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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The skeleton is the privileged target of metastatic human breast cancer cells. Bone metastases are indeed found in virtually all advanced breast cancer patients and generate major morbidity. The high osteotropism of breast cancer cells suggests that they exhibit a selective affinity for mineralized tissues. The observation that mammary malignant cells are able to induce hydroxyapatite crystals deposition within the primary tumour suggests that they can generate a microenvironment that favors the crystallization of calcium and phosphate ions into the bone specific hydroxyapatite. Osteonectin (OSN), osteopontin (OPN) and bone sialoprotein (BSP), 3 bone matrix proteins involved in bone matrix mineralization, are expressed in human breast cancers. BSP, an RGD (Arg-Gly-Asp) containing phosphoprotein, initiates hydroxyapatite deposition and mediates attachment of osteoclast to the same crystals prior to their resorption. Detection of BSP at both the protein and the mRNA levels in human breast cancer and in human breast cancer cell lines (MCF-7, T47-D and MDA-MB 231) indicates that mammary malignant cells synthesize directly BSP rather than uptaking it from the serum. Interestingly, the level of BSP expression correlates with the development of bone metastases and with poor survival. These data suggest that the ectopic expression of bone matrix proteins could be involved in conferring osteotropic properties to circulating metastatic breast cancer cells. These observations open new alleys of investigation for the identification of the molecular mechanisms responsible for the genesis of bone metastases.
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PMID:Expression of bone matrix proteins in human breast cancer: potential roles in microcalcification formation and in the genesis of bone metastases. 918 Aug 54

The urokinase plasminogen activator (uPA) system has been widely associated with the development of breast carcinoma. However, the role of the urokinase pathway in the development of osseous breast cancer metastases has been largely overlooked. We studied the expression of uPA, urokinase plasminogen activator receptor (uPAR)- and plasminogen activator inhibitor type-1 (PAI-1) in human breast carcinomas and their bone metastases, using in situ hybridisation. Studies were performed using paraffin-embedded tissue from 13 ductal carcinomas, 23 invasive ductal carcinomas, five normal breasts and 25 bone metastases. The majority of the tumours examined expressed low to moderate levels of uPA mRNA and low to high levels of uPAR and PAI-1 mRNA, which was predominantly localised to the epithelial tumour cells. There was slight over-expression of uPA and PAI-1 mRNA and a marked increase in uPAR mRNA expression in the malignant tumours compared with benign tissue. Overall, uPAR and PAI-1 mRNA expression was found to be more variable than uPA mRNA, suggesting a possible role of the receptor and inhibitor in the regulation of uPA activity. Increased alpha1(I) procollagen (COL) and osteopontin (OPN) mRNA expression was detected, primarily in the stromal cells, in malignant tumours compared with the benign tissue. The increased expression of the components of the uPA system on the epithelial tumour cells may account for the activation of the proteolytic cascade that occurs during breast cancer metastasis to bone. Furthermore, the over-expression of COL and OPN suggests a possible interaction between these matrix proteins and the uPA system.
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PMID:Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases--a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases. 1093 85

Bone sialoprotein (BSP) and osteopontin (OPN) are prominent, mineral-associated proteins in the extracellular matrix of bone that have been implicated in the metastatic activity of cancer cells. The expression of BSP, which is normally restricted to mineralizing tissues, has been observed in cancers with a high propensity for forming bone metastases. To investigate the relationship between BSP expression and the formation of bone metastases we have conducted an initial study of the expression of BSP in 10 intraductal breast carcinoma bone metastases using immunostaining and in situ hybridization, and compared the expression with OPN. The metastases were characterized by the infiltration of tumour cells into bone with extensive bone resorption evident. Moderate to strong staining for BSP was observed in all (100%) carcinomas, which also expressed BSP mRNA as determined by in situ hybridization. Variable staining for BSP was also observed in the mineralized bone and expression of BSP mRNA could be observed in osteoblastic cells on the bone surface and in some osteocytes at sites of bone remodelling. Contrary to a previous report, BSP expression could be demonstrated by PCR in three breast cancer cell lines, MCF-7, T47-D and MDA-MB-231. Moreover, in sub-cutaneous tumours formed by MDA-MB-231 breast cancer cells injected into athymic mice, higher immunostaining for BSP was seen in large ulcerating tumours in which mineral deposits were formed. In contrast to BSP, staining for OPN in bone metastases was generally restricted to the interface between tumor cells and bone surface of the carcinomas. While OPN staining was also observed in the cytoplasm of osteoclasts, which showed strong hybridization to a digoxygenin-labelled OPN cRNA probe, expression of OPN was not clearly detectable in the tumour cells. These studies provide the first demonstration of BSP expression by tumour cells in bone metastases and support the concept that BSP may have a role in targeting metastatic cells to bone. Expression of OPN in bone metastases appears to be related to increased bone resorptive activity by osteoclasts.
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PMID:Expression of bone sialoprotein and osteopontin in breast cancer bone metastases. 1131 99

Metastases from prostatic adenocarcinoma (prostate cancer) are characterized by their predilection for bone and typical osteoblastic features. An in vitro model of bone metastases from prostate cancer was developed using a bicompartment coculture system of mouse osteoblasts and human prostate cancer cells. In this model, the bone-derived prostate cancer cell lines MDA PCa 2a and MDA PCa 2b induced a specific and reproducible increase in osteoblast proliferation. Moreover, these cells were able to induce osteoblast differentiation, as assessed by increased alkaline phosphatase activity, Osteocalcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into severe combined immunodeficiency disease mice. In contrast, the highly undifferentiated, bone-derived human prostate cancer cell line PC3 did not produce an osteoblastic reaction in vitro and induced osteolytic lesions in vivo. The osteoblast differentiation induced by MDA PCa 2b cells was associated with up-regulation of the osteoblast-specific transcriptor factor Cbfa1. Moreover, treatment of osteoblasts with conditioned medium obtained from MDA PCa 2b cells resulted in up-regulation of Cbfa1 and Osteocalcin expression. In support of the differentiation studies, a microarray analysis showed that primary mouse osteoblasts grown in the presence of MDA PCa 2b cells showed a shift in the pattern of gene expression with an increase in mRNA-encoding Procollagen type I and Osteopontin and a decrease in mRNA-encoding proteins associated with myoblast differentiation, namely myoglobin and myosin light-chain 2. Taken together, these findings suggest that the bone-derived prostate cancer cells MDA PCa 2a and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent pathway. These results also established that soluble factors produced by prostate cancer cells can induce expression of osteoblast-specific genes. This in vitro model provides a valuable system to isolate molecules secreted by prostate cancer cells that favor osteoblast differentiation. Moreover, it allows to screen for therapeutic agents blocking the osteoblast response to prostate cancer.
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PMID:Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. 1145 20

Breast cancer is associated frequently with skeletal metastases, which cause significant morbidity. The main mechanism is an increase in osteoclast-mediated bone resorption. We postulated that osteoblasts could be other essential target cells and previously showed that conditioned medium (CM) of breast cancer cells (BCCs) inhibits the proliferation of osteoblast-like cells. In this study, we investigated the effects of BCC-secreted products on osteoprogenitor cells using a clonal fetal human bone marrow stromal preosteoblastic cell line (FHSO-6) that expresses alkaline phosphatase (ALP) activity, type I collagen (COLI), and increased osteocalcin (OC) and osteopontin under treatment with dexamethasone (Dex), 1,25-dihydroxyvitamin D [1,25(OH)2D], or recombinant human bone morphogenetic protein 2 (rhBMP-2). Treatment with MCF-7 CM inhibited FHSO-6 cell survival in a dose-dependent and irreversible manner. Morphological investigation indicated that MCF-7 CM increased both apoptotic and necrotic cell number. MCF-7 CM increased caspases activity and a broad inhibitor of caspase activity (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone [z-VAD-fmk]) partly reversed the CM-induced inhibition of FHSO-6 cell survival. Western blot analyses revealed an increased bax/bcl-2 ratio in MCF-7 CM-treated FHSO-6 cells. MCF-7 cells exhibit FasLigand as membrane-bound protein and as a soluble cytokine in the CM. Deprivation of MCF-7 CM from active FasLigand by saturation with a soluble Fas molecule suppressed the induction of FHSO-6 apoptosis, whereas fibroblast CM, which did not contain FasLigand, only weakly modified FHSO-6 cell survival because of increased cell necrosis. These data indicate that FasLigand secreted by BCCs induces apoptosis and necrosis of human preosteoblastic stromal cells through caspase cascade modulated by the bax and bcl-2 protein level. The induction of apoptosis in human bone marrow stromal cells by BCCs may contribute to the inappropriately low osteoblast reaction and bone formation during tumor-induced osteolysis in bone metastases.
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PMID:Breast cancer cells release factors that induced apoptosis in human bone marrow stromal cells. 1154 30

Malignant tumors are characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. Current therapeutic regimens mostly exert their effects through inhibition of cell cycle progression, leaving two major components of transformation untouched. The cytokine osteopontin is essential for the dissemination of various cancers. Past research has implied several modes in which osteopontin and its main receptors on tumor cells can be suppressed. Osteopontin expression is inhibitable on the levels of gene transcription and the RNA message, and the osteopontin protein can be blocked with antibodies or synthetic peptides. The osteopontin receptor CD44 has been targeted by diverse therapeutic strategies, including cytotoxic and immunotherapeutic approaches. The receptor integrin alpha(V)beta(3) contributes not only to tumor cell dissemination, but also to angiogenesis and osteolysis in bone metastases. Small molecule inhibitors of this receptor are under study as drug candidates. Because receptors and cytokine ligands that mediate metastasis formation are sparsely expressed in the adult healthy organism and are more readily reached by pharmaceuticals than intracellular drug targets they may represent a particularly suitable focus for therapeutic intervention.
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PMID:The metastasis gene osteopontin: a candidate target for cancer therapy. 1182 87

We have developed a series of novel mammary epithelial cell lines from tumors arising in strain 129 mice, with the ultimate goal of evaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with subcutaneously implanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary tumor development was efficient in the 129 strain and was independent of osteopontin (OPN) expression. Epithelial cell lines were isolated from these tumors; surprisingly, these cells did not form tumors upon inoculation into the mammary fat pad of syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft agar, and formed hormone-independent tumors efficiently in the mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from tumors arising in the fat pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fat pad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice, with few metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone metastases were not seen on x-ray; instead extensive liver metastasis was present in these mice, indicating that genetic factors in these two strains regulate tumor cell homing and distribution during metastasis. These cell lines provide an important new tool in the study of bone metastasis, particularly in elucidating the role of host factors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.
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PMID:Novel murine mammary epithelial cell lines that form osteolytic bone metastases: effect of strain background on tumor homing. 1270 32

Breast and prostate cancer often metastasise to the skeleton. Interestingly, the histopathological characteristics of the bone lesions that arise from these two cancer types differ. Breast tumours give rise to metastases in the skeleton with a mixed lytic/sclerotic pattern, whereas a predominantly sclerotic pattern is seen in metastases from prostate tumours. Osteopontin (OPN) and bone sialoprotein (BSP) are bone matrix proteins that have been implicated in the selective affinity of cancer cells for bone. In the present study, 21 patient cases with skeletal metastasis and their respective primary tumours (12 with breast cancer, 9 with prostate cancer) were investigated by immunohistochemistry in order to assess the level of OPN and BSP. Moderate to strong OPN expression was found in 42% of all breast tumours and in 56% of all prostate tumours. Significantly more breast cancer bone metastases exhibited high OPN expression, 83%, as compared with prostate tumour bone metastases, 11% (P = 0.0019). In contrast, moderate to strong BSP expression was found in 33% of breast tumours and in 89% of prostate tumours. In the bone lesions, only 33% of breast tumour metastases showed moderate/strong BSP expression compared to 100% of prostate tumour metastases (P = 0.0046). This divergent pattern of OPN/BSP expression could be an important determinant for the different characteristics of these two types of bone metastasis, i.e., lytic vs. sclerotic, consistent with the proposed role of OPN in differentiation and activation of osteoclasts and of BSP as a stimulator of bone mineralisation.
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PMID:Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma. 1452 33

Melanoma has a propensity to metastasize to bone, where it is exposed to high concentrations of transforming growth factor-beta (TGF-beta). Because TGF-beta promotes bone metastases from other solid tumors, such as breast cancer, we tested the role of TGF-beta in melanoma metastases to bone. 1205Lu melanoma cells, stably transfected to overexpress the natural TGF-beta/Smad signaling inhibitor Smad7, were studied in an experimental model of bone metastasis whereby tumor cells are inoculated into the left cardiac ventricle of nude mice. All mice bearing parental and mock-transfected 1205Lu cells developed osteolytic bone metastases 5 weeks post-tumor inoculation. Mice bearing 1205Lu-Smad7 tumors had significantly less osteolysis on radiographs and longer survival compared with parental and mock-transfected 1205Lu mice. To determine if the reduced bone metastases observed in mice bearing 1205Lu-Smad7 clones was due to reduced expression of TGF-beta target genes known to enhance metastases to bone from breast cancer cells, we analyzed gene expression of osteolytic factors, parathyroid hormone-related protein (PTHrP) and interleukin-11 (IL-11), the chemotactic receptor CXCR4, and osteopontin in 1205Lu cells. Quantitative reverse transcription-PCR analysis indicated that PTHrP, IL-11, CXCR4, and osteopontin mRNA steady-state levels were robustly increased in response to TGF-beta and that Smad7 and the TbetaRI small-molecule inhibitor, SB431542, prevented such induction. In addition, 1205Lu-Smad7 bone metastases expressed significantly lower levels of IL-11, connective tissue growth factor, and PTHrP. These data suggest that TGF-beta promotes osteolytic bone metastases due to melanoma by stimulating the expression of prometastatic factors via the Smad pathway. Blockade of TGF-beta signaling may be an effective treatment for melanoma metastasis to bone.
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PMID:Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. 1733 63

Breast cancer cells preferentially metastasize to bone, leading to the formation of primarily osteolytic lesions. Osteoprotegerin (OPG) plays multifactorial roles in the development of osteolytic bone metastases. An increase in the ratio of receptor activator of nuclear factor kappaB ligand (RANKL) to OPG increases osteoclastogenesis within the bone microenvironment. OPG also acts as a survival factor for cancer cells by protecting them from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis. This study compares OPG production in vitro in a number of breast cancer cell lines exhibiting both differences in metastatic capacity and in preferential metastasis to bone. Our studies demonstrated that OPG expression by MDA-231, MDA-MET, and MDA-231/K cancer cells was directly correlated with bone specific homing and colonization potential but not with metastasis of cancer cells to other organs; both in IL-1 beta stimulated and control cells. We also demonstrated expression of other bone-related markers including type I collagen, osteocalcin, osteopontin, and Runx2 in these cells. However, the generally lower expression of these markers in the bone selective cell line MDA-MET suggested that increased OPG expression in the bone specific variant was not merely a consequence of enhanced osteomimicry by these cells but that it has a significant role in the metastatic process. Co-culture of breast cancer cells with osteoblastic cells (hFOB 1.19) led to an overall downregulation in OPG production, which was not affected by the bone homing and colonization potential of the cell lines, suggesting that OPG alone is not indicative of osteolytic bone activity by breast cancer cells.
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PMID:Osteoprotegrin and the bone homing and colonization potential of breast cancer cells. 1747 10


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