04 Apr PAP May Provide New Therapeutic Target For Bone Metastatic Prostate Cancer
MedicalResearch.com Interview with
Dr. Alice Levine MD
Professor, Medicine, Endocrinology, Diabetes and Bone Disease
Associate Professsor ,Oncological Sciences
Icahn School of Medicine at Mount Sinai
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer (PCa) bone metastases are a major cause of morbidity and mortality. This cancer is unique in its tendency to produce osteoblastic (OB) bone metastases, which affects 90% of men with PCa bone metastases, compared to others that produce osteolytic bone metastases. Currently, there are no existing therapies that specifically target the OB phase and no effective therapies for PCa bone metastases that prolong survival. We have identified a secretory protein that promotes the development PCa osteoblastic bone metastases, Prostatic acid phosphatase (PAP). Prostatic epithelial cells produce PAP. The physiologic function of PAP is unknown. It was the first human tumor marker ever described. Patients with PCa bone metastases demonstrated high levels of PAP. PAP is expressed by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization.
MedicalResearch.com: What are the main findings?
Response: In normal bone remodeling, OB mediate osteoclast differentiation and function by secreting two proteins: Receptor Activator of Nuclear factor Kappa-B (RANK) Ligand (RANKL), that induces osteoclastic activity when bound to the RANK receptor on osteoclasts, and Osteoprotegerin (OPG), a decoy receptor that binds to RANKL and inhibits the activation of osteoclasts and a known survival factor for PCa cells in bone. Previous reports demonstrate that PCa cells in bone also express RANK, RANKL and OPG and communicate directly with bone cells via this same signaling pathway. We postulated that the bone modulating effects of PAP may be mediated by alterations in the RANK/RANKL/OPG system.
Recently our work showed that PCa cells over-expressing PAP increases OB growth, development and bone differentiation. In this study, we tested the impact of PAP knockdown or overexpression in human PCa cell lines on the in vitro expression. We identified that PAP-knockout through CRISPR technology decreased OPG and increased RANKL protein expression within PCa cells, LNCaP.
Next, we studied the correlation between PAP expression by PCa cells and their differentiation in 3D spheroid formation. Spheroid formation positively correlated with the expression levels of PAP in the prostate cancer cell lines: VCaP cells (high PAP expression) produced self-assembled spheroids with characteristic necrotic core, LNCaP cells and PC3 cells overexpressing PAP (moderate PAP expression) self-assembled into a spheroid-like flattened structure without a necrotic core, C4-2B cells (low PAP expression) self-assembled into a smaller flattened clustered structures without a necrotic core, whereas PC3 cells (PAP-negative expression) did not aggregate to form spheroids or clustered structures. PAP expression by prostate cancer epithelial cells increased PCa differentiation in 3D spheroids.
MedicalResearch.com: What should readers take away from your report?
Response: These findings taken together with our recently published data indicate that PAP is a promoter of prostate cancer epithelial differentiation and alters the OPG/RANKL balance favoring osteoblastic bone metastases. At this endstage of prostate cancer, there is vicious crosstalk between prostate cancer cells and bone osteoblasts leading to the demise of the patient. Taken together, our data demonstrate that secretory PAP has both autocrine and paracrine effects on prostate cancer bone metastases, playing a causal role in this crosstalk.
Therefore targeted inhibition of secretory prostatic acid phosphatase may provide a new therapy for men with this devastating disease.
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ENDO 2017 abstract:
Prostatic Acid Phosphatase Secreted by Prostate Cancer Cells Alters Autocrine Secretion of Osteoprotegerin and Growth in 3D Culture.
Sudeh Izadmehr*1, Alexander Kirschenbaum2, Kieley O’Connor-Chapman3, Shen Yao4, Thomas Kraus3, Derek Rammelkamp5, Yizhi Meng5 and Alice C Levine6
1Mount Sinai School of Medicine, New York, NY, 2Mount Sinai School of Medicine, New York, 3Icahn School of Medicine at Mount Sinai, 4Mount Sinai School of Medicine, 5Stonybrook University, 6Icahn School of Medicine at Mount Sinai, New York, NY
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