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TumorDiagnostik & Therapie 2013; 34(3): 147-153
DOI: 10.1055/s-0033-1335193
Thieme Onkologie aktuell
© Georg Thieme Verlag KG Stuttgart · New York

RANK-, RANKL- und OPG-Expression beim Mammakarzinom – Einfluss auf ossäre Metastasierung

RANK, RANKL and OPG Expression in Breast Cancer – Influence on Osseous Metastasis
J. T. Ney
1   Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar
,
T. Fehm
2   Universitäts-Frauenklinik Tübingen, Universitätsklinikum Tübingen, Tübingen
,
I. Juhasz-Boess
1   Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar
,
E. F. Solomayer
1   Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar
› Author Affiliations
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Publication History

Publication Date:
19 April 2013 (online)

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Zusammenfassung

Maligne Erkrankungen der Brust zählen in Europa zu den häufigsten bösartigen Tumoren bei Frauen. Bei fortgeschrittenem Brustkrebs erhöht sich das Risiko einer Knochenmetastase auf 65 – 75 %. Die Entdeckung der physiologischen Knochenstoffwechselparameter RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) und OPG (osteoprotegerin) sowie deren pathophysiologische Beteiligung bei ossär bedingten Erkrankungen ist Gegenstand neuer Therapiestrategien. Gerade die Entstehung von osteolytischen Knochenmetastasen setzt eine gesteigerte Osteoklastenaktivität voraus. Eine Aktivierung der Osteoklasten durch übermäßige direkte RANKL- oder reduzierte OPG-Expression ossär metastasierter Tumorzellen ist bis heute nicht eindeutig geklärt. In über 50 % der Fälle exprimierten primäre Mammakarzinomzellen OPG und RANK, während RANKL in nur 14 – 60 % nachgewiesen werden konnte. Erhöhte OPG-Konzentrationen im Serum von Patientinnen mit Knochenmetastasen konnten in mehreren Studien gezeigt werden, während die RANKL-Resultate gegensätzlich beschrieben sind. Eine Verwendung von OPG als Biomarker zur Detektion von osteolytischen Knochenmetastasen ist nicht einheitlich und muss durch weitere Studien belegt werden. Eine erhöhte RANKL-Aktivität konnte bei Krankheiten mit ausgedehntem Knochenverlust gefunden werden und bildete die Grundlage neuer Therapieoptionen. In mehreren Studien wurde ein humaner monoklonaler Antikörper gegen RANKL (Denosumab) zur Behandlung ossär bedingter Erkrankungen untersucht. Denosumab stellt wegen seiner knochenprotektiven Wirkung eine vielversprechende Therapieoption dar.

Abstract

In women, malignant breast tumours are among the most common malignant diseases in Europe. In advanced breast cancer, the risk of bone metastasis increases to 65 – 75 %. The discovery of the physiological bone metabolism parameters RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) and OPG (osteoprotegerin) as well as their pathophysiological involvement in bone-related diseases is the subject of new therapeutic strategies. The formation of osteolytic bone metastasis requires increased osteoclast activity. Activation of osteoclasts by excessive direct RANKL or reduced OPG expression of osseous metastatic tumour cells remains to be elucidated. More than 50 % of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14 – 60 %. Increased OPG concentrations in the serum of patients with bone metastases have been shown in several studies, whereas the RANKL results are described in an opposite manner. The use of OPG as a biomarker for the detection of osteolytic bone metastases is not consistent and needs to be proved in further studies. Increased RANKL activity was found in diseases characterised by excessive bone loss and formed the basis of new therapeutic options. In several studies, a human monoclonal antibody to RANKL (denosumab) was investigated for the treatment of bone diseases. Denosumab is a promising therapeutic option due to its bone-protective effects.

Schlüsselwörter

RANKL - OPG - Mammakarzinom - Knochenmetastase - Denosumab

Key words

RANKL - OPG - breast cancer - bone metastasis - denosumab
 

  • Literatur

  • 1 Keck AV, Pecherstorfer M. Knochenstoffwechsel bei malignen Erkrankungen. J Miner Stoffwechs 2003; 10: 6-11
    PubMedGoogle Scholar
  • 2 Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010; 285: 25 103-25 108
    CrossrefPubMedGoogle Scholar
  • 3 Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4: 638-649
    CrossrefPubMedGoogle Scholar
  • 4 Kong YY, Feige U, Sarosi I et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402: 304-309
    CrossrefPubMedGoogle Scholar
  • 5 Lacey DL, Timms E, Tan HL et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-176
    CrossrefPubMedGoogle Scholar
  • 6 Lum L, Wong BR, Josien R et al. Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 1999; 274: 13 613-13 618
    CrossrefPubMedGoogle Scholar
  • 7 Fuller K, Wong B, Fox S et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998; 188: 997-1001
    CrossrefPubMedGoogle Scholar
  • 8 O'Brien EA, Williams JH, Marshall MJ. Osteoprotegerin ligand regulates osteoclast adherence to the bone surface in mouse calvaria. Biochem Biophys Res Commun 2000; 274: 281-290
    CrossrefPubMedGoogle Scholar
  • 9 Anderson DM, Maraskovsky E, Billingsley WL et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997; 390: 175-179
    CrossrefPubMedGoogle Scholar
  • 10 Hsu H, Lacey DL, Dunstan CR et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96: 3540-3545
    CrossrefPubMedGoogle Scholar
  • 11 Dougall WC, Glaccum M, Charrier K et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13: 2412-2424
    CrossrefPubMedGoogle Scholar
  • 12 Kong YY, Yoshida H, Sarosi I et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315-323
    CrossrefPubMedGoogle Scholar
  • 13 Stolina M, Dwyer D, Ominsky MS et al. Continuous RANKL inhibition in osteoprotegerin transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses. J Immunol 2007; 179: 7497-7505
    PubMedGoogle Scholar
  • 14 Mizuno A, Kanno T, Hoshi M et al. Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis. J Bone Miner Metab 2002; 20: 337-344
    CrossrefPubMedGoogle Scholar
  • 15 Lloyd SA, Yuan YY, Kostenuik PJ et al. Soluble RANKL induces high bone turnover and decreases bone volume, density, and strength in mice. Calcif Tissue Int 2008; 82: 361-372
    CrossrefPubMedGoogle Scholar
  • 16 Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
    CrossrefPubMedGoogle Scholar
  • 17 Tsuda E, Goto M, Mochizuki S et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997; 234: 137-142
    CrossrefPubMedGoogle Scholar
  • 18 Yamaguchi K, Kinosaki M, Goto M et al. Characterization of structural domains of human osteoclastogenesis inhibitory factor. J Biol Chem 1998; 273: 5117-5123
    CrossrefPubMedGoogle Scholar
  • 19 Gori F, Hofbauer LC, Dunstan CR et al. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology 2000; 141: 4768-4776
    CrossrefPubMedGoogle Scholar
  • 20 Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand. J Biol Chem 2005; 280: 41155-41164
    CrossrefPubMedGoogle Scholar
  • 21 Shalhoub V, Faust J, Boyle WJ et al. Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors. J Cell Biochem 1999; 72: 251-261
    CrossrefPubMedGoogle Scholar
  • 22 Bucay N, Sarosi I, Dunstan CR et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-1268
    CrossrefPubMedGoogle Scholar
  • 23 Quattrocchi CC, Piciucchi S, Sammarra M et al. Bone metastases in breast cancer: higher prevalence of osteosclerotic lesions. Radiol Med 2007; 112: 1049-1059
    CrossrefPubMedGoogle Scholar
  • 24 Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483-2494
    CrossrefPubMedGoogle Scholar
  • 25 Charhon SA, Chapuy MC, Delvin EE et al. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer 1983; 51: 918-924
    CrossrefPubMedGoogle Scholar
  • 26 Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005; 12: 549-583
    CrossrefPubMedGoogle Scholar
  • 27 Goltzman D. Osteolysis and cancer. J Clin Invest 2001; 107: 1219-1220
    CrossrefPubMedGoogle Scholar
  • 28 Bendre MS, Margulies AG, Walser B et al. Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 2005; 65: 11001-11009
    CrossrefPubMedGoogle Scholar
  • 29 Perez M, Migliaccio S, Taranta A et al. Melanoma cells stimulate osteoclastogenesis, c-Src expression and osteoblast cytokines. Eur J Cancer 2001; 37: 629-640
    CrossrefPubMedGoogle Scholar
  • 30 Thomas RJ, Guise TA, Yin JJ et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 1999; 140: 4451-4458
    CrossrefPubMedGoogle Scholar
  • 31 Blum B, Moseley J, Miller L et al. Measurement of bone morphogenetic proteins and other growth factors in demineralized bone matrix. Orthopedics 2004; 27: s161-s165
    PubMedGoogle Scholar
  • 32 Guise TA, Chirgwin JM. Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res 2003; S32-S38
    PubMedGoogle Scholar
  • 33 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002; 2: 584-593
    CrossrefPubMedGoogle Scholar
  • 34 Park HR, Min SK, Cho HD et al. Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis. J Korean Med Sci 2003; 18: 541-546
    PubMedGoogle Scholar
  • 35 Schubert A, Schulz H, Emons G et al. Expression of osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in HCC70 breast cancer cells and effects of treatment with gonadotropin-releasing hormone on RANKL expression. Gynecol Endocrinol 2008; 24: 331-338
    CrossrefPubMedGoogle Scholar
  • 36 Reinholz MM, Iturria SJ, Ingle JN et al. Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 2002; 74: 255-269
    CrossrefPubMedGoogle Scholar
  • 37 Nicolin V, Bortul R, Bareggi R et al. Breast adenocarcinoma MCF‑7 cell line induces spontaneous osteoclastogenesis via a RANK-ligand-dependent pathway. Acta Histochem 2008; 110: 388-396
    CrossrefPubMedGoogle Scholar
  • 38 Nicolin V, Narducci P. Soluble TRAIL could enhance bone destruction acting on Rank-ligand in estrogen-independent human breast cancer cell line MDA‑MB‑231. Acta Histochem 2010; 112: 189-192
    CrossrefPubMedGoogle Scholar
  • 39 Bhatia P, Sanders MM, Hansen MF. Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res 2005; 11: 162-165
    PubMedGoogle Scholar
  • 40 Santini D, Perrone G, Roato I et al. Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol 2011; 226: 780-784
    CrossrefPubMedGoogle Scholar
  • 41 Trinkaus M, Ooi WS, Amir E et al. Examination of the mechanisms of osteolysis in patients with metastatic breast cancer. Oncol Rep 2009; 21: 1153-1159
    PubMedGoogle Scholar
  • 42 Santini D, Schiavon G, Vincenzi B et al. Receptor activator of NF‑kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One 2011; 6: e19234
    CrossrefPubMedGoogle Scholar
  • 43 Van Poznak C, Cross SS, Saggese M et al. Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. J Clin Pathol 2006; 59: 56-63
    CrossrefPubMedGoogle Scholar
  • 44 Cross SS, Harrison RF, Balasubramanian SP et al. Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. J Clin Pathol 2006; 59: 716-720
    CrossrefPubMedGoogle Scholar
  • 45 Huang L, Cheng YY, Chow LT et al. Tumour cells produce receptor activator of NF-kappaB ligand (RANKL) in skeletal metastases. J Clin Pathol 2002; 55: 877-878
    CrossrefPubMedGoogle Scholar
  • 46 Holen I, Cross SS, Neville-Webbe HL et al. Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo – a role in tumour cell survival?. Breast Cancer Res Treat 2005; 92: 207-215
    CrossrefPubMedGoogle Scholar
  • 47 Jones DH, Nakashima T, Sanchez OH et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006; 440: 692-696
    CrossrefPubMedGoogle Scholar
  • 48 Emery JG, McDonnell P, Burke MB et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14 363-14 367
    CrossrefPubMedGoogle Scholar
  • 49 Vitovski S, Phillips JS, Sayers J et al. Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways. J Biol Chem 2007; 282: 31601-31609
    CrossrefPubMedGoogle Scholar
  • 50 Lipton A, Ali SM, Leitzel K et al. Serum osteoprotegerin levels in healthy controls and cancer patients. Clin Cancer Res 2002; 8: 2306-2310
    PubMedGoogle Scholar
  • 51 Mountzios G, Dimopoulos MA, Bamias A et al. Abnormal bone remodeling process is due to an imbalance in the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis in patients with solid tumors metastatic to the skeleton. Acta Oncol 2007; 46: 221-229
    CrossrefPubMedGoogle Scholar
  • 52 Mercatali L, Ibrahim T, Sacanna E et al. Bone metastases detection by circulating biomarkers: OPG and RANK‑L. Int J Oncol 2011; 39: 255-261
    PubMedGoogle Scholar
  • 53 Leeming DJ, Koizumi M, Byrjalsen I et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomarkers Prev 2006; 15: 32-38
    CrossrefPubMedGoogle Scholar
  • 54 Martinetti A, Bajetta E, Ferrari L et al. Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrozole. Endocr Relat Cancer 2004; 11: 771-779
    CrossrefPubMedGoogle Scholar
  • 55 Yano K, Tsuda E, Washida N et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 1999; 14: 518-527
    CrossrefPubMedGoogle Scholar
  • 56 Mountzios G, Terpos E, Syrigos K et al. Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. Transl Res 2010; 155: 247-255
    CrossrefPubMedGoogle Scholar
  • 57 Bekker PJ, Holloway D, Nakanishi A et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001; 16: 348-360
    CrossrefPubMedGoogle Scholar
  • 58 Body JJ, Greipp P, Coleman RE et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97: 887-892
    CrossrefPubMedGoogle Scholar
  • 59 Bekker PJ, Holloway DL, Rasmussen AS et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. 2004 J Bone Miner Res 2005; 20: 2275-2282
    PubMedGoogle Scholar
  • 60 Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005; 5: 618-625
    CrossrefPubMedGoogle Scholar
  • 61 Eastell R, Christiansen C, Grauer A et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 2011; 26: 530-537
    CrossrefPubMedGoogle Scholar
  • 62 McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821-831
    CrossrefPubMedGoogle Scholar
  • 63 Deodhar A, Dore RK, Mandel D et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2010; 62: 569-574
    CrossrefPubMedGoogle Scholar
  • 64 Dore RK, Cohen SB, Lane NE et al. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69: 872-875
    CrossrefPubMedGoogle Scholar
  • 65 Body JJ, Facon T, Coleman RE et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006; 12: 1221-1228
    CrossrefPubMedGoogle Scholar
  • 66 Lipton A, Steger GG, Figueroa J et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007; 25: 4431-4437
    CrossrefPubMedGoogle Scholar
  • 67 Lipton A, Steger GG, Figueroa J et al. Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 2008; 14: 6690-6696
    CrossrefPubMedGoogle Scholar
  • 68 Fizazi K, Lipton A, Mariette X et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009; 27: 1564-1571
    CrossrefPubMedGoogle Scholar
  • 69 Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28: 5132-5139
    CrossrefPubMedGoogle Scholar
  • 70 Ellis GK, Bone HG, Chlebowski R et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 2009; 118: 81-87
    CrossrefPubMedGoogle Scholar
  • 71 Sterling JA, Edwards JR, Martin TJ et al. Advances in the biology of bone metastasis: how the skeleton affects tumor behavior. Bone 2010; 48: 6-15
    PubMedGoogle Scholar