Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2011  |  Volume : 7  |  Issue : 2  |  Page : 115-119

Serum bone sialoprotein levels and bone metastases

Department of Senescence, Urological and Neurological Sciences, University of Catania, Italy

Date of Web Publication12-Jul-2011

Correspondence Address:
Mario Uccello
Department of Senescence, Urological and Neurological Sciences, University of Catania
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.82912

Rights and Permissions
 > Abstract 

The skeleton is the most common site of tumor metastasis. The detection of metastatic bone disease is critical for primary cancer staging because it will condition the therapeutic decision and the prognosis. For the diagnosis of bone metastases, imaging techniques are usually employed, even if these techniques have some limitations in terms of accuracy and costs. An innovative, cheaper method for the screening of skeletal metastases could be the measurement of bone turnover markers. This article is aimed at providing a literature review on the clinical significance of increased serum levels of bone sialoprotein (BSP) observed in patients suffering from metastatic bone lesions. In addition, we have briefly summarized recent studies reporting the biological and pathological roles of BSP in bone remodeling and bone metastasis. Some studies have demonstrated that serum BSP can be considered as an early marker and a prognostic factor for the development of bone metastases. BSP may help in assessing osteolytic bone disease, in evaluating additional prognostic information and in monitoring treatment modalities.

Keywords: Bone metastasis, bone remodeling, bone sialoprotein, bone turnover markers, breast cancer, multiple myeloma

How to cite this article:
Uccello M, Malaguarnera G, Vacante M, Motta M. Serum bone sialoprotein levels and bone metastases. J Can Res Ther 2011;7:115-9

How to cite this URL:
Uccello M, Malaguarnera G, Vacante M, Motta M. Serum bone sialoprotein levels and bone metastases. J Can Res Ther [serial online] 2011 [cited 2022 Jul 7];7:115-9. Available from: https://www.cancerjournal.net/text.asp?2011/7/2/115/82912

 > Introduction Top

The skeleton is the most common metastatic site, especially in patients with osteotropic malignancies such as breast, prostate, lung, thyroid and renal cancers [1] and multiple myeloma (MM). [2] Around 65-75% of patients affected by advanced prostate or breast cancer and up to 40% of patients with other advanced solid tumors will develop osseous metastases. Moreover, in the course of advanced cancer disease the finding of metastasis clinically limited to the skeleton is a frequent event. [3] The molecular basis of bone metastasis is intricate and involves the stimulation of both osteoblasts and osteoclasts, and the response of the bone microenvironment. [4] The presence of tumor cells disrupts the equilibrium of bone remodeling, causing bone lesions that result from an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. [5],[6] Bone metastatic lesions are detectable through imaging techniques and have been classified as osteoblastic, osteolytic or mixed according to the radiographic appearance of the lesion. [6] Bone metastases increase the risk of skeletal-related events (SREs) such as severe bone pain, functional impotence, pathological fractures, spinal cord or nerve roots' compression, alteration of hematopoiesis by bone marrow infiltration and hypercalcemia which may have a decisive impact on the quality of life, morbidity and mortality of cancer patients. [3] The detection of metastatic bone disease is critical for primary cancer staging because it will condition the therapeutic decision and the prognosis. [7] For the diagnosis of bone metastases, imaging techniques are usually employed, even if these techniques have some limitations in terms of accuracy and costs. [8] An innovative, cheaper method for the screening of skeletal metastases could be the measurement of bone turnover markers. In recent years, there has been increasing attention around bone metabolism markers. However, the sensitivity and specificity of this innovative approach have not been fully assessed yet. Two different types of bone metabolism markers can be analyzed: markers of bone formation (osteocalcin, alkaline phosphatase (ALP), etc.) and markers of bone resorption (tartrate-resistant acid phosphatase, deoxypyridinoline and many others). [9] This review is especially focused on the clinical significance of serum levels of bone sialoprotein (BSP), usually considered to be a bone resorption marker, [10] in osseous metastases.

 > Bone Sialoprotein: A Multifunctional Protein Top

BSP is a sialic acid-rich, phosphorylated glycoprotein constituting one of the major non-collagenous organic matrix fractions in human bone. [11] It has a molecular mass of 70-80 KDa and contains several glutamic acid and glycine residues which represent 32% of all residues. The glutamic acid residues are typically distributed in clusters of up to 10 consecutive residues. [12] BSP belongs to the small integrin-binding ligand, N-linked glycoproteins (SIBLING) family of proteins which also includes osteopontin, dentin matrix protein-1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein. The SIBLINGs, clustered on human Chromosome 4, interact with several types of cells, especially via integrins, and with bone mineral, thus playing a crucial role in the regulation of bone development, remodeling and repair. [13] BSP is synthesized by osteoblasts, osteoclasts, osteocytes and chondrocytes [13],[14] and its functional specificities remain not perfectly clear yet. However, several studies have indicated BSP as a promoter for the initial formation of mineral crystals in bone, cementum and dentine and as an early marker of osteogenic differentiation. [15],[16],[17],[18] It is also conceivable that it is particularly involved in the process of osteoclastogenesis. [19] It has been suggested that BSP may contribute to the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated bone resorption by inducing osteoclastogenesis and osteoclast survival and decreasing osteoclast apoptosis. [20],[21] Many factors, including hormones, growth factors and cytokines, may interfere in regulating BSP transcription through tyrosine kinase, mitogen-activated protein kinase and cAMP-dependent pathways. [22],[23] Obtained data indicate BSP as an intriguing, multifunctional protein mainly involved in bone metabolism. In summary, BSP may intervene at several steps of bone remodeling by its capability to nucleate hydroxyapatite crystal formation under steady-state conditions, promote mineralization of some osteoblastic cell lines, induce osteoblast and osteoclast adhesion and increase osteoclastogenesis and bone resorption. [24],[25],[26],[27],[28] BSP levels are increased in patients affected by bone diseases with high bone remodeling, such as osteoporosis, hyperparathyroidism, Paget's disease of bone and rheumatoid arthritis, when compared with controls. [28],[29],[30],[31] Furthermore, serum BSP concentrations are significantly higher in postmenopausal women than in premenopausal ones.[29],[32] The reference interval of BSP concentration in healthy people is around 2-24 ng/ml and shows a Gaussian distribution. [32],[33] Nevertheless, the clinical interest around BSP largely stems from its role as an early marker or prognostic factor for the subsequent development of bone metastases. Although BSP is not considered a well-established tumor marker, its increased serum levels have been associated with bone metastases. [29],[32],[33],[34],[35]

 > BSP and Bone Metastasis Top

Numerous studies have suggested that BSP is involved in the process of bone metastasis though the underlying mechanisms are not perfectly clear yet. [27],[36] BSP expression is increased in many tumors that metastasize to bone, such as breast, [37],[38],[39],[40] lung, [41],[42] prostate [43] and thyroid [44] cancers, and represents a predictive factor for further development of bone metastases. [45] Immunohistochemical staining demonstrated that BSP expression was higher in bone metastases than in visceral metastases in breast and prostate cancer patients. [46] BSP may promote tumor cell growth, adhesion and migratory response via interaction with αvβ3 and αvβ5 integrins through a specific integrin-binding Arg-Gly-Asp (RGD) motif [Figure 1] [47],[48],[49],[50] which is a common recognition sequence for several integrins. [51] BSP may be used by cancer cells to increase their ability to successfully migrate through matrix barriers while metastasizing to various tissues, particularly the bone. [36],[49],[50],[52] BSP may contribute to tumor cell progression because of its ability to interact with transforming growth factor-β (TGF-β) [53] and matrix metalloproteinase 2 (MMP-2). [50],[52] TGF-β behaves as a tumor suppressor in early-stage tumors but is paradoxically diverted into a potent prometastatic factor in advanced cancers. [54] MMP-2 cooperates to modulate homeostasis of the extracellular environment by regulating oncogenic signaling networks and degrading extracellular matrix components; [55],[56] however, the results obtained from a Hwang et al., study [57] do not support the role of BSP in promoting metastasis through mediating MMP-2 activation. There is evidence that endogenous BSP synthesized by osteoclasts induces tumor cell attachment to the bone, promotes osteoclast differentiation in metastatic osteolysis of breast cancer and consequently facilitates bone metastasis of this malignancy. [27],[46],[48],[58],[59] BSP has been shown to act as a pro-angiogenic factor: it mediates the attachment and migration of human endothelial cells through αvβ3 integrin and induces angiogenesis in the chick chorioallantoic membrane assay. [36],[60] Moreover, the potential efficacy of future BSP-targeted therapies has been demonstrated by several preclinical animal models. [58],[61],[62],[63] The studies aimed at measuring BSP in sera of tumor patients reported scheming results. Seibel et al.,[29] found higher serum BSP levels in 19 patients with breast cancer and in 32 patients with MM in comparison with healthy controls. Serum BSP levels were highest in patients affected by MM, with a significant increase from early to advanced stages of the disease. Furthermore, in a subgroup of 15 patients with metastatic breast cancer, intravenous bisphosphonate treatment caused a rapid reduction of serum BSP levels. Woitge et al.,[33] measured serum BSP concentrations in 62 newly diagnosed MM patients who were followed over a period of four years. The values were found to be significantly increased in these subjects and were associated with tumor burden, bone involvement and overall survival. Indeed, tumor patients with normal levels of BSP had a better prognosis than patients with initially higher BSP concentrations. Wolfgang et al.,[32] measured BSP and other markers of bone metabolism in the serum of 77 patients with various malignant diseases. According to scintigraphic criteria, 55 patients were without bone metastases and 22 patients presented bone metastases. Serum BSP levels were found to be significantly greater in tumor patients with osseous metastases than in those without osseous metastases, even if serum alkaline phosphatase (ALP) resulted better in discerning between patients with and without bone metastases. Diel et al.,[34] analyzed serum BSP values in 388 patients with non-metastatic breast cancer disease and in 30 control patients. A 24 ng/ml value was selected as cut-off for elevated serum BSP levels. After a median follow-up period of only 20 months, among the 19 women that subsequently developed skeletal metastases serum BSP values were elevated in 17 of them, and by means of a multivariate regression analysis, BSP was found to be an independent prognostic factor for the development of bone metastases in breast cancer. A study by Loibl et al.[35] confirmed the role of BSP as a prognostic marker for development of bone metastases. The investigation was performed in 89 women with primary breast cancer, and 17 of them subsequently developed skeletal metastases. In contrast with this evidence, in a study performed by Jung et al.,[64] which aimed to compare 10 serum bone turnover markers in 117 men with prostate carcinoma, BSP was not found to be a predictor for further development of bone metastases: its concentrations were already elevated in patients without bone metastases. Nevertheless, it was shown that among the compared markers only osteoprotegerin and BSP were independent prognostic factors for cancer-related death. In these studies serum BSP levels were measured by immunoassays (ELISA or RIA). However, BSP has been shown to bind to complement factor H in the serum. On the one hand this binding protects tumor cells from complement-mediated attack, but on the other, it has to be disrupted to accurately measure total BSP levels. [65],[66] Using a method capable of detecting the full quota of BSP, Fedarko et al.,[66] analyzed serum BSP levels of 20 patients for each of four different types of cancer. The values were significantly higher in colon, breast and prostate cancers while in lung cancer there was no difference in comparison with the controls. In a more recent study conducted by Jain et al.,[67] on 102 prostate cancer patients, BSP concentrations were higher than in the control group, but the values were found to be significantly increased only in late stages.
Figure 1: Integrin αvβ3 and Arg-Gly-Asp (RGD) motif play a fundamental role in allowing bone sialoprotein (BSP) interactions with endothelial cells, osteoclasts and tumor cells

Click here to view

 > Discussion Top

The occurrence of bone metastases is an important prognostic factor for survival and has a major influence on therapeutic decision. [7] Scintigraphic screening is the widely standardized method for the diagnosis of bone metastases, but its specificity is poor as inflammation and traumatic fractures lead to pseudopositivity. Thus, a positive scan often requires confirmation by other more expensive, time-consuming imaging modalities, most often computerized tomography (CT) and magnetic resonance (MR), and sometimes by histology. [8] According to data emerging from several studies, [1],[7],[68] markers of bone metabolism may be an additional, useful, noninvasive diagnostic and prognostic tool to improve cancer disease management. ALP has extensively been used for the screening of skeletal metastases although it does not have as great sensitivity for bone involvement as the isoform bone alkaline phosphatase (BALP). ALP and BALP in conjunction have demonstrated high accuracy in screening for the presence of bone metastases and probably they can avoid most of the bone scans that are routinely performed. [68] Several studies have shown an association between increased levels of other bone turnover markers, such as the cross-linked N-terminal telopeptide of Type I collagen (NTx), and both the presence and extent of bone metastases and the incidence of SREs. [1],[9],[69],[70] BSP belongs to the SIBLING family and represents one of the major non-collagenous organic matrix fractions in human bone. [11],[12],[13] Accumulating evidence supports the role of BSP as an important cooperator in the process of osteotropic cancer metastasis. [27],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[58],[59],[60],[61],[62],[63],[64],[65] It is conceivable that BSP may mediate the attachment and activation of osteoclasts and facilitate tumor cell invasion, migration, adhesion and proliferation to bone tissue. [27],[36],[47],[48],[49] Some studies have demonstrated a significant correlation between BSP serum values and both the presence and the risk for the subsequent detection of bone metastases, especially in patients affected by breast cancer and MM. [29],[32],[33],[34],[35] Moreover, a decrease in BSP levels has been shown after intravenous bisphosphonate treatment. [29] In conclusion, it is necessary to develop better techniques in order to effectively and accurately diagnose metastatic bone lesions. BSP may provide additional prognostic information in monitoring treatment modalities. Serum BSP could be considered as an early, independent marker and a prognostic factor for the development of bone metastases. The expression of BSP also correlates with bone metastases and may serve as negative prognostic factor. Additionally, the BSP-mediated interaction between tumor cells and bone tissue could prove to be another piece in the intricate puzzle of the pathogenesis of bone metastasis. Further studies are needed in order to evaluate the diagnostic and prognostic utility of bone metabolism markers. Among these markers BSP may be regarded as one of the most promising.

 > References Top

1.Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97:59-69.  Back to cited text no. 1
2.Terpos E. Biochemical markers of bone metabolism in multiple myeloma. Cancer Treat Rev 2006;32:15-9.  Back to cited text no. 2
3.Coleman RE. Risks and benefits of bisphosphonates. Br J Cancer 2008;98:1736-40.   Back to cited text no. 3
4.Lipton A, Berenson JR, Body JJ, Boyce BF, Bruland OS, Carducci MA, et al. Advances in treating metastatic bone cancer: Summary statement for the First Cambridge Conference. Clin Cancer Res 2006;12:6209s-12.  Back to cited text no. 4
5.Brown JE, Sim S. Evolving role of bone biomarkers in castration-resistant prostate cancer. Neoplasia 2010;12:685-96.  Back to cited text no. 5
6.Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 2006;12:6213s-6.  Back to cited text no. 6
7.Fontana A, Delmas PD. Markers of bone turnover in bone metastases. Cancer 2000;88:2952-60.  Back to cited text no. 7
8.Schoenberger J, Rozeboom S, Wirthgen-Beyer E, Eilles C. Evaluation of the clinical value of bone metabolic parameters for the screening of osseous metastases compared to bone scintigraphy. BMC Nucl Med 2004;4:3.  Back to cited text no. 8
9.Coleman R, Brown J, Terpos E, Lipton A, Smith MR, Cook R, et al. Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions. Cancer Treat Rev 2008;34:629-39.  Back to cited text no. 9
10.Shaarawy M, Hasan M. Serum bone sialoprotein: a marker of bone resorption in postmenopausal osteoporosis. Scand J Clin Lab Invest 2001;61:513-21.  Back to cited text no. 10
11.Fisher LW, McBride OW, Termine JD, Young MF. Human bone sialoprotein. Deduced protein sequence and chromosomal localization. J Biol Chem 1990;265:2347-51.  Back to cited text no. 11
12.Oldberg A, Franzén A, Heinegård D. The primary structure of a cell-binding bone sialoprotein. J Biol Chem 1988;263:19430-2.  Back to cited text no. 12
13.Fisher LW, Fedarko NS. Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res 2003;44:33-40.  Back to cited text no. 13
14.Masi L, Brandi ML, Robey PG, Crescioli C, Calvo JC, Bernabei P, et al. Biosynthesis of bone sialoprotein by a human osteoclast-like cell line (FLG 29.1). J Bone Miner Res 1995;10:187-96.  Back to cited text no. 14
15.Chen J, Shapiro HS, Sodek J. Development expression of bone sialoprotein mRNA in rat mineralized connective tissues. J Bone Miner Res 1992;7:987-97.  Back to cited text no. 15
16.Kasugai S, Nagata T, Sodek J. Temporal studies on the tissue compartmentalization of bone sialoprotein (BSP), osteopontin (OPN), and SPARC protein during bone formation in vitro. J Cell Physiol 1992;152:467-77.  Back to cited text no. 16
17.Sodek J, Overall CM. Matrix metalloproteinases in periodontal tissue remodelling. Matrix Suppl 1992;1:352-62.  Back to cited text no. 17
18.Fisher LW, Torchia DA, Fohr B, Young MF, Fedarko NS. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun 2001;280:460-5.  Back to cited text no. 18
19.Malaval L, Wade-Guéye NM, Boudiffa M, Fei J, Zirngibl R, Chen F, et al. Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med 2008;205:1145-53.  Back to cited text no. 19
20.Valverde P, Tu Q, Chen J. BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res 2005;20:1669-79.  Back to cited text no. 20
21.Valverde P, Zhang J, Fix A, Zhu J, Ma W, Tu Q, et al. Overexpression of bone sialoprotein leads to an uncoupling of bone formation and bone resorption in mice. J Bone Miner Res 2008;23:1775-88.  Back to cited text no. 21
22.Ogata Y. Bone sialoprotein and its transcriptional regulatory mechanism. J Periodontal Res 2008;43:127-35.   Back to cited text no. 22
23.Li Z, Wang Z, Yang L, Li X, Sasaki Y, Wang S, et al. Fibroblast growth factor 2 regulates bone sialoprotein gene transcription in human breast cancer cells. J Oral Sci 2010;52:125-32.   Back to cited text no. 23
24.Razzouk S, Brunn JC, Qin C, Tye CE, Goldberg HA, Butler WT. Osteopontin posttranslational modifications, possibly phosphorylation, are required for in vitro bone resorption but not osteoclast adhesion. Bone 2002;30:40-7.  Back to cited text no. 24
25.Hunter GK, Goldberg HA. Modulation of crystal formation by bone phosphoproteins: Role of glutamic acid-rich sequences in the nucleation of hydroxyapatite by bone sialoprotein. Biochem J 1994;302:175-9.  Back to cited text no. 25
26.Roach HI. Why does bone matrix contain noncollagenous proteins? The possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption. Cell Biol Int 1994;18:617-28.  Back to cited text no. 26
27.Tu Q, Zhang J, Fix A, Brewer E, Li YP, Zhang ZY, et al. Targeted overexpression of BSP in osteoclasts promotes bone metastasis of breast cancer cells. J Cell Physiol 2009;218:135-45.  Back to cited text no. 27
28.Gordon JA, Tye CE, Sampaio AV, Underhill TM, Hunter GK, Goldberg HA. Bone sialoprotein expression enhances osteoblast differentiation and matrix mineralization in vitro. Bone 2007;41:462-73.  Back to cited text no. 28
29.Seibel MJ, Woitge HG, Pecherstorfer M, Karmatschek M, Horn E, Ludwig H, et al. Serum immunoreactive bone sialoprotein as a new marker of bone turnover in metabolic and malignant bone disease. J Clin Endocrinol Metab 1996;81:3289-94.  Back to cited text no. 29
30.Mansson B, Carey D, Alini M, Ionescu M, Rosenberg LC, Poole AP, et al. Cartilage and bone metabolism in rheumatoid arthritis: Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism. J Clin Invest 1995;95:1071-7.  Back to cited text no. 30
31.Saxne T, Zunino L, Heinegard D. Increased release of bone sialoprotein into synovial fluid reflects tissue destruction in rheumatoid arthritis. Arthritis Rheum 1995;38:82-90.  Back to cited text no. 31
32.Wolfgang W, Armbruster FP, Karmatschek M, Reinauer H. Bone sialoprotein in serum of patients with malignant bone diseases. Clin Chem 1997;43:85-91.  Back to cited text no. 32
33.Woitge HW, Pecherstorfer M, Horn E, Keck AV, Diel IJ, Bayer P, et al. Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma. Br J Cancer 2001;84:344-51.  Back to cited text no. 33
34.Diel IJ, Solomayer EF, Seibel MJ, Pfeilschifter J, Maisenbacher H, Gollan C, et al. Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis. Clin Cancer Res 1999;5:3914-9.  Back to cited text no. 34
35.Loibl S, Königs A, Kaufmann M, Costa SD, Bischoff J. PTHrP and bone sialoprotein as prognostic markers for developing bone metastases in breast cancer patients. Zentralbl Gynakol 2006;128:330-5.  Back to cited text no. 35
36.Chen J, Rodriguez JA, Barnett B, Hashimoto N, Tang J, Yoneda T. Bone sialoprotein promotes tumor cell migration in both in vitro and in vivo models. Connect Tissue Res 2003;44:279-84.  Back to cited text no. 36
37.Bellahcène A, Merville MP, Castronovo V. Expression of bone sialoprotein, a bone matrix protein, in human breast cancer. Cancer Res 1994;54:2823-6.  Back to cited text no. 37
38.Bellahcène A, Menard S, Bufalino R, Moreau L, Castronovo V. Expression of bone sialoprotein in primary human breast cancer is associated with poor survival. Int J Cancer 1996;69:350-3.  Back to cited text no. 38
39.Gillespie MT, Thomas RJ, Pu ZY, Zhou H, Martin TJ, Findlay DM. Calcitonin receptors, bone sialoprotein and osteopontin are expressed in primary breast cancers. Int J Cancer 1997;73:812-5.  Back to cited text no. 39
40.Ibrahim T, Leong I, Sanchez-Sweatman O, Khokha R, Sodek J, Tenenbaum HC, et al. Expression of bone sialoprotein and osteopontin in breast cancer bone metastases. Clin Exp Metastasis 2000;18:253-60.  Back to cited text no. 40
41.Papotti M, Kalebic T, Volante M, Chiusa L, Bacillo E, Cappia S, et al. Bone sialoprotein is predictive of bone metastases in resectable non-small-cell lung cancer: A retrospective case-control study. J Clin Oncol 2006;24:4818-24.  Back to cited text no. 41
42.Zhang L, Hou X, Lu S, Rao H, Hou J, Luo R, et al. Predictive significance of bone sialoprotein and osteopontin for bone metastases in resected Chinese non-small-cell lung cancer patients: A large cohort retrospective study. Lung Cancer 2010;67:114-9.  Back to cited text no. 42
43.Waltregny D, Bellahcène A, Van Riet I, Fisher LW, Young M, Fernandez P, et al. Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer. J Natl Cancer Inst 1998;90:1000-8.  Back to cited text no. 43
44.Bellahcène A, Albert V, Pollina L, Basolo F, Fisher LW, Castronovo V. Ectopic expression of bone sialoprotein in human thyroid cancer. Thyroid 1998;8:637-41.  Back to cited text no. 44
45.Bellahcène A, Kroll M, Liebens F, Castronovo V. Bone sialoprotein expression in primary human breast cancer is associated with bone metastases development. J Bone Miner Res 1996;11:665-70.  Back to cited text no. 45
46.Waltregny D, Bellahcène A, de Leval X, Florkin B, Weidle U, Castronovo V. Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. J Bone Miner Res 2000;15:834-43.  Back to cited text no. 46
47.Sung V, Stubbs JT 3rd, Fisher L, Aaron AD, Thompson EW. Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J Cell Physiol 1998;176:482-94.  Back to cited text no. 47
48.Ross FP, Chappel J, Alvarez JI, Sander D, Butler WT, Farach-Carson MC, et al. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem 1993;268:9901-7.  Back to cited text no. 48
49.Byzova TV, Kim W, Midura RJ, Plow EF. Activation of integrin alpha(V)beta(3) regulates cell adhesion and migration to bone sialoprotein. Exp Cell Res 2000;254:299-308.  Back to cited text no. 49
50.Karadag A, Oqbureke KU, Fedarko NS, Fisher LW. Bone sialoprotein, matrix metalloproteinase 2, and alpha(v)beta3 integrin in osteotropic cancer cell invasion. J Natl Cancer Inst 2004;96:956-65.  Back to cited text no. 50
51.Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol 1996;12:697-715.  Back to cited text no. 51
52.Karadag A, Fisher LW. Bone sialoprotein enhances migration of bone marrow stromal cells through matrices by bridging MMP-2 to alpha(v)beta3-integrin. J Bone Miner Res 2006;21:1627-36.  Back to cited text no. 52
53.Nam JS, Suchar AM, Kang MJ, Stuelten CH, Tang B, Michalowska AM, et al. Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer. Cancer Res 2006;66:6327-35.  Back to cited text no. 53
54.Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 2007;1775:21-62.  Back to cited text no. 54
55.Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161-74.  Back to cited text no. 55
56.Overall CM, Kleifeld O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer 2006;94:941-6.  Back to cited text no. 56
57.Hwang Q, Cheifetz S, Overall CM, McCulloch CA, Sodek J. Bone sialoprotein does not interact with pro-gelatinase A (MMP-2) or mediate MMP-2 activation. BMC Cancer 2009;9:121.  Back to cited text no. 57
58.Zhang JH, Tang J, Wang J, Ma W, Zheng W, Yoneda T, et al. Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. Int J Oncol 2003;23:1043-8.  Back to cited text no. 58
59.Zhang JH, Wang J, Tang J, Barnett B, Dickson J, Hahsimoto N, et al. Bone sialoprotein promotes bone metastasis of a non-bone-seeking clone of human breast cancer cells. Anticancer Res 2004;24:1361-8.  Back to cited text no. 59
60.Bellahcène A, Bonjean K, Fohr B, Fedarko NS, Robey FA, Young MF, et al. Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis. Circ Res 2000;86:885-91.  Back to cited text no. 60
61.Adwan H, Bäuerle T, Najajreh Y, Elazer V, Golomb G, Berger MR. Decreased levels of osteopontin and bone sialoprotein II are correlated with reduced proliferation, colony formation, and migration of GFP-MDA-MB-231 cells. Int J Oncol 2004;24:1235-44.  Back to cited text no. 61
62.Bäuerle T, Adwan H, Kiessling F, Hilbig H, Armbruster FP, Berger MR. Characterization of a rat model with site-specific bone metastasis induced by MDA-MB-231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein. Int J Cancer 2005;115:177-86.  Back to cited text no. 62
63.Melquist JJ, Kacka M, Li Y, Malaeb BS, Elmore J, Baseman AG, et al. Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: an orthotopic in vivo model. Urol Oncol 2006;24:362-71.   Back to cited text no. 63
64.Jung K, Lein M, Stephan C, Von Hösslin K, Semjonow A, Sinha P, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: Diagnostic and prognostic implications. Int J Cancer 2004;111:783-91.  Back to cited text no. 64
65.Fedarko NS, Fohr B, Robey PG, Young MF, Fisher LW. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. J Biol Chem 2000;275:16666-72.  Back to cited text no. 65
66.Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7:4060-6.  Back to cited text no. 66
67.Jain A, McKnight DA, Fisher LW, Humphreys EB, Mangold LA, Partin AW, et al. Small integrin-binding proteins as serum markers for prostate cancer detection. Clin Cancer Res 2009;15:5199-207.  Back to cited text no. 67
68.Schindler F, Lajolo PP, Pinczowski H, Fonseca FL, Barbieri A, Massonetto LH, et al. Bone and total alkaline phosphatase for screening skeletal metastasis in patients with solid tumours. Eur J Cancer Care (Engl) 2008;17:152-6.  Back to cited text no. 68
69.Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 2008;113:193-201.  Back to cited text no. 69
70.Lipton A, Costa L, Ali SM, Demers LM. Bone markers in the management of metastatic bone disease. Cancer Treat Rev 2001;27:181-5.  Back to cited text no. 70


  [Figure 1]

This article has been cited by
1 Conditional knockdown of integrin beta-3 reveals its involvement in osteolytic and soft tissue lesions of breast cancer skeletal metastasis
Marineta Kovacheva, Michael Zepp, Stefan Berger, Martin R. Berger
Journal of Cancer Research and Clinical Oncology. 2021; 147(2): 361
[Pubmed] | [DOI]
2 Value of SUVmax for the Prediction of Bone Invasion in Oral Squamous Cell Carcinoma
Stephanie A. Stalder, Paul Schumann, Martin Lanzer, Martin W. Hüllner, Niels J. Rupp, Martina A. Broglie, Grégoire B. Morand
Biology. 2020; 9(2): 23
[Pubmed] | [DOI]
3 Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis
Marineta Kovacheva, Michael Zepp, Stefan M. Berger, Martin R. Berger
Oncotarget. 2014; 5(14): 5510
[Pubmed] | [DOI]
4 Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis
Klaus Jung,Michael Lein
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2014; 1846(2): 425
[Pubmed] | [DOI]
5 Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers
Thomas E. Kruger,Andrew H. Miller,Andrew K. Godwin,Jinxi Wang
Critical Reviews in Oncology/Hematology. 2013;
[Pubmed] | [DOI]
6 Serum markers of intrahepatic cholangiocarcinoma
Malaguarnera, G. and Paladina, I. and Giordano, M. and Malaguarnera, M. and Bertino, G. and Berretta, M.
Disease Markers. 2013; 34(4): 219-228
7 Postoperative simple biochemical markers for prediction of bone metastases in Egyptian breast cancer patients
Morcos, N.Y.S. and Zakhary, N.I. and Said, M.M. and Tadros, M.M.M.
ecancermedicalscience. 2013; 7(1)
8 Silencing of skeletal metastasis-associated genes impairs migration of breast cancer cells and reduces osteolytic bone lesions
Reufsteck, C. and Lifshitz-Shovali, R. and Zepp, M. and Bäuerle, T. and Kübler, D. and Golomb, G. and Berger, M.R.
Clinical and Experimental Metastasis. 2012; 29(5): 441-456
9 Silencing of skeletal metastasis-associated genes impairs migration of breast cancer cells and reduces osteolytic bone lesions
Christina Reufsteck,Rinat Lifshitz-Shovali,Michael Zepp,Tobias Bäuerle,Dieter Kübler,Gershon Golomb,Martin R. Berger
Clinical & Experimental Metastasis. 2012; 29(5): 441
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Bone Sialoprotei...>BSP and Bone Met...>Discussion>Article Figures
  In this article

 Article Access Statistics
    PDF Downloaded662    
    Comments [Add]    
    Cited by others 9    

Recommend this journal