UMLS:C0376358 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

Cancer of the prostate commonly metastasizes to bony sites where cells acquire an aggressive, rapidly proliferating, androgen-independent phenotype. The interaction between bone and prostate, thus, becomes a key factor in disease progression. Fluctuations in intracellular ionized Ca2+ [Ca2+]i are rapid, regulated signal transduction events often associated with cell proliferation. Hence, Ca2+ signals provide a convenient measure of early events in cancer cell growth. This study developed single cell fluorescent imaging techniques to visualize Ca2+ signals in Fura-2 loaded prostatic cancer cell lines of various metastatic phenotypes. Solubilized bone fractions containing extracellular matrix and associated proteins were tested for the ability to trigger Ca2+ signals in prostate cancer cell lines. Fractions representing the complete repertoire of non-collagenous proteins present in mineralized bone were tested. Results demonstrated that two bone fractions termed D3b- and D4a-triggered Ca2+ signals in prostate cancer cells derived from bone (PC-3), but not brain (DU-145) metastases of prostate cancer. Lymph-node derived LNCaP cells also did not produce a Ca2+ signal in response to addition of soluble bone matrix. No other bone fractions produced a Ca2+ signal in PC-3 cells. It is of interest that bone fractions D3b and D4a contain a number of non-collagenous matrix proteins including osteonectin (SPARC) and osteopontin (OPN), as well as prothrombin. Moreover, antibody LM609 that recognizes the alpha v beta 3 integrin, blocks the ability of OPN to trigger a Ca2+ transient in PC-3 cells. These studies support a conclusion that bone-matrix proteins play a role in the growth and progression of metastatic prostate cancer, and that prior growth in bone may be associated with development of a bone-matrix-responsive phenotype.
...
PMID:Calcium signals in prostate cancer cells: specific activation by bone-matrix proteins. 1072 9

The precise mechanism(s) involved in invasion and metastasis of prostate cancer (CaP) is poorly understood. Osteonectin [ON (also known as SPARC or BM-40)] is an antiadhesive protein known to be involved in cell-matrix interactions, migration, and angiogenesis. In this report, we studied the expression of ON in human prostate cell lines, primary tumors, and metastatic foci of CaP. Reverse transcription-PCR and nonradioactive in situ hybridization (ISH) techniques were used to determine ON gene expression. Immunohistochemistry was carried out using the polyclonal antibody LF37 and/or the monoclonal antibody ON-mAb. Low to moderate levels of ON mRNA and protein were observed in glandular epithelial cells of normal tissue as well as a few primary CaPs. However, high levels of ON mRNA and protein were observed in most of the CaP metastatic foci, both osseous and nonosseous. This correlated well with our findings that multiple different CaP cell lines including four CaP cell lines derived from metastases show high levels of ON gene expression. Furthermore, ISH analyses and cell-specific reverse transcription-PCR evaluation showed that both the luminal and basal cells express the ON gene. We conclude that the differential pattern of ON expression suggests that it may play an important role in the progression of CaP.
...
PMID:Differential expression of osteonectin/SPARC during human prostate cancer progression. 1074 45

The molecular mechanism leading to the cancer metastasis to bone is poorly understood but yet determines prognosis and therapy. Here, we define a new molecular pathway that may account for the extraordinarily high osteotropism of prostate cancer. By using SPARC (secreted protein, acidic and rich in cysteine)-deficient mice and recombinant SPARC, we demonstrated that SPARC selectively supports the migration of highly metastatic relative to less metastatic prostate cancer cell lines to bone. Increased migration to SPARC can be traced to the activation of integrins alphaVbeta3 and alphaVbeta5 on tumor cells. Such activation is induced by an autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop on the tumor cells, which also supports the growth and proliferation of prostate cancer cells. A consequence of SPARC recognition by alphaVbeta5 is enhanced VEGF production. Thus, prostate cancer cells expressing VEGF/VEGFR-2 will activate alphaVbeta3 and alphaVbeta5 on their surface and use these integrins to migrate toward SPARC in bone. Within the bone environment, SPARC engagement of these integrins will stimulate growth of the tumor and further production of VEGF to support neoangiogenesis, thereby favoring the development of the metastatic tumor. Supporting this model, activated integrins were found to colocalize with VEGFR-2 in tissue samples of metastatic prostate tumors from patients.
...
PMID:Molecular pathway for cancer metastasis to bone. 1288 81

Skeletal metastases occur with high incidence in patients with breast cancer and cause long-term skeletal morbidity. Osteonectin (SPARC, BM-40) is a bone matrix factor that is an in vitro chemoattractant for breast and prostate cancer cells. Increased expression of osteonectin is found in malignant breast tumors. We infected MDA-231 breast cancer cells with an adenovirus expressing osteonectin to examine the role of osteonectin expression in breast cancer cells and its effect on metastasis, in particular to bone. Expression of osteonectin did not affect MDA-231 cell proliferation, apoptosis, migration, cell aggregation, or protease cleavage of collagen IV. However, in vitro invasion of these osteonectin-infected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dose-dependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelet-tumor cell aggregation, because exogenous osteonectin inhibited platelet aggregation in vitro and the high osteonectin expression in MDA-231 cells reduced tumor cell-induced thrombocytopenia in vivo compared with control-infected cells. These studies suggest that high endogenous expression of osteonectin in breast cancer cells may reduce metastasis via reduced invasive activity and reduced tumor cell-platelet aggregation.
...
PMID:Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. 1610 89

DNA methylation and copy number in the genomes of three immortalized prostate epithelial and five cancer cell lines (LNCaP, PC3, PC3M, PC3M-Pro4, and PC3M-LN4) were compared using a microarray-based technique. Genomic DNA is cut with a methylation-sensitive enzyme HpaII, followed by linker ligation, polymerase chain reaction (PCR) amplification, labeling, and hybridization to an array of promoter sequences. Only those parts of the genomic DNA that have unmethylated restriction sites within a few hundred base pairs generate PCR products detectable on an array. Of 2732 promoter sequences on a test array, 504 (18.5%) showed differential hybridization between immortalized prostate epithelial and cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, there were eight (CD44, CDKN1A, ESR1, PLAU, RARB, SFN, TNFRSF6, and TSPY) previously observed in prostate cancer and 13 previously known methylation targets in other cancers (ARHI, bcl-2, BRCA1, CDKN2C, GADD45A, MTAP, PGR, SLC26A4, SPARC, SYK, TJP2, UCHL1, and WIT-1). The majority of genes that appear to be both differentially methylated and differentially regulated between prostate epithelial and cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, and GG2-1, representing a rich new source of candidate genes used to study the role of DNA methylation in prostate tumors.
...
PMID:Survey of differentially methylated promoters in prostate cancer cell lines. 1620 77

Multiple lines of evidence have provided compelling evidence for the existence of a tumor suppressor gene (TSG) on chromosome 7q31.1. ST7 may be the target of this genetic instability but its designation as a TSG is controversial. In this study, we show that, functionally, ST7 behaves as a tumor suppressor in human cancer. ST7 suppressed growth of PC-3 prostate cancer cells inoculated subcutaneously into severe combined immunodeficient mice, and increased the latency of tumor detection from 13 days in control tumors to 23 days. Re-expression of ST7 was also associated with suppression of colony formation under anchorage-independent conditions in MDA-MB-231 breast cancer cells and ST7 mRNA expression was downregulated in 44% of primary breast cancers. Expression profiling of PC-3 cells revealed that ST7 predominantly induces changes in genes involved in re-modeling the extracellular matrix such as SPARC, IGFBP5 and several matrix metalloproteinases. These data indicate that ST7 may mediate tumor suppression through modification of the tumor microenvironment.
...
PMID:ST7-mediated suppression of tumorigenicity of prostate cancer cells is characterized by remodeling of the extracellular matrix. 1647 48

Satraplatin [BMS 182751, BMY 45594, JM 216] belongs to a series of orally-active platinum compounds with anticancer activity. It was jointly originated by Bristol-Myers Squibb, Johnson Matthey and the Institute of Cancer Research in the UK; however, Johnson Matthey has since ceased involvement with drug development. Subsequently, the agent has been licensed to and is under development with GPC Biotech, Pharmion and Spectrum Pharmaceuticals. Clinical trials are underway to evaluate satraplatin among patients with different tumour types, including prostate, breast, cervical and lung cancers. The compound is under regulatory review with the US FDA for the treatment of hormone-refractory prostate cancer. NeoTherapeutics (now Spectrum Pharmaceuticals) granted GPC Biotech an exclusive worldwide licence to develop and market satraplatin in October 2002. Under the terms of the agreement, GPC Biotech is fully funding development costs and commercialisation requirements for the drug. The deal also involves GPC Biotech paying a signing fee, milestone and royalty payments. Spectrum is a member of a joint development committee headed by GPC Biotech to govern development of satraplatin. Previously in October 2001, NeoOncoRx (Spectrum Pharmaceuticals) gained the rights to develop and market the compound worldwide. In December 2005, GPC Biotech and Pharmion Corporation entered into a co-development and license agreement for satraplatin. Under the agreement terms, Pharmion has exclusive commercialisation rights for Europe, Turkey, the Middle East, Australia and New Zealand, while GPC Biotech retains rights to North America and all other territories. Pharmion made an upfront payment of $US37.1 million to GPC Biotech, which included reimbursement for past clinical development costs plus funding for ongoing and certain clinical development activities to be jointly conducted by the companies. In addition, both parties will pursue a joint development plan for satraplatin in a variety of tumour types and will share global development costs, for which Pharmion has made an additional commitment of $US22.2 million. GPC Biotech could also receive up to $US270 million in milestone payments and royalties on sales. Both companies will manage regulatory and commercial activities in their respective territories. A registrational phase III study is ongoing among 950 patients with HRPC. This global, multicentre, randomised study, called SPARC (Satraplatin and Prednisone Against Refractory Cancer), is assessing satraplatin plus prednisone versus prednisone alone as second-line therapy in HRPC patients. Top-line results from the trial showed that patients who received satraplatin plus prednisone had a 40% reduction in the risk of progression compared with patients who received prednisone plus placebo. In accordance with the recommendation of the independent Data Monitoring Board for the SPARC trial, patients who have not progressed will continue to be treated and all patients will be followed for overall survival. The company expects to have final overall survival results in the fall of 2007. The company intends to complete the NDA filing with the FDA before the end of 2006. In February 2006, GPC Biotech raised euro36.2 million from a private placement of shares; the funds will be used in the commercialisation of satraplatin in the US. GBC Biotech received a Scientific Advice letter from the EMEA in January 2004, enabling the company to use the SPARC trial for registrational plans in both Europe and the US. Data from the pivotal phase III trial are expected in the second half of 2006. If positive, the findings will form the basis of a MAA filing with the EMEA for satraplatin as a second-line therapy of HRPC. The EMEA has confirmed that it would accept the final analysis for progression-free survival (PFS) from the SPARC trial and the available overall survival data as the basis for the MAA submission expected in the first quarter of 2007. In December 2005, enrolment started for a phase II study of satraplatin plus paclitaxel as a first-line treatment for unresectable advanced NSCLC. This open-label study is enrolling up to 40 patients at sites in the US. In addition, GPC Biotech and Spectrum have initiated a phase I/II trial of satraplatin plus radiation therapy among patients with NSCLC. The study is expected to enrol up to 30 patients in the phase I portion to determine dose-limiting toxicities and maximum tolerated doses. Once these are established, the phase II portion will enrol patients to evaluate efficacy and safety. This trial is expected to be closely followed by phase I/II trials of satraplatin in combination with docetaxel and paclitaxel. GPC Biotech initiated a phase I trial in July 2005 investigating satraplatin plus docetaxel among patients with advanced solid tumours in the US. The study is primarily focused on establishing the toxicity and maximum tolerated doses of combination therapy to determine suitable dosages for phase II trials. Enrolment is ongoing for the open-label, single-centre study with a target of up to 48 patients. A phase I study is evaluating satraplatin in combination with gemcitabine in patients with advanced solid tumours. Previously, Bristol-Myers Squibb initiated phase III development of satraplatin in Europe and the US in 1996. The trials were being conducted in patients with ovarian, non-small cell lung and small-cell lung cancers. However, the company closed all ongoing trials of satraplatin in 1999. Satraplatin is protected by a number of patents issued in the US, EU, Japan, Canada and Australia. The patents have been assigned to Johnson Matthey, a multinational chemical company in the UK, which has exclusively sub-licensed these to GPC Biotech under a co-development and licensing agreement with Spectrum Pharmaceuticals. The patents cover the composition of matter and anticancer uses of various platinum-based compounds, including satraplatin. Two of the US patents will expire in 2008 and 2010, respectively, while patents in most other countries will expire in 2009.
...
PMID:Satraplatin: BMS 182751, BMY 45594, JM 216. 1732 11

The propensity for prostate cancer to metastasize to bone led us and others to propose that bidirectional interactions between prostate cancer cells and bone are critical for the preferential metastasis of prostate cancer to bone. We identified previously a secreted isoform of ErbB3 (p45-sErbB3) in bone marrow supernatant samples from men with prostate cancer and bone metastasis and showed by immunohistochemical analysis of human tissue specimens that p45-sErbB3 was highly expressed in metastatic prostate cancer cells in bone. Here, we show that p45-sErbB3 stimulated mouse calvaria to secrete factors that increased the invasiveness of prostate cancer cells in a Boyden chamber invasion assay. Using gene array analysis to identify p45-sErbB3-responsive genes, we found that p45-sErbB3 up-regulated the expression of osteonectin/SPARC, biglycan, and type I collagen in calvaria. We further show that recombinant osteonectin increased the invasiveness of PC-3 cells, whereas osteonectin-neutralizing antibodies blocked this p45-sErbB3-induced invasiveness. These results indicate that p45-sErbB3 enhances the invasiveness of PC-3 cells in part by stimulating the secretion of osteonectin by bone. Thus, p45-sErbB3 may mediate the bidirectional interactions between prostate cancer cells and bone via osteonectin.
...
PMID:A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. 1763 62

Secreted protein, acidic and rich in cysteine (SPARC, also known as osteonectin or BM-40) is a glycoprotein component of the extracellular matrix that has been reported to be involved with a variety of cellular processes. Although SPARC expression levels are frequently altered in a variety of tumor types, the exact implications of deregulated SPARC expression--whether it promotes, inhibits or has no effect on tumor progression--have remained unclear. Our recent gene expression analyses have shown that SPARC is significantly downregulated in highly metastatic human prostate cancer cells. To test the role of endogenous SPARC in tumorigenesis directly, we examined cancer progression and metastasis in SPARC(+/-) and SPARC(-/-) mice using two separate transgenic mouse tumor models: transgenic adenocarcinoma of the mouse prostate (TRAMP) and murine mammary tumor virus-polyoma middle T (MMTV-PyMT). Surprisingly, in both instances, we found that loss of SPARC had no significant effects on tumor initiation, progression or metastasis. Tumor angiogenesis and collagen deposition were also largely unaffected. Our results indicate that, although differential SPARC expression may be a useful marker of aggressive, metastasis-prone tumors, loss of SPARC is not sufficient either to promote or to inhibit cancer progression in two spontaneous mouse tumor models.
...
PMID:Analyses of the role of endogenous SPARC in mouse models of prostate and breast cancer. 1805 30

Satraplatin is an orally bioavailable platinum chemotherapeutic agent under development for several cancer types, including hormone-refractory prostate cancer (HRPC). Satraplatin is being developed for the treatment of men with chemorefractory HRPC for several reasons: 1) relative ease of administration, 2) potential lack of cross-resistance with other platinum agents, 3) clinical benefits seen in early studies of HRPC, and 4) an unmet need in this patient population after docetaxel failure. As men who have progressed after docetaxel and prednisone have an expected median survival of approximately 12 months, there is great opportunity for improved palliation in this disease. Satraplatin may provide a palliative benefit for these men in terms of progression-free survival according to the most recent analyses of the phase III SPARC trial comparing satraplatin and prednisone to prednisone alone in the second-line setting for HRPC, and is currently under USFDA review for this indication. Whether satraplatin and prednisone offer an advantage over docetaxel retreatment or other cytotoxic agents in this setting is an unanswered question and worthy of study. Investigation of predictors of platinum sensitivity and the use of satraplatin in patients with neuroendocrine subsets of metastatic prostate cancer may be warranted given the advances in biomarker and genomic technology and the known sensitivity of small cell cancers to platinum agents. Further study of satraplatin alone or in combination with docetaxel or other molecular and chemotherapeutic agents seems warranted to improve on current outcomes.
...
PMID:Satraplatin in the treatment of hormone-refractory metastatic prostate cancer. 1847 11

1 2 3 Next >>