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01-02-2018 | Review

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

Authors: Sun H. Park, Evan T. Keller, Yusuke Shiozawa

Published in: Calcified Tissue International | Issue 2/2018

Abstract

Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients’ quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms through which prostate cancer metastasizes to bone are unclear, growing evidence suggests that the bone marrow microenvironment, particularly its hematopoietic activity, is a significant mediator of prostate cancer bone tropism. Moreover, the bone microenvironment may regulate metastatic prostate cancer cells between dormant and proliferative states. In this review, we discuss (1) how prostate cancer cells interact with the bone microenvironment to establish bone metastases and (2) current and future potential treatments for prostate cancer patients with bone metastases.

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun JM (2007) Cancer statistics. CA Cancer J Clin 57(1):43–66PubMedCrossRef

Morash C, Tey R, Agbassi C, Klotz L, McGowan T, Srigley J, Evans A (2015) Active surveillance for the management of localized prostate cancer: guideline recommendations. Can Urol Assoc J 9(5–6):171–178. doi:10.5489/cuaj.2806 PubMedPubMedCentralCrossRef

Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31(5):578–583PubMedCrossRef

Batson OV (1940) The function of the vertebral veins and their role in the spread of metastases. Ann Surg 112(1):138–149PubMedPubMedCentralCrossRef

Rahim F, Hajizamani S, Mortaz E, Ahmadzadeh A, Shahjahani M, Shahrabi S, Saki N (2014) Molecular regulation of bone marrow metastasis in prostate and breast cancer. Bone Marrow Res 2014:405920. doi:10.1155/2014/405920 PubMedPubMedCentralCrossRef

Mazo IB, von Andrian UH (1999) Adhesion and homing of blood-borne cells in bone marrow microvessels. J Leukoc Biol 66(1):25–32PubMedCrossRef

Miftakhova R, Hedblom A, Semenas J, Robinson B, Simoulis A, Malm J, Rizvanov A, Heery DM, Mongan NP, Maitland NJ, Allegrucci C, Persson JL (2016) Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow. Cancer Res 76(8):2453–2464. doi:10.1158/0008-5472.CAN-15-2340 PubMedCrossRef

Chu GC, Zhau HE, Wang R, Rogatko A, Feng X, Zayzafoon M, Liu Y, Farach-Carson MC, You S, Kim J, Freeman MR, Chung LW (2014) RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr Relat Cancer 21(2):311–326. doi:10.1530/ERC-13-0548 PubMedPubMedCentralCrossRef

Zalucha JL, Jung Y, Joseph J, Wang J, Berry JE, Shiozawa Y, Taichman RS (2015) The role of osteoclasts in early dissemination of prostate cancer tumor cells. J Cancer Stem Cell Res 3:e1005PubMedPubMedCentralCrossRef

10.

Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, Wang J, Zalucha S, Loberg RD, Pienta KJ, Taichman RS (2010) GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia 12(2):116–127PubMedPubMedCentralCrossRef

11.

Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, Cher ML (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate 66(1):32–48. doi:10.1002/pros.20318 PubMedCrossRef

12.

Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281(17):1591–1597PubMedCrossRef

13.

Tsuzuki S, Park SH, Eber MR, Peters CM, Shiozawa Y (2016) Skeletal complications in cancer patients with bone metastases. Int J Urol 23(10):825–832. doi:10.1111/iju.13170 PubMedPubMedCentralCrossRef

14.

Dimitroff CJ, Lechpammer M, Long-Woodward D, Kutok JL (2004) Rolling of human bone-metastatic prostate tumor cells on human bone marrow endothelium under shear flow is mediated by E-selectin. Cancer Res 64(15):5261–5269. doi:10.1158/0008-5472.CAN-04-0691 PubMedCrossRef

15.

Dimitroff CJ, Descheny L, Trujillo N, Kim R, Nguyen V, Huang W, Pienta KJ, Kutok JL, Rubin MA (2005) Identification of leukocyte E-selectin ligands, P-selectin glycoprotein ligand-1 and E-selectin ligand-1, on human metastatic prostate tumor cells. Cancer Res 65(13):5750–5760. doi:10.1158/0008-5472.CAN-04-4653 PubMedPubMedCentralCrossRef

16.

Barthel SR, Wiese GK, Cho J, Opperman MJ, Hays DL, Siddiqui J, Pienta KJ, Furie B, Dimitroff CJ (2009) Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking. Proc Natl Acad Sci USA 106(46):19491–19496. doi:10.1073/pnas.0906074106 PubMedPubMedCentralCrossRef

17.

Chen C, Zhang Q, Liu S, Parajuli KR, Qu Y, Mei J, Chen Z, Zhang H, Khismatullin DB, You Z (2015) IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44-VCAM-1 interaction. Prostate 75(8):883–895. doi:10.1002/pros.22971 PubMedPubMedCentralCrossRef

18.

Cooper CR, Chay CH, Pienta KJ (2002) The role of alpha(v)beta(3) in prostate cancer progression. Neoplasia 4(3):191–194. doi:10.1038/sj/neo/7900224 PubMedPubMedCentralCrossRef

19.

Barthel SR, Hays DL, Yazawa EM, Opperman M, Walley KC, Nimrichter L, Burdick MM, Gillard BM, Moser MT, Pantel K, Foster BA, Pienta KJ, Dimitroff CJ (2013) Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res 73(2):942–952. doi:10.1158/0008-5472.CAN-12-3264 PubMedCrossRef

20.

Engl T, Relja B, Marian D, Blumenberg C, Muller I, Beecken WD, Jones J, Ringel EM, Bereiter-Hahn J, Jonas D, Blaheta RA (2006) CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8(4):290–301. doi:10.1593/neo.05694 PubMedPubMedCentralCrossRef

21.

Sloan EK, Pouliot N, Stanley KL, Chia J, Moseley JM, Hards DK, Anderson RL (2006) Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res 8(2):R20. doi:10.1186/bcr1398 PubMedPubMedCentralCrossRef

22.

Jung Y, Wang J, Schneider A, Sun YX, Koh-Paige AJ, Osman NI, McCauley LK, Taichman RS (2006) Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone 38(4):497–508. doi:10.1016/j.bone.2005.10.003 PubMedCrossRef

23.

Sun YX, Fang M, Wang J, Cooper CR, Pienta KJ, Taichman RS (2007) Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate 67(1):61–73. doi:10.1002/pros.20500 PubMedCrossRef

24.

Shiozawa Y, Taichman RS (2012) Getting blood from bone: an emerging understanding of the role that osteoblasts play in regulating hematopoietic stem cells within their niche. Exp Hematol 40(9):685–694. doi:10.1016/j.exphem.2012.05.004 PubMedPubMedCentralCrossRef

25.

Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62(6):1832–1837PubMed

26.

Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A (2013) Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther 6:1347–1361. doi:10.2147/OTT.S36109 PubMedPubMedCentral

27.

Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Loberg R, Taichman RS (2008) The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem 283(7):4283–4294. doi:10.1074/jbc.M707465200 PubMedCrossRef

28.

Conley-LaComb MK, Semaan L, Singareddy R, Li Y, Heath EI, Kim S, Cher ML, Chinni SR (2016) Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis. Mol Cancer 15(1):68. doi:10.1186/s12943-016-0552-0 PubMedPubMedCentralCrossRef

29.

Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563. doi:10.1038/nature06188 PubMedCrossRef

30.

Jung Y, Kim JK, Shiozawa Y, Wang J, Mishra A, Joseph J, Berry JE, McGee S, Lee E, Sun H, Wang J, Jin T, Zhang H, Dai J, Krebsbach PH, Keller ET, Pienta KJ, Taichman RS (2013) Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun 4:1795. doi:10.1038/ncomms2766 PubMedPubMedCentralCrossRef

31.

Singh R, Kapur N, Mir H, Singh N, Lillard JW Jr, Singh S (2016) CXCR6-CXCL16 axis promotes prostate cancer by mediating cytoskeleton rearrangement via Ezrin activation and alphavbeta3 integrin clustering. Oncotarget 7(6):7343–7353. doi:10.18632/oncotarget.6944 PubMedPubMedCentralCrossRef

32.

Lu Y, Wang J, Xu Y, Koch AE, Cai Z, Chen X, Galson DL, Taichman RS, Zhang J (2008) CXCL16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol Cancer Res 6(4):546–554. doi:10.1158/1541-7786.MCR-07-0277 PubMedCrossRef

33.

Ha HK, Lee W, Park HJ, Lee SD, Lee JZ, Chung MK (2011) Clinical significance of CXCL16/CXCR6 expression in patients with prostate cancer. Mol Med Rep 4(3):419–424. doi:10.3892/mmr.2011.446 PubMed

34.

Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21(2):139–146. doi:10.1016/j.semcancer.2011.01.002 PubMedCrossRef

35.

Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827. doi:10.1038/nature04186 PubMedPubMedCentralCrossRef

36.

Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J, Zhang T, Theilen TM, Garcia-Santos G, Williams C, Ararso Y, Huang Y, Rodrigues G, Shen TL, Labori KJ, Lothe IM, Kure EH, Hernandez J, Doussot A, Ebbesen SH, Grandgenett PM, Hollingsworth MA, Jain M, Mallya K, Batra SK, Jarnagin WR, Schwartz RE, Matei I, Peinado H, Stanger BZ, Bromberg J, Lyden D (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17(6):816–826. doi:10.1038/ncb3169 PubMedPubMedCentralCrossRef

37.

Valencia K, Luis-Ravelo D, Bovy N, Anton I, Martinez-Canarias S, Zandueta C, Ormazabal C, Struman I, Tabruyn S, Rebmann V, De Las Rivas J, Guruceaga E, Bandres E, Lecanda F (2014) miRNA cargo within exosome-like vesicle transfer influences metastatic bone colonization. Mol Oncol 8(3):689–703. doi:10.1016/j.molonc.2014.01.012 PubMedPubMedCentralCrossRef

38.

Di Vizio D, Morello M, Dudley AC, Schow PW, Adam RM, Morley S, Mulholland D, Rotinen M, Hager MH, Insabato L, Moses MA, Demichelis F, Lisanti MP, Wu H, Klagsbrun M, Bhowmick NA, Rubin MA, D’Souza-Schorey C, Freeman MR (2012) Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 181(5):1573–1584. doi:10.1016/j.ajpath.2012.07.030 PubMedPubMedCentralCrossRef

39.

Di Vizio D, Kim J, Hager MH, Morello M, Yang W, Lafargue CJ, True LD, Rubin MA, Adam RM, Beroukhim R, Demichelis F, Freeman MR (2009) Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res 69(13):5601–5609. doi:10.1158/0008-5472.CAN-08-3860 PubMedPubMedCentralCrossRef

40.

Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM, Pienta MJ, Song J, Wang J, Loberg RD, Krebsbach PH, Pienta KJ, Taichman RS (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Investig 121(4):1298–1312. doi:10.1172/JCI43414 PubMedPubMedCentralCrossRef

41.

Wang H, Yu C, Gao X, Welte T, Muscarella AM, Tian L, Zhao H, Zhao Z, Du S, Tao J, Lee B, Westbrook TF, Wong ST, Jin X, Rosen JM, Osborne CK, Zhang XH (2015) The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27(2):193–210. doi:10.1016/j.ccell.2014.11.017 PubMedPubMedCentralCrossRef

42.

Shiozawa Y, Havens AM, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang J, Lu G, Roodman GD, Loberg RD, Pienta KJ, Taichman RS (2008) Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem 105(2):370–380. doi:10.1002/jcb.21835 PubMedPubMedCentralCrossRef

43.

Jung Y, Wang J, Song J, Shiozawa Y, Wang J, Havens A, Wang Z, Sun YX, Emerson SG, Krebsbach PH, Taichman RS (2007) Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood 110(1):82–90. doi:10.1182/blood-2006-05-021352 PubMedPubMedCentralCrossRef

44.

Jung Y, Shiozawa Y, Wang J, Patel LR, Havens AM, Song J, Krebsbach PH, Roodman GD, Taichman RS (2011) Annexin-2 is a regulator of stromal cell-derived factor-1/CXCL12 function in the hematopoietic stem cell endosteal niche. Exp Hematol 39(2):151–166e151. doi:10.1016/j.exphem.2010.11.007 PubMedCrossRef

45.

Jung Y, Wang J, Lee E, McGee S, Berry JE, Yumoto K, Dai J, Keller ET, Shiozawa Y, Taichman RS (2015) Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol Cancer Res 13(1):197–207. doi:10.1158/1541-7786.MCR-14-0118 PubMedCrossRef

46.

Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, Calandra G, Bridger G, Dale DC, Srour EF (2005) Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 201(8):1307–1318. doi:10.1084/jem.20041385 PubMedPubMedCentralCrossRef

47.

Taichman RS, Emerson SG (1998) The role of osteoblasts in the hematopoietic microenvironment. Stem Cells 16(1):7–15. doi:10.1002/stem.160007 PubMedCrossRef

48.

Kerr BA, Miocinovic R, Smith AK, West XZ, Watts KE, Alzayed AW, Klink JC, Mir MC, Sturey T, Hansel DE, Heston WD, Stephenson AJ, Klein EA, Byzova TV (2015) CD117(+) cells in the circulation are predictive of advanced prostate cancer. Oncotarget 6(3):1889–1897. doi:10.18632/oncotarget.2796 PubMedCrossRef

49.

Wiesner C, Nabha SM, Dos Santos EB, Yamamoto H, Meng H, Melchior SW, Bittinger F, Thuroff JW, Vessella RL, Cher ML, Bonfil RD (2008) C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis. Neoplasia 10(9):996–1003PubMedPubMedCentralCrossRef

50.

Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schoffski P, Scheffold C, Weitzman AL, Hussain M (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 31(4):412–419. doi:10.1200/JCO.2012.45.0494 PubMedCrossRef

51.

Shiozawa Y, Pienta KJ, Taichman RS (2011) Hematopoietic stem cell niche is a potential therapeutic target for bone metastatic tumors. Clin Cancer Res 17(17):5553–5558. doi:10.1158/1078-0432.CCR-10-2505 PubMedPubMedCentralCrossRef

52.

Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293. doi:10.1038/nrc2621 PubMedPubMedCentralCrossRef

53.

Ghajar CM (2015) Metastasis prevention by targeting the dormant niche. Nat Rev Cancer 15(4):238–247. doi:10.1038/nrc3910 PubMedPubMedCentralCrossRef

54.

Lam HM, Vessella RL, Morrissey C (2014) The role of the microenvironment-dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol 11:41–47. doi:10.1016/j.ddtec.2014.02.002 PubMedPubMedCentralCrossRef

55.

Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208(13):2641–2655. doi:10.1084/jem.20110840 PubMedPubMedCentralCrossRef

56.

Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63(7):1684–1695PubMed

57.

Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12(4):863–879PubMedPubMedCentralCrossRef

58.

Sharma S, Xing F, Liu Y, Wu K, Said N, Pochampally R, Shiozawa Y, Lin HK, Balaji KC, Watabe K (2016) Secreted protein acidic and rich in cysteine (SPARC) mediates metastatic dormancy of prostate cancer in bone. J Biol Chem 291(37):19351–19363. doi:10.1074/jbc.M116.737379 PubMedPubMedCentralCrossRef

59.

Jung Y, Shiozawa Y, Wang J, McGregor N, Dai J, Park SI, Berry JE, Havens AM, Joseph J, Kim JK, Patel L, Carmeliet P, Daignault S, Keller ET, McCauley LK, Pienta KJ, Taichman RS (2012) Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment. Neoplasia 14(5):429–439PubMedPubMedCentralCrossRef

60.

Taichman RS, Patel LR, Bedenis R, Wang J, Weidner S, Schumann T, Yumoto K, Berry JE, Shiozawa Y, Pienta KJ (2013) GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE 8(4):e61873. doi:10.1371/journal.pone.0061873 PubMedPubMedCentralCrossRef

61.

Cackowski FC, Eber MR, Rhee J, Decker AM, Yumoto K, Berry JE, Lee E, Shiozawa Y, Jung Y, Aguirre-Ghiso JA, Taichman RS (2016) Mer tyrosine kinase regulates disseminated prostate cancer cellular dormancy. J Cell Biochem. doi:10.1002/jcb.25768

62.

Cook LM, Shay G, Araujo A, Aruajo A, Lynch CC (2014) Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev 33(2–3):511–525. doi:10.1007/s10555-014-9494-4 PubMedPubMedCentralCrossRef

63.

Body JJ, Casimiro S, Costa L (2015) Targeting bone metastases in prostate cancer: improving clinical outcome. Nat Rev Urol 12(6):340–356. doi:10.1038/nrurol.2015.90 PubMedCrossRef

64.

Sottnik JL, Keller ET (2013) Understanding and targeting osteoclastic activity in prostate cancer bone metastases. Curr Mol Med 13(4):626–639PubMedPubMedCentralCrossRef

65.

Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola TC, Begtrup JL, Peterson TE, Fingleton B, Shirai T, Matrisian LM, Futakuchi M (2005) MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7(5):485–496. doi:10.1016/j.ccr.2005.04.013 PubMedCrossRef

66.

Hall CL, Daignault SD, Shah RB, Pienta KJ, Keller ET (2008) Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate 68(13):1396–1404. doi:10.1002/pros.20805 PubMedPubMedCentralCrossRef

67.

Thudi NK, Martin CK, Murahari S, Shu ST, Lanigan LG, Werbeck JL, Keller ET, McCauley LK, Pinzone JJ, Rosol TJ (2011) Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate 71(6):615–625. doi:10.1002/pros.21277 PubMedCrossRef

68.

Dai J, Hall CL, Escara-Wilke J, Mizokami A, Keller JM, Keller ET (2008) Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Res 68(14):5785–5794. doi:10.1158/0008-5472.CAN-07-6541 PubMedPubMedCentralCrossRef

69.

Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC (2008) RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 68(1):92–104. doi:10.1002/pros.20678 PubMedCrossRef

70.

Zhang J, Dai J, Qi Y, Lin DL, Smith P, Strayhorn C, Mizokami A, Fu Z, Westman J, Keller ET (2001) Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Investig 107(10):1235–1244. doi:10.1172/JCI11685 PubMedPubMedCentralCrossRef

71.

Zheng Y, Basel D, Chow SO, Fong-Yee C, Kim S, Buttgereit F, Dunstan CR, Zhou H, Seibel MJ (2014) Targeting IL-6 and RANKL signaling inhibits prostate cancer growth in bone. Clin Exp Metastasis 31(8):921–933. doi:10.1007/s10585-014-9680-3 PubMedCrossRef

72.

Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, Pomonis JD, Keyser CP, Clohisy DR, Adams DJ, O’Leary P, Mantyh PW (2002) Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113(1):155–166PubMedCrossRef

73.

Patel MS, Elefteriou F (2007) The new field of neuroskeletal biology. Calcif Tissue Int 80(5):337–347. doi:10.1007/s00223-007-9015-3 PubMedCrossRef

74.

Elefteriou F, Campbell P, Ma Y (2014) Control of bone remodeling by the peripheral sympathetic nervous system. Calcif Tissue Int 94(1):140–151. doi:10.1007/s00223-013-9752-4 PubMedCrossRef

75.

Elefteriou F (2005) Neuronal signaling and the regulation of bone remodeling. Cell Mol Life Sci 62(19–20):2339–2349. doi:10.1007/s00018-005-5175-3 PubMedCrossRef

76.

Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, Frenette PS (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124(2):407–421. doi:10.1016/j.cell.2005.10.041 PubMedCrossRef

77.

Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C, Battista M, Leboeuf M, Prophete C, van Rooijen N, Tanaka M, Merad M, Frenette PS (2011) Bone marrow CD169 + macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 208(2):261–271. doi:10.1084/jem.20101688 PubMedPubMedCentralCrossRef

78.

Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834. doi:10.1038/nature09262 PubMedPubMedCentralCrossRef

79.

Elefteriou F (2016) Role of sympathetic nerves in the establishment of metastatic breast cancer cells in bone. J Bone Oncol 5(3):132–134. doi:10.1016/j.jbo.2016.03.003 PubMedPubMedCentralCrossRef

80.

Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D, Thompson T, Miles BJ, Ittmann MM, Rowley D (2008) Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 14(23):7593–7603. doi:10.1158/1078-0432.CCR-08-1164 PubMedCrossRef

81.

Ayala GE, Wheeler TM, Shine HD, Schmelz M, Frolov A, Chakraborty S, Rowley D (2001) In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. Prostate 49(3):213–223PubMedCrossRef

82.

Ciftci S, Yilmaz H, Ciftci E, Simsek E, Ustuner M, Yavuz U, Muezzinoglu B, Dillioglugil O (2015) Perineural invasion in prostate biopsy specimens is associated with increased bone metastasis in prostate cancer. Prostate 75(15):1783–1789. doi:10.1002/pros.23067 PubMedCrossRef

83.

Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341(6142):1236361. doi:10.1126/science.1236361 PubMedCrossRef

84.

Palm D, Lang K, Niggemann B, Drell TL 4th, Masur K, Zaenker KS, Entschladen F (2006) The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer 118(11):2744–2749. doi:10.1002/ijc.21723 PubMedCrossRef

85.

Hassan S, Karpova Y, Baiz D, Yancey D, Pullikuth A, Flores A, Register T, Cline JM, D’Agostino R Jr, Danial N, Datta SR, Kulik G (2013) Behavioral stress accelerates prostate cancer development in mice. J Clin Investig 123(2):874–886. doi:10.1172/JCI63324 PubMedPubMedCentral

86.

Grytli HH, Fagerland MW, Fosså SD, Taskén KA (2014) Association between use of β-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol 65(3):635–641. doi:10.1016/j.eururo.2013.01.007 PubMedCrossRef

87.

Jimenez-Andrade JM, Bloom AP, Stake JI, Mantyh WG, Taylor RN, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW (2010) Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J Neurosci 30(44):14649–14656. doi:10.1523/JNEUROSCI.3300-10.2010 PubMedPubMedCentralCrossRef

88.

Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R (2008) Opioid complications and side effects. Pain Phys 11(2 Suppl):S105–S120

89.

Zylla D, Gourley BL, Vang D, Jackson S, Boatman S, Lindgren B, Kuskowski MA, Le C, Gupta K, Gupta P (2013) Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer 119(23):4103–4110. doi:10.1002/cncr.28345 PubMedCrossRef

90.

Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, Howell D, Konski A, Kachnic L, Lo S, Sahgal A, Silverman L, von Gunten C, Mendel E, Vassil A, Bruner DW, Hartsell W, American Society for Radiation O (2011) Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 79(4):965–976. doi:10.1016/j.ijrobp.2010.11.026 PubMedCrossRef

91.

Chow E, van der Linden YM, Roos D, Hartsell WF, Hoskin P, Wu JS, Brundage MD, Nabid A, Tissing-Tan CJ, Oei B, Babington S, Demas WF, Wilson CF, Meyer RM, Chen BE, Wong RK (2014) Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol 15(2):164–171. doi:10.1016/S1470-2045(13)70556-4 PubMedCrossRef

92.

Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, Suh JH, Demas WF, Movsas B, Petersen IA, Konski AA, Cleeland CS, Janjan NA, DeSilvio M (2005) Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97(11):798–804. doi:10.1093/jnci/dji139 PubMedCrossRef

93.

El-Amm J, Aragon-Ching JB (2016) Targeting bone metastases in metastatic castration-resistant prostate cancer. Clin Med Insights Oncol 10(Suppl 1):11–19. doi:10.4137/CMO.S30751 PubMedPubMedCentral

94.

Harrison MR, Wong TZ, Armstrong AJ, George DJ (2013) Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res 5:1–14. doi:10.2147/CMAR.S25537 PubMedPubMedCentralCrossRef

95.

Bruland OS, Nilsson S, Fisher DR, Larsen RH (2006) High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 12(20 Pt 2):6250s–6257s. doi:10.1158/1078-0432.CCR-06-0841 PubMedCrossRef

96.

Nilsson S, Larsen RH, Fossa SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS (2005) First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 11(12):4451–4459. doi:10.1158/1078-0432.CCR-04-2244 PubMedCrossRef

97.

Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franzen L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland OS, Sartor O, Investigators A (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369(3):213–223. doi:10.1056/NEJMoa1213755 PubMedCrossRef

98.

Saad F, Carles J, Gillessen S, Heidenreich A, Heinrich D, Gratt J, Levy J, Miller K, Nilsson S, Petrenciuc O, Tucci M, Wirth M, Federhofer J, O’Sullivan JM, Radium-223 International Early Access Program I (2016) Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol 17(9):1306–1316. doi:10.1016/S1470-2045(16)30173-5 PubMedCrossRef

99.

Vuong W, Sartor O, Pal SK (2014) Radium-223 in metastatic castration resistant prostate cancer. Asian J Androl 16(3):348–353. doi:10.4103/1008-682X.127812 PubMedPubMedCentralCrossRef

100.

Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83(9):1032–1045. doi:10.4065/83.9.1032 PubMedPubMedCentralCrossRef

101.

Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ (2000) Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 15(8):1467–1476. doi:10.1359/jbmr.2000.15.8.1467 PubMedCrossRef

102.

Benford HL, McGowan NW, Helfrich MH, Nuttall ME, Rogers MJ (2001) Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone 28(5):465–473PubMedCrossRef

103.

Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B, Zoledronic Acid Prostate Cancer Study G (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94(19):1458–1468PubMedCrossRef

104.

Paller CJ, Carducci MA, Philips GK (2012) Management of bone metastases in refractory prostate cancer–role of denosumab. Clin Interv Aging 7:363–372. doi:10.2147/CIA.S27930 PubMedPubMedCentralCrossRef

105.

Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377(9768):813–822. doi:10.1016/S0140-6736(10)62344-6 PubMedPubMedCentralCrossRef

106.

Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damiao R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gomez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379(9810):39–46. doi:10.1016/S0140-6736(11)61226-9 PubMedCrossRef

107.

Thellenberg-Karlsson C, Nyman C, Nilsson S, Blom R, Marquez M, Castellanos E, Holmberg AR (2016) Bone-targeted novel cytotoxic polybisphosphonate conjugate in castration-resistant prostate cancer: a multicenter phase 1 study. Anticancer Res 36(12):6499–6504. doi:10.21873/anticanres.11249 PubMedCrossRef

108.

Alaiya A, Fox J, Bobis S, Matic G, Shinwari Z, Barhoush E, Marquez M, Nilsson S, Holmberg AR (2014) Proteomic analysis of soft tissue tumor implants treated with a novel polybisphosphonate. Cancer Genom Proteom 11(1):39–49

109.

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, Investigators IS (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422. doi:10.1056/NEJMoa1001294 PubMedCrossRef

110.

Nilsson S (2016) Radionuclide therapies in prostate cancer: integrating radium-223 in the treatment of patients with metastatic castration-resistant prostate cancer. Curr Oncol Rep 18(2):14. doi:10.1007/s11912-015-0495-4 PubMedPubMedCentralCrossRef

111.

Morris MJ, Higano CS, Scher HI, Sweeney C, Antonarakis ES, Shevrin DH, Ryan CJ, Loriot Y, Fizazi K, Pandit-Taskar N, Garcia-Vargas JE, Lyseng K, Bloma M, Carrasquillo JA (2015) Effects of radium-223 dichloride (Ra-223) with docetaxel (D) vs D on prostate-specific antigen (PSA) and bone alkaline phosphatase (bALP) in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases (mets): a phase 1/2a clinical trial. J Clin Oncol 33(7 Suppl):202. doi:10.1200/jco.2015.33.7_suppl.202 CrossRef

112.

O’Sullivan J GS, Heidenreich A, Heinrich D, Gratt J, Lévy J et al (2015) Effects of concomitant use of abiraterone and/or enzalutamide with radium-223 on safety and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients treated in an international early access program (EAP). In: European society for medical oncology, Vienna, Austria, 2015. Abstract 2561

Title: Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis
Authors: Sun H. Park
Evan T. Keller
Yusuke Shiozawa
Publication date: 01-02-2018
Publisher: Springer US
Published in: Calcified Tissue International / Issue 2/2018
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-017-0350-8

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