Prognostic Value of Bone Sialoprotein Expression in Clinically Localized Human Prostate Cancer

Waltregny, David; Bellahcène, Akeila; Castronovo, Vincent; Dewé, Walthère; Leval, Jean de; Riet, Ivan Van; Fisher, Larry W.; Young, Marian F.; Fernández, Pedro

doi:10.1093/jnci/90.13.1000

Cited by 143 publications

(116 citation statements)

References 33 publications

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“…However, little progress has been made in understanding the molecular mechanisms responsible for bone metastasis in prostate cancer. Our lab and others found that noncollagenous bone matrix proteins such as osteopontin, OC, and bone sialoprotein are expressed at high levels in advanced bone metastatic prostate tumor specimens (33)(34)(35) and AI bone metastatic prostate cancer cell lines. There seems to be a remarkable parallelism in the temporal expression of bone matrix proteins by prostate cancer cells and mature osteoblasts.…”

Section: Discussionmentioning

confidence: 67%

Regulation of Human Osteocalcin Promoter in Hormone-independent Human Prostate Cancer Cells

Yeung¹,

Law²,

Yeh³

et al. 2002

Journal of Biological Chemistry

107

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Osteocalcin (OC) is a small (6 kDa) polypeptide whose expression was thought to be limited to mature osteoblasts. The discovery of OC expression in prostate cancer specimens led us to study the regulation of OC gene in androgen-independent metastatic human prostate PC3 cells. An 800-bp human OC (hOC) promoter-luciferase construct exhibited strong basal and vitamin D-induced activity in OC-positive human prostate and osteosarcoma cell lines. Through deletion analysis of the hOC promoter, the functional hierarchy of the cis-acting elements, OSE1, OSE2, and AP-1/VDRE, was established in PC3 cells (OSE1 > AP-1/VDRE > OSE2). By juxtaposing dimers of these 3 cis-elements, we produced a minimal hOC promoter capable of displaying high tissue specific activity in prostate cancer cells. Our study demonstrated three groups of transcription factors, Runx2, JunD/Fra-2, and Sp1, responsible for the high hOC promoter activity in PC3 cells by binding to the OSE2, AP-1/VDRE, and OSE1 elements, respectively. Among the three groups of transcription factors, the expression levels of Runx2 and Fra-2 are higher in the OC-positive PC3 cells and osteoblasts, compared with the OC-negative LNCaP cells. Interestingly, unlike the mouse OC promoter, the OSE1 site in hOC promoter is regulated by members of Sp1 family instead of the osteoblast-specific factor Osf1. The molecular basis for androgen-independent prostate cancer cells behaving like mature osteoblasts may be explained by the interplay and coordination of these transcription factors under the tight regulation of autocrine and paracrine mediators.Osteocalcin (OC) 1 is the major noncollagenous bone matrix protein expressed in bone (1). OC expression is transcriptionally regulated by vitamin D and limited exclusively to cells of the osteoblast lineage (2). OC is synthesized, secreted, and deposited by mature osteoblasts at the time of bone mineralization. It serves as a phenotypic marker for mature osteoblasts (3). Despite its well characterized specificity of expression in transgenic mouse (4), the precise function of OC in bone remodeling remains unclear. The location of OC at the bone-forming surfaces (5) and the increased bone mineralization observed in OC gene knockout mice (6) supports a role of OC in suppression of bone mineralization.Due to its tissue specificity, regulation of OC expression has been studied extensively in bone cells. Many regulatory elements have been identified in the proximal 800-bp region of the promoters. These include OSE1, OSE2 (7), AP-1/VDRE (8), and GRE (9). OSE1 and OSE2 were identified in mouse OC (mOC) promoter and are responsible for its tissue specific activity in osteoblasts. Both of these cis-elements are occupied by osteoblast-specific transcription factors, Osf1 and Runx2, respectively (7, 10). Runx2 belongs to the RUNT domain transcription factor family (11) and it has an indispensable role in osteoblast differentiation, maturation, and bone formation (12). Runx2 was shown to bind the OSE2 site and regulates the mOC promoter in a tissue-spec...

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Section: Discussionmentioning

confidence: 67%

Regulation of Human Osteocalcin Promoter in Hormone-independent Human Prostate Cancer Cells

Yeung¹,

Law²,

Yeh³

et al. 2002

Journal of Biological Chemistry

107

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“…[28][29][30] They are secreted by certain tumor cells with metastatic affinity to bone tissue, as for example by breast, prostate, lung and other cancer cells. 2,3,12,13,18,[31][32][33][34] In addition, they show various functions; OPN can bind to a number of receptors such as integrins as well as to certain variant forms of CD44, [35][36][37] it can act as a cytokine 29 and has function in the urinary tract. 31 BSPII is closely related to OPN, 38,9 but ON differs from OPN and BSPII by its chromosomal origin, its lack in an RGD binding domain, and its function that is related for example to the maintenance of lens transparency as has been described in knockout mice.…”

Section: Discussionmentioning

confidence: 99%

“…9 These proteins often function by bridging two proteins of fixed structures into a biologically active complex. The structural similarity of BSPII with OPN is paralleled by the observation that both proteins are expressed by certain tumor cells such as breast cancer, 10,11 as well as colon, prostate 12 and lung cancer, 13 and have been related to the pathogenesis of bone metastasis. 8 The calcium binding properties of BSPII 14 and its role in initiating and controlling hydroxylapatite crystallization 15 have been related to the formation of microcalcification in breast cancer.…”

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confidence: 97%

Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB-231 human breast cancer cells

2003

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Osteopontin (OPN), bone sialoprotein (BSPII), and osteonectin (ON) belong to a family of glycoproteins, which have been linked to cancer metastasis and progression. Here, we report on the selection of antisense oligonucleotides (ASOs), which are effective in reducing their protein levels. In human MDA-MB-231 breast cancer cells, the maximum inhibition of protein expression ranged from 84% (OPN) to 75% (BSPII) and 70% (ON). Erucylphospho-NNN-trimethylpropanolamine (ErPC 3 ) was used as positive control and combination partner. Exposure to ErPC 3 inhibited colony formation of MDA-MB-231 cells by 11% (10 mM), 45% (14 mM) and 78% (20 mM). The clonogenicity of breast cancer cells was reduced by 15%, 11%, 8% (5 mM), 39%, 19%, 14% (10 mM) and 46%, 39%, 21% (20 mM) in response to ASO-OPN-04, ASO-BSPII-06 and ASO-ON-03, respectively. Combination of ErPC 3 with the ASOs caused additive combination effects. Pre-exposure to the ASOs, but not to the NSO, inhibited formation of osteolytic metastasis in three of four (ASO-OPN-04, Po0.03) and two of four (ASO-BSPII-06) nude rats, and reduced metastasis lesions significantly (T/C% ¼ 4.3 and 9.1, P ¼ 0.05, respectively). We conclude that downregulation of OPN and BSPII reduces colony formation of MDA-MB-231 cells and formation of osteolytic metastasis in nude rats.

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“…In breast and prostate cancer, the expression of BSP has already been shown to be highly predictive of neoplastic bone involvement (Bellachène et al, 1996a;Waltregny et al, 1998;Diel et al, 1999). In these cancers, as well as in myeloma, the interaction between tumour cells and osteoclasts seems to be pivotal for the growth and propagation of the neoplastic cell clone in the bone marrow and for the subsequent bone destruction (Mundy and Yoneda, 1998).…”

Section: Discussionmentioning

confidence: 99%

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma

Pecherstorfer

Horn

et al. 2001

Br J Cancer

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SummaryTo test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P < 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P < 0.001), and serum β 2 -microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P < 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P < 0.001, logrank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM.

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Prognostic Value of Bone Sialoprotein Expression in Clinically Localized Human Prostate Cancer

Abstract: To our knowledge, this study is the first to demonstrate BSP expression in human prostate cancer and to highlight the protein's statistically significant prognostic value in patients with clinically confined prostate adenocarcinomas.

Cited by 143 publications

References 33 publications

Regulation of Human Osteocalcin Promoter in Hormone-independent Human Prostate Cancer Cells

Regulation of Human Osteocalcin Promoter in Hormone-independent Human Prostate Cancer Cells

Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB-231 human breast cancer cells

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma

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