Host-derived RANKL is responsible for osteolysis in a C4-2 human prostate cancer xenograft model of experimental bone metastases

<p>Abstract</p> <p>Background</p> <p>C4-2 prostate cancer (CaP) cells grown in mouse tibiae cause a mixed osteoblastic/osteolytic response with increases in osteoclast numbers and bone resorption. Administration of osteoprotegerin (OPG) blocks these increases, indicating the critical role of RANKL in osteolysis in this model. The objective of our study was to investigate whether RANKL expressed by tumor cells (human origin) directly stimulates osteolysis associated with the growth of these cells in bone or whether the increased osteolysis is caused by RANKL expressed by the host environment cells (murine origin). The relative contribution of tumor-<it>vs. </it>host-derived RANKL has been difficult to establish, even with human xenografts, because murine and human RANKL are both capable of stimulating osteolysis in mice, and the RANKL inhibitors used to date (OPG and RANK-Fc) inhibit human and murine RANKL.</p> <p>Methods</p> <p>To address this question we used a neutralizing, antibody (huRANKL MAb), which specifically neutralizes the biological activities of human RANKL and thereby the contribution of C4-2 derived RANKL in this tibial injection model of experimental bone metastases.</p> <p>Results</p> <p>Administration of huRANKL MAb did not inhibit the osteolytic response of the bone to these cells, or affect the establishment and growth of the C4-2 tumors in this environment.</p> <p>Conclusion</p> <p>In conclusion, our results suggest that in this model, murine RANKL and not the tumor-derived human RANKL is the mediator of the osteolytic reaction associated with C4-2 growth in bone. We hypothesize that C4-2 cells express other factor/s inducing host production of RANKL, thereby driving tumor-associated osteolysis.</p

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment

BACKGROUND: After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL), a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. METHODS: Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. RESULTS: ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. CONCLUSION: In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option

Bone Morphogenetic Protein 7 Is Expressed in Prostate Cancer Metastases and Its Effects on Prostate Tumor Cells Depend on Cell Phenotype and the Tumor Microenvironment1

Bone morphogenetic protein (BMP) signaling is important in prostate development and prostate cancer (PCa) progression. However, because of the multiple effects of different BMPs, no final conclusions have been made as to the role of BMPs in PCa. In our studies, we have focused on BMP-7 because it is involved in prostate morphogenesis, and its expression is regulated by androgens. The objective of our study was to determine BMP-7 expression in PCa metastases and investigate the effects of BMP-7 on PCa cells. Our results show that BMP-7 is expressed in metastatic PCa and its levels are increased in castration-resistant PCa versus androgen-dependent PCa, whereas the expression of BMP-7 is decreased in primary PCa versus normal prostate. Our in vitro results show that BMP-7 inhibits proliferation of androgen-sensitive LNCaP cells, stimulates androgen receptor signaling, increases the expression of differentiation-associated genes, and decreases the levels of some wingless-regulated transcripts. Interestingly, these effects were not detected in C4-2 castration-resistant PCa cells. In vivo expression of BMP-7 in castration-resistant C4-2 cells did not alter proliferation when these cells were grown subcutaneously, but their growth was inhibited in the bone environment. In summary, our results show that BMP-7 is expressed at the highest level in advanced castration-resistant PCa cells and that the inhibitory effects of BMP-7 are dependent on the differentiation status of PCa cells and the tumor microenvironment. Further studies are needed to identify changes in BMP-7 signaling that lead to the loss of its control of proliferation during PCa progression

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment-2

<p><b>Copyright information:</b></p><p>Taken from "Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment"</p><p>BMC Cancer 2006;6():15-15.</p><p>Published online 17 Jan 2006</p><p>PMCID:PMC1360086.</p><p>Copyright © 2006 Brubaker et al; licensee BioMed Central Ltd.</p>ured twice a week and blood was drawn weekly for determination of serum PSA levels. Mean ± SEM is plotted.: Docetaxel administration significantly decreased tumor volume compared to that of the control group. : Docetaxel decreased PSA levels significantly compared to those in the control animals

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment-1

<p><b>Copyright information:</b></p><p>Taken from "Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment"</p><p>BMC Cancer 2006;6():15-15.</p><p>Published online 17 Jan 2006</p><p>PMCID:PMC1360086.</p><p>Copyright © 2006 Brubaker et al; licensee BioMed Central Ltd.</p>treatment significantly increased bone volume compared to that of the control group (p = 0.0164, *). %BV/TV of the ZOL group was increased in comparison to the control group but the changes did not reach significance (p = 0.0839). . Blood was drawn weekly from each treatment group, control (■), ZOL (●), Docetaxel (▼), or ZOL + docetaxel (○), and analyzed for PSA levels (ng/ml). The combination of ZOL + docetaxel decreased PSA levels significantly compared to those in the control animals. . Tumor volume as a percentage of the total volume was determined by bone histomorphometrical analysis for the four treatment groups. The ZOL and ZOL + docetaxel treatments decreased tumor volume significantly (p = 0.027, 0.0002, respectively *) compared to that of the control group. The combination of ZOL and docetaxel resulted in decreased tumor volume in comparison to animals receiving ZOL alone; however, these results did not reach significance (p = 0.111)

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment-0

<p><b>Copyright information:</b></p><p>Taken from "Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment"</p><p>BMC Cancer 2006;6():15-15.</p><p>Published online 17 Jan 2006</p><p>PMCID:PMC1360086.</p><p>Copyright © 2006 Brubaker et al; licensee BioMed Central Ltd.</p>on is also visible with ZOL and ZOL + docetaxel, these tibiae exhibit decreased periosteal activity compared to the control and docetaxel-treated tibiae. . Sections stained with Goldner reagent show marrow or tumored areas in pink and bone in green. The growth plate is marked with the letter G. The ZOL- (C) and ZOL + docetaxel-treated groups (E) exhibit substantial increases in bone volume and decreases in tumor volume compared to the control (B) and docetaxel-treated (D) groups. . BMD was measured for the non-tumored and tumored legs of all four treatment groups. BMD was higher in tumored tibiae than in non-tumored tibiae, but there were no significant differences among the four treatment groups

Validity and reliability of the Internalized Stigma of Smoking Inventory: An exploration of shame, isolation, and discrimination in smokers with mental health diagnoses.

Background and objectivesDe-normalization of smoking as a public health strategy may create shame and isolation in vulnerable groups unable to quit. To examine the nature and impact of smoking stigma, we developed the Internalized Stigma of Smoking Inventory (ISSI), tested its validity and reliability, and explored factors that may contribute to smoking stigma.MethodsWe evaluated the ISSI in a sample of smokers with mental health diagnoses (N = 956), using exploratory and confirmatory factor analysis, and assessed construct validity.ResultsResults reduced the ISSI to eight items with three subscales: smoking self-stigma related to shame, felt stigma related to social isolation, and discrimination experiences. Discrimination was the most commonly endorsed of the three subscales. A multivariate generalized linear model predicted 21-30% of the variance in the smoking stigma subscales. Self-stigma was greatest among those intending to quit; felt stigma was highest among those experiencing stigma in other domains, namely ethnicity and mental illness-based; and smoking-related discrimination was highest among women, Caucasians, and those with more education.Discussion and conclusionSmoking stigma may compound stigma experiences in other areas. Aspects of smoking stigma in the domains of shame, isolation, and discrimination were related to modeled stigma responses, particularly readiness to quit and cigarette addiction, and were found to be more salient for groups where tobacco use is least prevalent.Scientific significanceThe ISSI measure is useful for quantifying smoking-related stigma in multiple domains

Validity and reliability of the Internalized Stigma of Smoking Inventory: An exploration of shame, isolation, and discrimination in smokers with mental health diagnoses.

Background and objectivesDe-normalization of smoking as a public health strategy may create shame and isolation in vulnerable groups unable to quit. To examine the nature and impact of smoking stigma, we developed the Internalized Stigma of Smoking Inventory (ISSI), tested its validity and reliability, and explored factors that may contribute to smoking stigma.MethodsWe evaluated the ISSI in a sample of smokers with mental health diagnoses (N = 956), using exploratory and confirmatory factor analysis, and assessed construct validity.ResultsResults reduced the ISSI to eight items with three subscales: smoking self-stigma related to shame, felt stigma related to social isolation, and discrimination experiences. Discrimination was the most commonly endorsed of the three subscales. A multivariate generalized linear model predicted 21-30% of the variance in the smoking stigma subscales. Self-stigma was greatest among those intending to quit; felt stigma was highest among those experiencing stigma in other domains, namely ethnicity and mental illness-based; and smoking-related discrimination was highest among women, Caucasians, and those with more education.Discussion and conclusionSmoking stigma may compound stigma experiences in other areas. Aspects of smoking stigma in the domains of shame, isolation, and discrimination were related to modeled stigma responses, particularly readiness to quit and cigarette addiction, and were found to be more salient for groups where tobacco use is least prevalent.Scientific significanceThe ISSI measure is useful for quantifying smoking-related stigma in multiple domains