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Journal of Cancer Research and Therapeutics, Vol. 7, No. 2, April-June, 2011, pp. 115-119 Review Article Serum bone sialoprotein levels and bone metastases Mario Uccello, Giulia Malaguarnera, Marco Vacante, Massimo Motta Department of Senescence, Urological and Neurological Sciences, University of Catania, Italy Code Number: cr11029 PMID: 21768695 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 Introduction 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 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 Metastasi 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. Discussion 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
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