UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44 is a glycosylated adhesion molecule and osteopontin is one of its ligand. CD44 undergoes alternative splicing to produce variant isoforms. Our recent studies have shown an increase in the surface expression of CD44 isoforms (sCD44 and v4-v10 variant CD44) in prostate cancer cells over-expressing osteopontin (PC3/OPN). Formation of CD44/MMP9 complex on the cell surface is indispensable for MMP9 activity. In this study, we have characterized the expression of variant CD44 using RT-PCR, surface labeling with NHS-biotin, and immunoblotting. Expression of variant CD44 encompassing v4-v10 and sCD44 at mRNA and protein levels are of the same levels in PC3 and PC3/OPN cells. However, an increase in the surface expression of v6, v10, and sCD44 in PC3/OPN cells suggest that OPN may be a ligand for these isoforms. We then proceeded to determine the role of sCD44 in MMP9 activation. Based on our previous studies in osteoclasts, we hypothesized that phosphorylation of CD44 has a role on its surface expression and subsequent activation of MMP9. We have prepared TAT-fused CD44 peptides comprising unphosphorylated and constitutively phosphorylated serine residues at positions Ser323 and Ser325. Transduction of phosphopeptides at Ser323 and Ser323/325 into PC3 cells reduced the surface levels of CD44, MMP9 activity, and cell migration; but had no effect on the membrane localization of MMP9. However, MMP9 knock-down PC3 cells showed reduced CD44 at cellular and surface levels. Thus we conclude that surface expression of CD44 and activation of MMP9 on the cell surface are interdependent.
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PMID:Characterization of the expression of variant and standard CD44 in prostate cancer cells: identification of the possible molecular mechanism of CD44/MMP9 complex formation on the cell surface. 1958 79

The molecular mechanisms involved in prostate cancer (PC) metastasis and bone remodeling are poorly understood. We recently reported that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) mediates transcriptional regulation and activation of bone morphogenetic protein (BMP)-2 signaling by nuclear factor (NF)-kappaB in bone metastatic prostate cancer cells. In the present study, we demonstrate that NF-kappaB, whether activated by recombinant human tumor necrosis factor (TNF)-alpha or by ectopic expression of the p65 subunit, is involved in extracellular matrix adhesion and invasion of osteotropic PC-3 and C4-2B, but not LNCaP, cells. The enhanced metastatic potential was associated with transcriptional upregulation of osteopontin, osteocalcin, and collagen IA1 in osteotropic PC cells, suggesting their role in osteomimicry of PC cells. Unlike BMP-4, BMP-2 protein enhanced the invasive properties of C4-2B cells, but not in LNCaP cells. Also, this effect was nullified by Noggin. In addition, BMP-2 mediates TNF-alpha-induced invasion of C4-2B cells in a NF-kappaB-dependent fashion. TNF-alpha or conditioned media (CM) of TNF-alpha-stimulated C4-2B cells upregulated BMP-2 and BMP-dependent Smad transcripts and inhibited receptor activator of NF-kappaB ligand transcripts in RAW 264.7 preosteoclast cells, respectively, implying that this factor may contribute to suppression of osteoclastogenesis via direct and paracrine mechanisms. In contrast, CM of TNF-alpha-stimulate or BMP2-stimulated C4-2B cells induced in vitro mineralization of MC3T3-E1 osteoblast cells in a BMP-2-dependent and NF-kappaB-dependent manner, respectively. Taken together, the results suggest that mutual interactions between these factors may be pivotal not only in enhancing the osteomimicry and metastatic potential of PC cells, but also in bone remodeling and in shifting the balance from osteoclastogenesis towards osteoblastogenesis.
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PMID:Independent and cooperative roles of tumor necrosis factor-alpha, nuclear factor-kappaB, and bone morphogenetic protein-2 in regulation of metastasis and osteomimicry of prostate cancer cells and differentiation and mineralization of MC3T3-E1 osteoblast-like cells. 1981 99

Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.
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PMID:Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. 1991 14

Osteopontin (OPN), a secreted phosphoglycoprotein, is frequently associated with cell proliferation and tumor metastatic spread in a variety of cancers. It has been reported that OPN induce matrix metalloproteinase (MMP)-2 and MMP-9 activations through nuclear factor kappaB (NF-kappaB)-mediated signaling pathways. In this study, we investigated the roles of OPN in human prostate cancer cells and provided clues about the possible functions of IkappaB kinase (IKK) in NF-kappaB-mediated OPN-induced activations of MMP-2 and MMP-9. Short-hairpin RNA (shRNA) expression vectors were used to inhibit OPN expression in PC-3 cells, human prostate cancer cell line, and IKK inhibitor VII were applied to inhibit the activities of IKK-1 and IKK-2. The results showed that OPN shRNA-mediated RNA interference can downregulate OPN, MMP-2 and MMP-9 expressions, thereby resulting in suppression of the proliferation, migration and invasion of PC-3 cells in vitro and tumor growth in vivo. Moreover, the inhibition of IKK-2 can suppress MMP-2 and MMP-9 expressions, in contrast, the inhibition of IKK-1 has no effects on the OPN, MMP-2 and MMP-9 expression levels. Thus, this study demonstrated that OPN knockdown could downregulate MMP-2 and MMP-9 expressions result in inhibiting the malignant physiological behaviors of PC-3 cell and that IKK-2 may play a crucial role in OPN-induced MMP-2 and MMP-9 expressions via NF-kappaB-mediated signaling pathways.
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PMID:A short-hairpin RNA targeting osteopontin downregulates MMP-2 and MMP-9 expressions in prostate cancer PC-3 cells. 2020 76

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of markerlevel changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters.
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PMID:Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. 2040 80

Prostate cancer is one of the most frequently diagnosed cancer in men. Treatment by radical prostatectomy, radiotherapy and anti-androgen drugs is successful in patients with localized cancer. However, prolonged androgen deprivation often leads to hormone refractory condition, associated with disease relapse. ErbB1 and ErbB2 activity has been correlated with androgen-independence. We determined the effects of GW2974, a dual inhibitor of ErbB-1 and ErbB-2 tyrosine kinase activity, on growth, NSE, chromogranin A and osteopontin cytosol content in the androgen-independent prostate cancer cell line PC-3. We found that PC-3 cell growth was inhibited by GW2974, whereas NSE and chromogranin A cell contents were stimulated and osteopontin cytosol level was not affected. The present data may have clinical implications for the treatment of advanced prostate cancer.
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PMID:Effects of the ErbB1/ErbB2 kinase inhibitor GW2974 on androgen-independent prostate cancer PC-3 cell line growth and NSE, chromogranin A and osteopontin content. 2051 64

Prostate cancer metastasis is reliant on the reciprocal interactions between cancer cells and the bone niche/micro-environment. The production of suitable matrices to study metastasis, carcinogenesis and in particular prostate cancer/bone micro-environment interaction has been limited to specific protein matrices or matrix secreted by immortalised cell lines that may have undergone transformation processes altering signaling pathways and modifying gene or receptor expression. We hypothesize that matrices produced by primary human osteoblasts are a suitable means to develop an in vitro model system for bone metastasis research mimicking in vivo conditions. We have used a decellularized matrix secreted from primary human osteoblasts as a model for prostate cancer function in the bone micro-environment. We show that this collagen I rich matrix is of fibrillar appearance, highly mineralized, and contains proteins, such as osteocalcin, osteonectin and osteopontin, and growth factors characteristic of bone extracellular matrix (ECM). LNCaP and PC3 cells grown on this matrix, adhere strongly, proliferate, and express markers consistent with a loss of epithelial phenotype. Moreover, growth of these cells on the matrix is accompanied by the induction of genes associated with attachment, migration, increased invasive potential, Ca(2+) signaling and osteolysis. In summary, we show that growth of prostate cancer cells on matrices produced by primary human osteoblasts mimics key features of prostate cancer bone metastases and thus is a suitable model system to study the tumor/bone micro-environment interaction in this disease.
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PMID:Mineralized human primary osteoblast matrices as a model system to analyse interactions of prostate cancer cells with the bone microenvironment. 2068 84

Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.
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PMID:Stromal activation associated with development of prostate cancer in prostate-targeted fibroblast growth factor 8b transgenic mice. 2107 17

CD44 is a cell adhesion glycoprotein that also governs cell signaling. Dysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses the novel splice variant (v) isoform, CD44v7-10. We studied CD44 in PCa for more than a decade, and in a series of papers, established its functional significance. Using retrovi-ral gene delivery to PC-3M PCa cells, we expressed luciferase-only, enforced CD44s re-expression as a fusion protein with luciferase at its C-terminus or as a protein separate from luciferase, or knocked down CD44v7-10 by RNAi. Invasion, migration, proliferation, soft agar colony formation, adhesion, Docetaxel sensitivity, and xenograft growth assays were carried out. Compared to luciferase-only PC-3M cells, all 3 treatments reduced invasion and migration. Growth and soft agar colony formation were reduced only by re-expression of CD44s as a separate or fusion protein but not CD44v7-10 RNAi. Hyaluronan and osteopontin binding were greatly strengthened by CD44s expression as a separate protein, but not a fusion protein. CD44v7-10 RNAi in PC-3M cells caused marked sensitization to Docetaxel; the 2 CD44s re-expression approaches caused minimal sensitization. In limited numbers of mouse subcutaneous xeno-grafts, all 3 alterations produced only nonsignificant trends toward slower growth compared with luciferase-only controls. In further work, we tested the effects of the anti-growth compound silibinin, a milk thistle derivative. Using a luciferase promoter construct to test for CD44 promoter activity, silibinin significantly and dose-dependently inhibited promoter activity at physiologic doses. Total CD44 RNA and CD44v7-10 RNA were significantly decreased; both were also decreased at the protein level. Phenyl-methylene hydantoins (PMH), guanidine alkaloids derived from Red Sea sponges, have the ability to increase cell-cell adhesion in prostate cancer cells and reduce invasion. Expression of CD44 total mRNA and CD44v7-10 were markedly decreased by PMH and its S-ethyl derivative. The oncogenic mi-croRNAs, miR-373 and miR-520c, which interact with CD44, were studied in prostate cancer cells and human tissues. We found that they bound the 3' untranslated region of the CD44 RNA, and suppressed CD44 in prostate cancer, by preventing the translation of CD44 RNA, rather than by degrading the RNA. Thus, stable re-expression of CD44s reduces PCa growth and invasion in vitro, and possibly in vivo, suggesting CD44's potential as gene therapy. Finally, CD44v7-10 may be a target for chemosensitization, and plays a role in nutraceutical abrogation of tumor development. In vivo effects of CD44 alteration still need to be investigated by use of orthotopic or renal capsule xenografts, which confer a different stromal microenvironment than that of the subcutaneous grafts.
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PMID:Cell adhesion molecule CD44: its functional roles in prostate cancer. 2113 2

Expression of osteopontin (OPN) is increased in prostate cancer cells. The possibility of utilising the increased OPN as a target to suppress the tumourigenicity was investigated in this study. Small interference RNAs against OPN were transfected into highly malignant DU145 prostate cancer cells, which express high level of OPN prior to the transfections, to establish OPN-suppressed clones. Compared with the control transfectants generated by scrambled RNA, suppressed expression of OPN significantly inhibited cell invasiveness and anchorage-independent growth. Similar results were obtained from in vivo experiments. OPN-suppressed transfectants produced significant reductions in average sizes of subcutaneous tumours after inoculation into nude mice. When the levels of OPN measured in transfectants before injection were related to tumour sizes, the reduction in tumour sizes was not propotionally related to the inhibition in OPN-levels. However, when the levels of OPN were analysed in the tumour tissues, it was found that the reduced OPN expression levels were significantly associated with the reducing tumour sizes. These results showed that changes in OPN levels had occurred after the transfectants were inoculated in mice. This study suggested while OPN can be an effective target for therapeutic suppression of prostate cancer, more effective way than RNAi is needed to inhibit OPN expression.
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PMID:Suppressing tumourigenicity of prostate cancer cells by inhibiting osteopontin expression. 2129 88

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