scholarly journals SUN-143 Prostatic Acid Phosphatase Is Not Regulated by Androgens During Prostate Development and Tumorigenesis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sudeh Izadmehr ◽  
Shen Yao ◽  
Alexander Kirschenbaum ◽  
Alice C Levine
Keyword(s):  
Acid Phosphatase ◽  
Bone Metastases ◽  
Mouse Models ◽  
Gestational Age ◽  
Prostatic Acid Phosphatase ◽  
Normal Prostate ◽  
Prostate Development ◽  
Castration Resistant ◽  
Castrate Resistant

Abstract INTRODUCTION: Prostatic acid phosphatase (PAP) is a soluble factor secreted by prostate luminal epithelial cells. PAP expression correlates with prostate cancer (PCa) bone metastases and poor survival. The androgenic regulation of PAP in prostate development and tumorigenesis is not fully understood. We investigated the relationship between PAP and androgens in human prostate specimens and in vivo. HYPOTHESIS AND OBJECTIVES: We hypothesized that PAP expression was independent of androgens. Our objectives were to determine the immunohistochemical expression of PAP in human fetal prostate tissue, human PCa bone metastases, and xenograft and surgical castration mouse models. METHODS: Immunohistochemical staining for PAP and three androgen-regulated proteins, the Androgen Receptor (AR), Prostate-Specific Antigen (PSA), and ETS-related gene (ERG) protein, was carried out on human fetal prostate (9.5, 11.5, 13, 16.5, 18 and 20 weeks of gestational age), archival human PCa bone metastases, and PCa mouse models. For xenograft studies, PAP-expressing PCa cell lines, LNCaP, C42B, and VCaP cells, were inoculated subcutaneously into SCID mice. A castration study with surgical or sham castration was performed after VCaP tumors were palpable. Mouse tumor growth and weight were measured biweekly, and tumor tissue isolated after mouse sacrifice. RESULTS: PAP expression was observed in the fetal prostate as early as 11.5 weeks of gestational age. Strong PAP expression was noted in all human PCa bone metastases examined, both treatment-naive and castrate-resistant (n=10). However, AR and ERG expression was absent in two of four castrate-resistant specimens. PSA was weakly expressed in human castration-resistant bone metastatic prostate specimens. In vivo, PAP expression was observed in all tumor models; however, the expression of PAP differed among androgen-sensitive models; LNCaP (low PAP), C42B (moderate PAP) and VCaP (high PAP). Castrated VCaP tumors underwent tumor stasis and were significantly smaller compared to intact mice. Strong expression of PAP was observed after castration. In contrast, AR, PSA, and ERG expression were reduced in castrated VCaP tumors compared to tumors from intact mice. Double staining of tumors for PAP and AR demonstrated a population of cells that were positive for PAP but negative for AR expression located in hypoxic areas near necrosis. CONCLUSIONS: Our findings demonstrated that PAP is expressed early in normal human fetal prostate development prior to the secretion of significant androgens or expression of AR. In mouse xenografts and human PCa bone metastases, androgens did not significantly regulate PAP expression. These data demonstrate that PAP is a marker of early progenitor cells in the normal prostate and is persistently expressed after castration. PAP may be a suitable target for the treatment of castration-resistant metastatic disease.

scholarly journals Prostatic Acid Phosphatase Is a Progenitor Cell Marker That Persists After Androgen Ablation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1030-A1031
Author(s):  
Sudeh Izadmehr ◽  
Alexander Kirschenbaum ◽  
Shen Yao ◽  
Alice C Levine
Keyword(s):  
Acid Phosphatase ◽  
Protein Expression ◽  
Bone Metastases ◽  
Cell Lines ◽  
Gestational Age ◽  
Prostatic Acid Phosphatase ◽  
Scid Mice ◽  
Castration Resistant

Abstract Introduction: Prostatic Acid Phosphatase (PAP), a protein phosphatase and 5’ecto-nucleotidase, is expressed in prostate cancer (PCa) bone metastases and correlates with poor survival. Growing evidence suggests that PAP is not regulated by androgens, but rather by factors in the tumor microenvironment. Hypothesis: We hypothesized that PAP is a marker for a more progenitor type PCa cell and its expression is androgen-independent, persisting in castration-resistant disease. Methods: Protein expression of PAP and three androgen-regulated proteins, the Androgen Receptor (AR), Prostate-Specific Antigen (PSA), and ETS-related gene (ERG) protein, was assessed with immunohistochemistry in human fetal prostate (9.5 - 20 weeks of gestational age), archival human PCa bone metastases, and human PCa cell lines. VCaP cells were treated in vitro with dihydrotestosterone (DHT) and the effects on AR and PAP protein expression determined with Western Blotting. PAP-expressing PCa cell lines (LNCaP, C42B, and VCaP) were inoculated subcutaneously (s.c.) into SCID mice. To model tumor-bone interaction, LNCaP and MC3T3 osteoblast cells were co-inoculated s.c. into SCID mice. A VCaP castration study with surgical or sham castration was performed after tumors were palpable and effects of castration on tumor growth and protein expression determined. Results: PAP expression was observed in the fetal prostate as early as 11.5 weeks of gestational age prior to PSA and AR expression. Strong PAP expression was noted in all human PCa bone metastases examined, both treatment-naive and castrate-resistant (n=10). In vitro, VCaP cells expressed high levels of AR and PAP protein and DHT treatment increased AR and decreased PAP protein expression. In vivo, PAP expression was observed in all tumor models; LNCaP (low PAP expression), C42B (moderate PAP expression) and VCaP (high PAP expression). Castrated VCaP tumors underwent tumor stasis, were significantly smaller compared to intact mice, had decreased AR, PSA and ERG expression but persistent expression of PAP. Double staining of tumors for PAP and AR demonstrated a population of cells that were positive for PAP but negative for AR expression in hypoxic areas near necrosis. Inoculation of LNCaP cells with MC3T3 osteoblastic cells increased PAP expression in vivo. Conclusions: PAP is expressed early in human fetal prostate development prior to the secretion of significant androgens or expression of AR. In mouse xenograft tumors and human PCa bone metastases, androgens did not significantly regulate PAP expression. Both hypoxia and stroma increased PAP expression. These data demonstrate that PAP is a marker of early progenitor cells, is persistently expressed after castration and is upregulated by tumor microenvironmental factors. PAP may be a suitable target for the treatment of castration-resistant metastatic disease.

scholarly journals Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase

2019 ◽  
Vol 3 (3) ◽  
pp. 655-664 ◽  
Author(s):  
Mariana Quiroz-Munoz ◽  
Sudeh Izadmehr ◽  
Dushyanthy Arumugam ◽  
Beatrice Wong ◽  
Alexander Kirschenbaum ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acid Phosphatase ◽  
Bone Metastases ◽  
Prostatic Acid Phosphatase ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Soluble Factors ◽  
Osteoblastic Phenotype ◽  
Receptor Activator ◽  
Castrate Resistant

Abstract Prostate cancer (PCa) preferentially metastasizes to bone, leading to complications including severe pain, fractures, spinal cord compression, bone marrow suppression, and a mortality of ∼70%. In spite of recent advances in chemo-, hormonal, and radiation therapies, bone-metastatic, castrate-resistant PCa is incurable. PCa is somewhat unique among the solid tumors in its tendency to produce osteoblastic lesions composed of hypermineralized bone with multiple layers of poorly organized type I collagen fibrils that have reduced mechanical strength. Many of the signaling pathways that control normal bone homeostasis are at play in pathologic PCa bone metastases, including the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin system. A number of PCa-derived soluble factors have been shown to induce the dysfunctional osteoblastic phenotype. However, therapies directed at these osteoblastic-stimulating proteins have yielded disappointing clinical results to date. One of the soluble factors expressed by PCa cells, particularly in bone metastases, is prostatic acid phosphatase (PAP). Human PAP is a prostate epithelium-specific secretory protein that was the first tumor marker ever described. Biologically, PAP exhibits both phosphatase activity and ecto-5′-nucleotidase activity, generating extracellular phosphate and adenosine as the final products. Accumulating evidence indicates that PAP plays a causal role in the osteoblastic phenotype and aberrant bone mineralization seen in bone-metastatic, castrate-resistant PCa. Targeting PAP may represent a therapeutic approach to improve morbidity and mortality from PCa osteoblastic bone metastases.

scholarly journals Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4526-4533 ◽  
Author(s):  
Alexander Kirschenbaum ◽  
Sudeh Izadmehr ◽  
Shen Yao ◽  
Kieley L. O’Connor-Chapman ◽  
Alan Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acid Phosphatase ◽  
Bone Metastases ◽  
Cross Talk ◽  
Bone Cells ◽  
Bone Mineralization ◽  
Critical Role ◽  
Prostatic Acid Phosphatase ◽  
Bone Lesions ◽  
Rankl Expression

Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.

scholarly journals Seminal Plasma Accelerates Semen-derived Enhancer of Viral Infection (SEVI) Fibril Formation by the Prostatic Acid Phosphatase (PAP248–286) Peptide

2012 ◽  
Vol 287 (15) ◽  
pp. 11842-11849 ◽  
Author(s):  
Joanna S. Olsen ◽  
John T. M. DiMaio ◽  
Todd M. Doran ◽  
Caitlin Brown ◽  
Bradley L. Nilsson ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Viral Infection ◽  
Seminal Plasma ◽  
Amyloid Fibrils ◽  
Divalent Cations ◽  
Prostatic Acid Phosphatase ◽  
Fibril Formation ◽  
Amyloid Formation ◽  
Precursor Peptide

Amyloid fibrils contained in semen, known as SEVI, or semen-derived enhancer of viral infection, have been shown to increase the infectivity of HIV dramatically. However, previous work with these fibrils has suggested that extensive time and nonphysiologic levels of agitation are necessary to induce amyloid formation from the precursor peptide (a proteolytic cleavage product of prostatic acid phosphatase, PAP248–286). Here, we show that fibril formation by PAP248–286is accelerated dramatically in the presence of seminal plasma (SP) and that agitation is not required for fibrillization in this setting. Analysis of the effects of specific SP components on fibril formation by PAP248–286revealed that this effect is primarily due to the anionic buffer components of SP (notably inorganic phosphate and sodium bicarbonate). Divalent cations present in SP had little effect on the kinetics of fibril formation, but physiologic levels of Zn2+strongly protected SEVI fibrils from degradation by seminal proteases. Taken together, these data suggest that in thein vivoenvironment, PAP248–286is likely to form fibrils efficiently, thus providing an explanation for the presence of SEVI in human semen.

Prostate-specific acid phosphatase: re-evaluation of radioimmunoassay in diagnosing prostatic disease.

1980 ◽  
Vol 26 (3) ◽  
pp. 433-436 ◽  
Author(s):  
J C Griffiths
Keyword(s):  
Acid Phosphatase ◽  
Diagnostic Yield ◽  
Stage Iv ◽  
Prostatic Acid Phosphatase ◽  
Prostatic Hyperplasia ◽  
Clinical Approach ◽  
Clinical Stages ◽  
Baseline Values ◽  
Colorimetric Assays

Abstract The availability of a radioimmunoassay for prostate-specific acid phosphatase has allowed a correlative study between this technique and conventional colorimetric assays in the four clinical stages of prostatic adenocarcinoma. Results of such a study show an increased diagnostic sensitivity of the radioimmunoassay in all stages, but in 14% of Stage IV adenocarcinomas there was no increase in prostatic acid phosphatase above the ranges ordinarily expected for all methods. In cases of benign prostatic hyperplasia, there was an increase associated with in vivo tissue cytolysis, comparable to Stage II and III adenocarcinoma. The sensitivity of the test in Stage I is still low, but testing for combinations of tumor markers might increase the diagnostic yield. Conversely, a different clinical approach might be to establish baseline values in the "at-risk" patient, followed by regular determinations of prostate-specific acid phosphatase activity. Increases in activity within the normal expected range may be interpreted by the clinician as a herald of disease.

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