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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human prostate cancer has a high predisposition to metastasize to bone, resulting in the formation of osteoblastic metastases. The mechanism through which prostate cancer cells promote osteoblastic lesions is undefined. Vascular endothelial growth factor (VEGF) has been implicated as a mediator of osteoblast activity. In the present study, we examined if prostate cancer cells promote osteoblastic activity through VEGF. We found that LNCaP and C4-2B prostate cancer cell lines and primary tumor and metastatic prostate cancer tissues from patients expressed VEGF. Bone morphogenetic proteins (BMPs), which are normally present in the bone environment, induced VEGF protein and mRNA expression in C4-2B cells. Furthermore, BMP-7 activated the VEGF promoter. Noggin, a BMP inhibitor, diminished VEGF protein expression and promoter activity in C4-2B cells. Conditioned media (CM) from C4-2B cells induced pro-osteoblastic activity (increased alkaline phosphatase, osteocalcin, and mineralization) in osteoblast cells. Both noggin alone and anti-VEGF antibody alone diminished C4-2B CM-induced pro-osteoblastic activity. Transfection of C4-2B cells with VEGF partially rescued the C4-2B CM-induced pro-osteoblastic activity from noggin inhibition. These observations indicate that BMPs promote osteosclerosis through VEGF in prostate cancer metastases. These results suggest a novel function for VEGF in skeletal metastases. Specifically, VEGF promotes osteoblastic lesion formation at prostate cancer bone metastatic sites.
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PMID:Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. 1487 30

To clarify metastatic patterns, and histologic and radiologic features in skeletal metastases from gastric cancer, 48 patients were retrospectively analyzed. The mean age of the patients at the time of diagnosis of gastric cancer was 59 years. In 31 patients with a history of the radical surgery, the mean interval between surgery and diagnosis of skeletal metastasis was 14 months. The mean duration between diagnosis of skeletal metastasis and death was 60 days. Scintigraphic assessment showed that solitary osseous lesions were found in four patients, whereas the remaining 44 had multiple skeletal lesions. In 28 patients with bone-only metastases with absence of visceral metastases, a higher incidence of thoracolumbar metastases at the level nearest the stomach was found. The incidence of skeletal metastasis in each histologic type was intestinal in 19 and diffuse in 29. Radiologic examination revealed that the ratio between the presence and the absence of osteosclerosis was 1:2. Osteosclerosis was seen in three of 19 patients with intestinal type metastasis, whereas with the diffuse type 13 of 29 patients had osteosclerosis.
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PMID:Skeletal metastasis in patients with gastric cancer. 1523 50

Bone architecture and mineralization are generally considered to be important components of bone quality, and determine bone strength in conjunction with bone mineral density. Although the features of bone quality have recently been studied under conditions in which bone density decreases, such as osteoporosis, little is known in osteosclerotic diseases. In this study, we compared the trabecular bone microarchitecture and degree of mineralization between osteoblastic bone metastasis and degenerative osteosclerosis using synchrotron radiation microcomputed tomography (SR-microCT). Small cubes of lumbar vertebrae were excised postmortem from the sites of osteoblastic metastasis, degenerative osteosclerosis, and comparative sites of normal subjects without skeletal lesions. The samples were imaged at high spatial resolution (voxel size = 6 microm) using the SR-microCT system developed at the synchrotron facility (SPring-8), Hyogo, Japan. The three-dimensional (3D) image data were then analyzed for the morphological parameters and the degree of mineralization of bone (DMB). Trabecular bone in metastatic lesions showed a highly connected and isotropic network pattern compared with the normal samples. Although the trabecular surface was markedly irregular in osteoblastic metastases, no significant difference was found in the mean trabecular thickness (Tb.Th) between osteoblastic metastases and normal tissue. The DMB of trabeculae in metastatic lesions had a broader range and lower mean than that of the normal tissue. In contrast, trabecular bone in degenerative osteosclerotic lesions showed a similar degree of anisotropy (DA) and connectivity to the normal tissue, whereas the trabecular thickness was greater in the degenerative osteosclerotic lesions. No significant difference in DBM between degenerative osteosclerosis and normal tissue was detected. These results characterize the difference in bone quality between osteoblastic bone metastasis and degenerative osteosclerosis. Further study on the relationship between bone quality and bone strength in these osteosclerotic lesions would improve our understanding of the pathogenesis of bone fragility.
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PMID:Analysis of three-dimensional microarchitecture and degree of mineralization in bone metastases from prostate cancer using synchrotron microcomputed tomography. 1526 94

This manuscript reviews the theories behind the propensity of prostate cancer to cause bone metastases and skeletal implications of the prostate cancer biology and treatment modalities. The escape of tumor cells from the primary tumor in the prostate to secondary tumor sites in the axial skeleton probably occurs before the primary tumor is detected. Several theories offer explanations for the observed proclivity of prostate tumors to selectively colonize the axial skeleton. The interaction between the tumor cells and cells that populate bone marrow, in particular osteoblasts and osteoclasts, is important for creating a 'fertile' environment where tumor cells can establish and grow. Prostate cancer cells are capable of producing growth factors that can affect both osteoblasts, resulting in osteoblastic bone formation, and osteoclasts, resulting in excessive bone resorption. In addition to the capability to progress from testosterone-dependent to testosterone-independent phenotype, the hallmark of metastatic prostate cancer is osteosclerosis similar to one induced experimentally in nude rats using CWR22 human prostate cancer cell line. Metastatic bone disease caused by excessive bone formation and bone resorption is the major cause of morbidity in patients with prostate cancer. The most common symptoms include pain, pathological fractures, spinal cord compression, cranial nerve palsies, bone marrow suppression and hypercalcemia. The introduction of prostate-specific antigen in clinical practice created a shift to where more prostate cancer patients with early disease receive androgen ablation treatment, which in return causes more bone loss and cancer-associated osteoporosis. Introduction of third generation bisphosphonates to treat skeletal consequences of malignancy further stressed the important interaction between the bone marrow stroma and cancer cells. Nevertheless, animal models and human prostate tumor cell lines that mimic all aspects of skeletal conditions in prostate cancer patients including osteoblastic bone response are needed to develop and screen for novel therapeutic and diagnostic modalities.
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PMID:Skeletal implications of prostate cancer. 1575 51

We investigated the utility of CWR22 human prostate cancer cells for modeling human metastatic prostate cancer, specifically their ability to induce bone formation following intra-tibial injections in the nude rat. Prostate cancer is unique in regard to its tropism for bone and ability to induce new bone formation. In contrast to humans, other mammalian species rarely develop prostatic cancer spontaneously upon aging and do not have the propensity for bone metastasis that is the hallmark of cancer malignancy in men. We chose human prostate cancer cell line CWR22 based on its properties, which closely resemble all of the features that characterize the early stages of prostatic cancer in human patients including slow growth rate, hormone dependence/independence and secretion of prostate-specific antigen. When CWR22 cells were injected directly into the proximal tibia of immunodeficient male rats, both osteoblastic and osteolytic features became evident after 4 to 6 weeks, with elevated levels of serum prostate-specific antigen. However, osteosclerosis dominates the skeletal response to tumor burden. Radiological and histological evidence revealed osteosclerotic lesions with trabeculae of newly formed bone lined by active osteoblasts and surrounded by tumor cells. Toward the end of the 7-week study, osteolytic bone lesions become more evident on X-rays. Paraffin and immunohistochemical evaluations revealed mature bone matrix resorption as evidenced by the presence of many tartrate resistant acid phosphatase positive multinucleated osteoclasts. We conclude that the CWR22 human prostate cell line used in an intra-tibial nude rat model provides a useful system to study mechanisms involved in osteoblastic and osteolytic bony metastases. This type of in vivo model that closely mimics all major features of metastatic disease in humans may provide a critical tool for drug development efforts focused on developing integrated systemic therapy targeting the tumor in its specific primary or/and metastatic microenvironments. In addition to targeting bone marrow stroma, this strategy will help to overcome classical drug resistance seen at the sites of prostate cancer metastasis to bones.
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PMID:Intra-tibial injection of human prostate cancer cell line CWR22 elicits osteoblastic response in immunodeficient rats. 1575 55

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.
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PMID:Role of Wnts in prostate cancer bone metastases. 1644 63

The pathophysiological changes and the oxidative-antioxidative status were evaluated in the bone microenvironment of rat inoculated with Walker 256/B mammary gland carcinoma cells, and used alpha-tocopherol acetate (ATA) as a countermeasure. Walker 256/B cells were injected into the right femora of aged male rats. Animals were randomized into three groups: 12 rats were injected with saline (control group); 14 rats were injected with Walker 256/B cells (5x10(4)) in the medullar cavity (W256 group); 14 rats were inoculated with Walker 256/B cells and treated with ATA (45mg/kg BW) (W256+ATA group). After 20 days, rats were euthanized and the femurs were radiographed. Micro architectural parameters were measured by microcomputed tomography and histology. Serum, bone and bone marrow were evaluated for oxidative damage. In parallel, cell cultures were done in the presence of ATA and ROS were measured by fluorescence; apoptotic cells were determined in parallel. W256 groups had osteolytic damages with marked resorption of cortical and trabecular bone. W256+ATA animals presented marked osteosclerotic areas associated with tumor necrosis areas inside the bone cavity. Levels of lipid peroxidation and protein oxidation were found to increase in W256 rats; a significant reduction in SOD and GSH-p activities was also observed. W256+ATA group had significantly reduced oxidative damage, but not reversed back to the control levels. The present study shows that Walker 256/B cells induce skeletal metastases associated with oxidative damage in the bone microenvironment. ATA reduced the oxidative stress damage, enhanced osteosclerosis and tumor cell apoptosis both in vitro and in vivo.
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PMID:Effect of alpha tocopherol acetate in Walker 256/B cells-induced oxidative damage in a rat model of breast cancer skeletal metastases. 1978 38

Bone metastases are severe complications of cancers associated with increased morbidity, pain, risk fracture, and reduced life span for patients. Bisphosphonates emerged as a relief treatment in bone metastases. A single dose of zoledronic acid (78 microg/kg) was injected into six Copenhagen rats 4 days before receiving an intraosseous inoculation of metastatic anaplastic tumor of lymph node and lung cell (MLL) prostate cancer cells. Rat femurs were analyzed for changes by microCT and histomorphometry; trabecular volume, trabecular characteristics, osteoid parameters, osteoblastic surfaces, and osteoclast number were measured. Values were compared to a group of SHAM animals, a group of SHAM animals having received zoledronic acid and animals inoculated with MLL cells. All rats were euthanized after 1 month. MLL cells induced osteolysis in the metaphysis with extension of the tumor to soft tissues through cortical perforations. Zoledronic acid induced a marked osteosclerosis in the primary spongiosa in both SHAM and rats inoculated with MLL. Osteosclerosis was obtained in the secondary spongiosa of MLL rats. The bisphosphonate preserved cortical integrity in all animals, and no extension to soft tissues was observed in most animals. The number of osteoclasts was elevated, indicating that there was no apoptosis of osteoclasts but they became inactive. Osteosclerosis was associated with increased osteoblastic surfaces. A single zoledronic acid injection turned osteolytic metastases into osteosclerotic and preserved cortical integrity.
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PMID:A single pretreatment by zoledronic acid converts metastases from osteolytic to osteoblastic in the rat. 1995 66

Breast and prostate cancers are specially metastasizing to bone. Metastases from breast cancer usually exhibit a mixed osteolytic/osteosclerotic aspect, with osteolysis predominating. Osteosclerosis is a common finding in prostatic cancer although osteolysis occurs within the sclerotic lesions. B-cell malignancies (lymphoma, myeloma) are also associated with marked osteolysis. Histopathological examination of bone biopsies was used for the diagnosis of malignancies and, prior to embedding, microcomputed tomography (microCT) was done on the bone specimens. Patients (247) who presented either a bone metastasis, an overt myeloma, a lymphoma or a monoclonal gammopathy of undetermined significance were studied. All patients had a bone biopsy studied by 2D histomorphometry for the histopathology. During the fixation time, the bone cores were analyzed by microCT. On the 3D reconstructed models provided by microCT, signs of osteolysis/osteosclerosis were searched: excess of bone resorption, focal disorganization of microarchitecture, bone metaplasia, osteosclerosis. A strong agreement was obtained between histomorphometry and microCT results using Cohen's kappa test (kappa = 0.713). MicroCT identified excess bone resorption on trabecular surfaces when eroded surfaces were >10.5% by histomorphometry. MicroCT failed to identify some patients with smoldering myeloma or some lymphomas with microresorption. MicroCT data are obtained within 4 hr and suggest the malignant invasion of bone marrow when excess of bone resorption/formation is obtained. MicroCT can be used in the immediate postbiopsy period making possible a fast identification of malignancy. However these signs are not specific and must be confirmed by histopathological analysis.
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PMID:Computed microtomography of bone specimens for rapid analysis of bone changes associated with malignancy. 2058 57

Metastasis is the rapid proliferation of cancer cells (secondary tumour) at a specific place, generally leading to death. This occurs at anatomical parts providing the necessary environment for vascularity, oxygen and food to hide their actions and trigger the rapid growth of cancer. Prostate and breast cancers, for example, use bone marrow for their proliferation. Bone-supporting cancer cells thus adapt to the environment, mimicking the behaviour of genetic and molecular bone cells. Evidence of this has been given in Cecchini et al. (2005, EAU Update Ser. 3:214-226), providing arguments such as how cancer cell growth is so active during bone reabsorption. This paper simulates metastasis activation in bone marrow. A mathematical model has been developed involving the activation of molecules from bone tissue cells, which are necessary for cancer to proliferate. Here, we simulate two forms of secondary tumour growth depending on the type of metastasis: osteosclerosis and osteolysis.
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PMID:A mathematical model for describing the metastasis of cancer in bone tissue. 2126 82


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