Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have selected and subcloned bone metastatic (PC-3 ML) and noninvasive, nonmetastatic (3 x N.I.) lines from human prostatic PC-3 parent cells. In this paper, we have compared relative levels of MMP-2 and TIMP-1 and 2 in PC-3 tumors grown in severe combined immunodeficient or SCID mice. Dot blots with polyclonal antibodies specific for MMP-2, TIMP-1 and TIMP-2 revealed that the MMP-2 levels were high in subcutaneously grown PC-3 ML clones but low in 3 x N.I. clones at days 20 and 40. The TIMP-1 levels were inversely proportional to MMP-2 in the two types of clones, respectively. The TIMP-2 levels were similar in both clones at days 20 and 40. Gelatin zymograms confirmed that PC-3 ML tumors contained MMP-2 (and not MMP-9) subcutaneously or in bone metastases in SCID mice. Slot blots of PC-3 ML bone tumors comparing MMP-2 and TIMP-1 levels showed at days 10, 15, 17, 19, 21, and 25 that the ratio of MMP-2 to TIMP-1 increased, especially at about day 21, when extensive secondary metastases to the peritoneal cavity occurred. The levels of TIMP-2 remained constant. Quantitative ELISAs confirmed the blotting data and showed that taxol blocked MMP-2 but not TIMP-1 production in these advanced tumors. We conclude that highly metastatic PC-3 ML variants contained relatively high levels of MMP-2 and low amounts of TIMP-1.
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PMID:Immunoassays of the metalloproteinase (MMP-2) and tissue inhibitor of metalloproteinase (TIMP 1 and 2) levels in noninvasive and metastatic PC-3 clones: effects of taxol. 784 42

The correlative effects of taxol on the reduction of circulating PC-3 ML human prostatic tumor cells and bone metastasis have been examined in SCID mice. Normally, following injection of 2 x 10(5) cells i.v., the circulating levels in peripheral blood drop by about 50 and 100%, after 8 and 24 h, respectively. In contrast, in taxol-treated mice (40-60 mg/m2/injection given 0, 3, 7 and 23 h following injection of the cells) the numbers of circulating human prostatic PC-3 ML tumor cells were reduced by 100% at 8 h. In similar experiments were mice were injected with taxol 2 h prior to injecting the cells, dosages of 40 and 60 mg/m2/injection reduced circulating tumor cells about 91 and 100%, respectively, by 8 h. Alternatively, if PC-3 Ml cells were pretreated with taxol (0.5 and 1.0 microM for 8 and 24 h) prior to injection, tumor cell clearance by 7 h was also significantly increased (80-100%). Correlative studies showed that the incidence of bone metastases (observed after 40 days) was reduced significantly (a) in mice treated with 40 and 60 mg/m2/injection (i.e. from 73-80% in controls to 15-0% in treated mice) and (b) in mice injected with PC-3 ML cells pre-exposed to 0.5-1.0 microM taxol for 7 h. Immunofluorescence studies with tubulin antibodies showed that the microtubules were disrupted in cells exposed to taxol in vivo and in vitro under conditions that significantly increased cellular clearance from the blood. Taken together, the data suggests that taxol at nontoxic dosages (to mice) can prevent metastases by directly reducing the circulating levels of tumor cells.
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PMID:Taxol reduces circulating tumor cells to prevent bone metastases in SCID mice. 876 98

The combined influence of alendronate, a bisphosphonate compound, and taxol on the establishment and growth of human PC-3 ML subclones injected intravenously via the tail vein in SCID mice was investigated. The pretreatment of SCID mice with alendronate (0.04-0.1 mg/kg twice weekly or 0.1 mg/kg weekly) partially blocked the establishment of bone metastases by human PC-3 ML cells and resulted in tumor formation in the peritoneum and other soft tissues. However, alendronate pretreatment of mice (0.1 mg/kg twice weekly or weekly) and dosing along with taxol (10-50 mg/kg/day, twice weekly, or weekly) blocked the growth of PC-3 ML tumors in the bone marrow and soft tissues in a statistically significant manner and improved survival rates significantly (p < 0.001) by 4-5 weeks. ELISAs and zymography of matrix metalloproteinase production in vitro and in vivo showed that alendronate and taxol alone partially inhibited metalloproteinase production, but that taxol in combination with alendronate totally blocked protease production and release. The combined activities of alendronate and taxol appeared to inhibit the establishment and growth of tumors in SCID mice, perhaps, in part, as a result of inhibition of protease production and release.
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PMID:Effects of alendronate and taxol on PC-3 ML cell bone metastases in SCID mice. 918 47

Lung cancer is commonly associated with multiorgan metastasis, and bone is a frequent metastatic site for lung cancer. Nevertheless, no bone metastasis model of lung cancer with multiorgan dissemination is available, which could provide opportunity to study the molecular pathogenesis. We examined the abilities of eight human lung cancer cell lines injected intravenously into natural killer (NK) cell-depleted SCID mice to generate metastatic nodules in bone and multiple organs, and explored the correlation of the parathyroid hormone-related protein (PTHrP) with the bone metastasis. Although all the small-cell carcinoma cell lines (SBC-5, SBC-3, SBC-3/ADM, H69, H69/VP) formed metastatic nodules in multiple organs (liver, kidney, and lymph nodes), only SBC-5 cells reproducibly developed bone metastases. Squamous cell carcinoma (RERF-LC-AI) cells metastasized mainly into the liver and kidneys, whereas adenocarcinoma (PC-14, A549) mainly produced colonies in the lungs. As assessed by X-ray photography, the osteolytic bone metastases produced by SBC-5 cells were detected as early as on day 28, and all recipient mice developed bone metastasis by day 35. The expression of PTHrP in eight cell lines was directly correlated with the formation of bone metastasis. No correlation was observed between the formation of bone metastasis and the expression of other metastasis-related cytokines (IL-1, IL-6, IL-8, IL-10, IL-11, TNF-alpha, VEGF, M-CSF). Consistent with the formation of bone metastasis by SBC-5 cells, the levels of PTHrP and calcium in the mouse serum were increased in a time-dependent manner, suggesting that PTHrP produced by human lung cancer may play a crucial role in the formation of bone metastasis and hypercalcemia. These findings indicate that a bone metastasis model of SBC-5 cells may be useful for clarifying the molecular aspects of the metastatic processes in different organ microenvironments and the development of therapeutic modalities for lung cancer patients with bone metastases.
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PMID:Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. 1141 46

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

The growth of metastatic prostate cancer cells in the bone involves an intimate interaction between the tumor cells and various elements of the bone microenvironment, resulting in increased rate of bone turnover and rapid tumor growth. The alpha(v)beta3 integrin has been shown to play an important role in tumor growth and angiogenesis, and is known to be critical to osteoclast formation and activity. This study was designed to examine the role of alpha(v)beta3 expressed by cells native to the bone in the growth and pathogenesis of prostate cancer bone metastases. Human prostate cancer cells which do not express alpha(v)beta3 or alpha(IIb)beta3 integrins were injected directly into human bone fragments previously implanted subcutaneously in SCID mice (SCID-human-bone model). At the same time treatment with anti-beta3 antibody fragment (m7E3 F(ab')2) i.p. at 300 microg/dose 3 x per week was initiated and continued for 2 weeks. In this system, m7E3 F(ab')2 only recognizes human bone-derived alpha(v)beta3. Antibody inhibition of alpha(v)beta3 integrin in vivo resulted in a specific reduction in the proportion of antigenically-human blood vessels within tumor-bearing bone implants (from 73.5% +/- 3.93 in controls to 17.74% +/- 5.64 in treated animals). Proliferation of the alpha(v)beta3-negative tumor cells was also reduced, although the overall vessel density was maintained by compensating mouse vasculature. Blockage of human bone-derived alpha(v)beta3 also significantly reduced the recruitment of osteoclasts in response to tumor cells, as well as degradation of calcified bone tissue. Together these observations confirm the importance of alpha(v)beta3 in bone metabolism and angiogenesis, and point to the role of these processes in controlling growth of metastatic prostate cancer cells in the bone.
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PMID:Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. 1452 30

Muscle invasive transitional cell carcinoma (TCC) of the bladder is associated with a high frequency of metastasis, resulting in poor prognosis for patients presenting with this disease. Models that capture and demonstrate step-wise enhancement of elements of the human metastatic cascade on a similar genetic background are useful research tools. We have utilized the transitional cell carcinoma cell line TSU-Pr1 to develop an in vivo experimental model of bladder TCC metastasis. TSU-Pr1 cells were inoculated into the left cardiac ventricle of SCID mice and the development of bone metastases was monitored using high resolution X-ray. Tumor tissue from a single bone lesion was excised and cultured in vitro to generate the TSU-Pr1-B1 subline. This cycle was repeated with the TSU-Pr1-B1 cells to generate the successive subline TSU-Pr1-B2. DNA profiling and karyotype analysis confirmed the genetic relationship of these three cell lines. In vitro, the growth rate of these cell lines was not significantly different. However, following intracardiac inoculation TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2 exhibited increasing metastatic potential with a concomitant decrease in time to the onset of radiologically detectable metastatic bone lesions. Significant elevations in the levels of mRNA expression of the matrix metalloproteases (MMPs) membrane type 1-MMP (MT1-MMP), MT2-MMP and MMP-9, and their inhibitor, tissue inhibitor of metalloprotease-2 (TIMP-2), across the progressively metastatic cell lines, were detected by quantitative PCR. Given the role of MT1-MMP and TIMP-2 in MMP-2 activation, and the upregulation of MMP-9, these data suggest an important role for matrix remodeling, particularly basement membrane, in this progression. The TSU-Pr1-B1/B2 model holds promise for further identification of important molecules.
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PMID:Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder. 1608 32

Metastasis to the bone is a major clinical complication in patients with prostate cancer (PC). However, therapeutic options for treatment of PC bone metastasis are limited. Gelatinases are members of the matrix metalloproteinase (MMP) family and have been shown to play a key role in PC metastasis. Herein, we investigated the effect of SB-3CT, a covalent mechanism-based MMP inhibitor with high selectivity for gelatinases, in an experimental model of PC bone metastases. Intraperitoneal (i.p.) treatment with SB-3CT (50 mg/kg) inhibited intraosseous growth of human PC3 cells within the marrow of human fetal femur fragments previously implanted in SCID mice, as demonstrated by histomorphometry and Ki-67 immunohistochemistry. The anti-osteolytic effect of SB-3CT was confirmed by radiographic images. Treatment with SB-3CT also reduced intratumoral vascular density and bone degradation in the PC3 bone tumors. A direct inhibition of bone marrow endothelial cell invasion and tubule formation in Matrigel by SB-3CT in vitro was also demonstrated. The use of the highly selective gelatinase inhibitors holds the promise of effective intervention of metastases of PC to the bone.
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PMID:Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor. 1638 Oct 9

Bone is the key metastatic site for prostate cancer. Endothelin 1 (ET-1) produced abundantly by prostate cancer cells binds to its receptor present on bone marrow stromal cells and favors osteoblastic response during bone metastases of prostate cancer. This suggests that interrupting ET-1 interaction with its endothelin A (ET(A)) receptor could be useful for inhibiting prostate cancer bone metastasis and, as such, may enhance the therapeutic activity of docetaxel (Taxotere), the most commonly used drug for the treatment of metastatic prostate cancer. Therefore, the goal of our study was to obtain preclinical data supporting our hypothesis that the combined use of ET(A) receptor antagonist (ABT-627; Atrasentan) with Taxotere will be superior in inducing apoptosis in vitro and inhibiting tumor growth in vivo in a SCID-hu model of experimental bone metastasis induced by C4-2b prostate cancer cells. In vitro studies were done on a panel of prostate cancer cell lines to understand the molecular basis of combination therapy, and we found that the combination was more effective in the inhibition of cell viability and induction of apoptosis in LNCaP and C4-2b cells (androgen receptor positive) but not in PC-3 cells. These results were correlated with inactivation of Akt/nuclear factor-kappaB and its target genes. For in vivo studies, the therapeutic regimen was initiated when the tumor began showing signs of growth and treatment was continued for 5 weeks. Tumor volume and serum prostate-specific antigen were used as terminal index to evaluate the therapeutic advantage of combination therapy relative to a single regimen and untreated control. At termination, we found a 90% reduction in tumor volume by combination treatment relative to the untreated control group. Most importantly, the antitumor activity was associated with the down-regulation of molecular markers in tumor tissues that were similar to those observed in vitro.
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PMID:In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. 3021 75

Bone metastasis is a critical problem of lung cancer patients. Reproducible animal models of lung cancer bone metastasis, like NK-cell depleted SCID mouse model with SCB-5 cells, are useful to explore the molecular mechanism and search of molecular targets. SBC-5 cells overexpressed PTHrP and that treatment with anti-PTHrP neutralizing antibody inhibited the production of bone metastases of SBC-5 cells in the NK-cell depleted SCID mouse model, indicating the critical role of PTHrP in bone metastasis in this model. In addition, we demonstrated that several compounds, including bisphosphonates and reveromycin A, potentially suppress osteoclast-activity were beneficial for the treatments of bone metastasis. Multi-modality therapy may be necessary for further augmenting the therapeutic efficacy against lung cancer bone metastasis.
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PMID:Molecular pathogenesis and its therapeutic modalities of lung cancer metastasis to bone. 1778 36


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