted by bone marrow mesenchymal stem cells (BM-MSC). Either drug decreased PC3 proliferation, though ZA was much more cytotoxic than LA. However, LA cytotoxic concentrations are higher than those usually reached in vivo. Subtoxic concentration of either drug inhibited migration especially under BM-MSC medium stimuli via an Akt-dependent mechanism. The capability of either drug to inhibit cellular migration is in line with their well-known effect in limiting metastatization. Intriguingly, no additive effect on the antiproliferative activity or in hindering migration is observed when the drugs are administered concomitantly, compared to the effects of each drug alone.

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Prostate cancer (PCa) is the most frequent genitourinary tumour and the third specific death cause, mostly because of bone metastasis. Currently, PCa is treated with GnRH analogues (leuprolide acetate-LA) and bisphosphonates (zoledronic acid-ZA) often in association. Thus, the aim of this work has been to study, in vitro, the effects of these drugs on cell line derived from PCa (DU-145). Particularly, we focused on some crucial aspects that drugs might play in tumor evolution and metastatization, by interfering with vitality, migration and interactions with bone cells. ZA cytotoxicity has been confirmed on DU-145 after 48-hours incubation at 5 μM, while LA cytotoxicity appears only after 72-hours contact at higher concentrations (100 μM). Both sub cytotoxic ZA and LA doses decreased 3D (transwell assay) PCa cell migration rate. pAkt/Akt ratio is diminished by LA and, even if less strikingly, by ZA, in agreement with the respective inhibition migration ratios. Cells underwent migration test in mesenchymal stem cells – MSC – conditioned medium (MSC-CM), which significantly increases the rate of migration (210%± 2.2; P<0.05). Addition of both ZA and LA quenched the attractive effect of conditioned medium. Our results suggest that LA and, mostly, ZA have a direct toxic effect on cancer cells. Furthermore, they inhibit cellular migration even under attractive stimuli exerted by MSC, and this might contribute to explain their effect in limiting metastatization.