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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 2/2014

01-02-2014 | Research Paper

Prostate cancer derived prostatic acid phosphatase promotes an osteoblastic response in the bone microenvironment

Authors: Sandy R. Larson, Jessica Chin, Xiaotun Zhang, Lisha G. Brown, Ilsa M. Coleman, Bryce Lakely, Martin Tenniswood, Eva Corey, Peter S. Nelson, Robert L. Vessella, Colm Morrissey

Published in: Clinical & Experimental Metastasis | Issue 2/2014

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Abstract

Approximately 90 % of patients who die of prostate cancer (PCa) have bone metastases, often promoting osteoblastic lesions. We observed that 88 % of castration-resistant PCa (CRPC) bone metastases express prostatic acid phosphatase (PAP), a soluble secreted protein expressed by prostate epithelial cells in predominately osteoblastic (n = 18) or osteolytic (n = 15) lesions. Additionally, conditioned media (CM) of an osteoblastic PCa xenograft LuCaP 23.1 contained significant levels of PAP and promoted mineralization in mouse and human calvaria-derived cells (MC3T3-E1 and HCO). To demonstrate that PAP promotes mineralization, we stimulated MC3T3-E1 cells with PAP and observed increased mineralization, which could be blocked with the specific PAP inhibitor, phosphonic acid. Furthermore, the mineralization promoted by LuCaP 23.1 CM was also blocked by phosphonic acid, suggesting PAP is responsible for the mineralization promoting activity of LuCaP 23.1. In addition, gene expression arrays comparing osteoblastic to osteolytic CRPC (n = 14) identified betacellulin (BTC) as a gene upregulated during the osteoblastic response in osteoblasts during new bone formation. Moreover, BTC levels were increased in bone marrow stromal cells in response to LuCaP 23.1 CM in vitro. Because new bone formation does occur in osteoblastic and can occur in osteolytic CRPC bone metastases, we confirmed by immunohistochemistry (n = 36) that BTC was highly expressed in osteoblasts involved in new bone formation occurring in both osteoblastic and osteolytic sites. These studies suggest a role for PAP in promoting the osteoblastic reaction in CRPC bone metastases and identify BTC as a novel downstream protein expressed in osteoblasts during new bone formation.
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Literature
1.
Bubendorf L, Schopfer A, Wagner U et al (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31:578–583PubMedCrossRef
2.
Nieder C, Haukland E, Pawinski A, Dalhaug A (2010) Pathologic fracture and metastatic spinal cord compression in patients with prostate cancer and bone metastases. BMC Urol 10:23PubMedCentralPubMedCrossRef
3.
Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, Ott SM (2008) Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol 180:1154–1160PubMedCentralPubMedCrossRef
4.
5.
Morrissey C, Roudier MP, Dowell A et al (2013) Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series. J Bone Miner Res 28:333–340PubMedCrossRef
6.
Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822PubMedCentralPubMedCrossRef
7.
8.
Valkenburg KC, Steensma MR, Williams BO, Zhong Z (2013) Skeletal metastasis: treatments, mouse models, and the wnt signaling. Chin J Cancer 32:380–396PubMedCrossRef
9.
Sturge J, Caley MP, Waxman J (2011) Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol 8:357–368PubMed
10.
Bagnato A, Loizidou M, Pflug BR, Curwen J, Growcott J (2011) Role of the endothelin axis and its antagonists in the treatment of cancer. Br J Pharmacol 163:220–233PubMedCrossRef
11.
Larson SR, Zhang X, Dumpit R et al (2013) Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate 73:932–940PubMedCrossRef
12.
Feeley BT, Gamradt SC, Hsu WK et al (2005) Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer. J Bone Miner Res 20:2189–2199PubMedCrossRef
13.
Ishibe M, Rosier RN, Puzas JE (1991) Human prostatic acid phosphatase directly stimulates collagen synthesis and alkaline phosphatase content of isolated bone cells. J Clin Endocrinol Metab 73:785–792PubMedCrossRef
14.
Kirschenbaum A, Liu XH, Yao S, Leiter A, Levine AC (2011) Prostatic acid phosphatase is expressed in human prostate cancer bone metastases and promotes osteoblast differentiation. Ann N Y Acad Sci 1237:64–70PubMedCrossRef
15.
Genetos DC, Rao RR, Vidal MA (2010) Betacellulin inhibits osteogenic differentiation and stimulates proliferation through HIF-1alpha. Cell Tissue Res 340:81–89PubMedCentralPubMedCrossRef
16.
Kim HS, Shin HS, Kwak HJ, Cho CH, Lee CO, Koh GY (2003) Betacellulin induces angiogenesis through activation of mitogen-activated protein kinase and phosphatidylinositol 3′-kinase in endothelial cell. FASEB J 17:318–320PubMed
17.
Schneider MR, Mayer-Roenne B, Dahlhoff M et al (2009) High cortical bone mass phenotype in betacellulin transgenic mice is EGFR dependent. J Bone Miner Res 24:455–467PubMedCrossRef
18.
Roudier MP, True LD, Higano CS et al (2003) Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum Pathol 34:646–653PubMedCrossRef
19.
Zhang X, Morrissey C, Sun S et al (2011) Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS ONE 6:e27970PubMedCentralPubMedCrossRef
20.
Kuroda C, Kubota S, Kawata K et al (2008) Distribution, gene expression, and functional role of EphA4 during ossification. Biochem Biophys Res Commun 374:22–27PubMedCrossRef
21.
Kawai S, Yamauchi M, Wakisaka S, Ooshima T, Amano A (2007) Zinc-finger transcription factor odd-skipped related 2 is one of the regulators in osteoblast proliferation and bone formation. J Bone Miner Res 22:1362–1372PubMedCrossRef
22.
Yoshiko Y, Maeda N, Aubin JE (2003) Stanniocalcin 1 stimulates osteoblast differentiation in rat calvaria cell cultures. Endocrinology 144:4134–4143PubMedCrossRef
23.
Billiard J, Way DS, Seestaller-Wehr LM, Moran RA, Mangine A, Bodine PV (2005) The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol 19:90–101PubMedCrossRef
24.
Dhodapkar MV, Abe E, Theus A et al (1998) Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation. Blood 91:2679–2688PubMed
25.
Lisignoli G, Manferdini C, Codeluppi K et al (2009) CCL20/CCR6 chemokine/receptor expression in bone tissue from osteoarthritis and rheumatoid arthritis patients: different response of osteoblasts in the two groups. J Cell Physiol 221:154–160PubMedCrossRef
26.
Bijsterbosch J, Kloppenburg M, Reijnierse M et al (2013) Association study of candidate genes for the progression of hand osteoarthritis. Osteoarthr Cartil 21:565–569PubMedCrossRef
27.
Kato K, Nishimasu H, Okudaira S et al (2012) Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling. Proc Natl Acad Sci USA 109:16876–16881PubMedCrossRef
28.
Erlandsen H, Ames JE, Tamkenath A et al (2012) Pleiotrophin expression during odontogenesis. J Histochem Cytochem 60:366–375PubMedCrossRef
29.
Seitz S, Rendenbach C, Barvencik F et al (2013) Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice. Bone 53:231–238PubMedCrossRef
30.
Ariizumi T, Ogose A, Kawashima H et al (2010) Expression of podoplanin in human bone and bone tumors: new marker of osteogenic and chondrogenic bone tumors. Pathol Int 60:193–202PubMedCrossRef
31.
Clarkin CE, Gerstenfeld LC (2013) VEGF and bone cell signalling: an essential vessel for communication? Cell Biochem Funct 31:1–11PubMedCrossRef
32.
Beers SA, Schwender CF, Loughney DA, Malloy E, Demarest K, Jordan J (1996) Phosphatase inhibitors–III. benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase. Bioorg Med Chem 4:1693–1701PubMedCrossRef
33.
Vovk AI, Mischenko IM, Tanchuk VY et al (2008) Stereoselectivity of binding of alpha-(N-benzylamino)benzylphosphonic acids to prostatic acid phosphatase. Bioorg Med Chem Lett 18:4620–4623PubMedCrossRef
34.
Thudi NK, Martin CK, Murahari S et al (2011) Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate 71:615–625PubMedCentralPubMedCrossRef
35.
Wittrant Y, Theoleyre S, Chipoy C et al (2004) RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 1704:49–57PubMed
36.
37.
Muniyan S, Chaturvedi NK, Dwyer JG, Lagrange CA, Chaney WG, Lin MF (2013) Human prostatic acid phosphatase: structure, function and regulation. Int J Mol Sci 14:10438–10464PubMedCentralPubMedCrossRef
38.
39.
Sheu TJ, Schwarz EM, Martinez DA et al (2003) A phage display technique identifies a novel regulator of cell differentiation. J Biol Chem 278:438–443PubMedCrossRef
40.
Chuang TD, Chen SJ, Lin FF et al (2010) Human prostatic acid phosphatase, an authentic tyrosine phosphatase, dephosphorylates ErbB-2 and regulates prostate cancer cell growth. J Biol Chem 285:23598–23606PubMedCrossRef
41.
Chaves Neto AH, Queiroz KC, Milani R et al (2011) Profiling the changes in signaling pathways in ascorbic acid/beta-glycerophosphate-induced osteoblastic differentiation. J Cell Biochem 112:71–77PubMedCrossRef
42.
Pinkas-Kramarski R, Lenferink AE, Bacus SS et al (1998) The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin. Oncogene 16:1249–1258PubMedCrossRef
43.
Gross M, Higano C, Pantuck A et al (2007) A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer. BMC Cancer 7:142PubMedCentralPubMedCrossRef
44.
45.
Chen D, Li Y, Zhou Z et al (2012) Synergistic inhibition of wnt pathway by HIF-1alpha and osteoblast-specific transcription factor osterix (Osx) in osteoblasts. PLoS ONE 7:e52948PubMedCentralPubMedCrossRef
Metadata
Title
Prostate cancer derived prostatic acid phosphatase promotes an osteoblastic response in the bone microenvironment
Authors
Sandy R. Larson
Jessica Chin
Xiaotun Zhang
Lisha G. Brown
Ilsa M. Coleman
Bryce Lakely
Martin Tenniswood
Eva Corey
Peter S. Nelson
Robert L. Vessella
Colm Morrissey
Publication date
01-02-2014
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 2/2014
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-013-9625-2

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