Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A neutralizing monoclonal antibody (MAb) 26-2F to human angiogenin, a potent inducer of neovascularization, has been shown previously to prevent or delay the appearance of angiogenin-secreting human colon, fibrosarcoma and lung tumor cell xenografts implanted subcutaneously (s.c.) into athymic mice. In an analogous model system, we report here that the antibody also prevents the establishment of PC-3 androgen-independent human prostate cancer tumors in, on average, 40% of treated mice (p < 0.0001, survivor analysis). Intriguingly, combining MAb 26-2F together with cisplatin and suramin, 2 therapeutic agents that together showed little antitumor activity in the aforementioned model, resulted in an even greater degree of protection (71% protected, p = 0.009 compared to antibody treatment alone). This protective effect persisted several weeks after cessation of treatment. Additionally, prophylactic systemic administration of MAb 26-2F dramatically reduced by 50% the formation of spontaneous regional metastasis originating from primary growth in the prostate gland of PC-3M cells, highly metastatic variants of PC-3. Protection from metastasis was still significant when treatment with MAb 26-2F was delayed until after the primary tumor was well established. The antibody is not directly cytotoxic to either cell type, both of which secrete angiogenin in vitro and when growing as tumors in vivo, but changes the pattern of vascularity in primary tumors growing orthotopically. These findings, together with the observation that angiogenin protein and mRNA are apparently overexpressed in cancerous vs. normal human prostate tissues, demonstrate that angiogenin antagonism represents a promising new approach for preventing progression and metastasis of clinical prostate cancer.
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PMID:Inhibition of prostate carcinoma establishment and metastatic growth in mice by an antiangiogenin monoclonal antibody. 1194 74

To determine whether Akt activation was sufficient for the transformation of normal prostate epithelial cells, murine prostate restricted Akt kinase activity was generated in transgenic mice (MPAKT mice). Akt expression led to p70S6K activation, prostatic intraepithelial neoplasia (PIN), and bladder obstruction. mRNA expression profiles from MPAKT ventral prostate revealed similarities to human cancer and an angiogenic signature that included three angiogenin family members, one of which was found elevated in the plasma of men with prostate cancer. Thus, the MPAKT model may be useful in studying the role of Akt in prostate epithelial cell transformation and in the discovery of molecular markers relevant to human disease.
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PMID:Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. 1279 64

Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D/D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D/D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the "Cambrian Explosion" in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the "disulfide zipper." The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.
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PMID:The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. 1537 56

Angiogenesis is an essential step in initial tumor development and metastasis. Consequently, compounds that inhibit angiogenesis would be useful in treating cancer. A variety of antitumor effects mediated by 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) have been reported, one of which is anti-angiogenesis; however, detailed mechanisms remain unclear. We have demonstrated that 1,25-VD inhibits prostate cancer (PCa) cell-induced human umbilical vein endothelial cell migration and tube formation, two critical steps involved in the angiogenesis. An angiogenesis factor, interleukin-8 (IL-8), secreted from PCa cell was suppressed by 1,25-VD at both mRNA and protein levels. Mechanistic dissection found that 1,25-VD inhibits NF-kappaB signal, one of the most important IL-8 upstream regulators. The 1,25-VD-mediated NF-kappaB signal reduction was shown to result from the blocking of nuclear translocation of p65, a subunit of the NF-kappaB complex, and was followed by attenuation of the NF-kappaB complex binding to DNA. The role of IL-8 in PCa progression was further examined by PCa tissue microarray analyses. We found that IL-8 expression was elevated during PCa progression, which suggests that IL-8 may play a role in tumor progression mediated through its stimulation on angiogenesis. These findings indicate that 1,25-VD could prevent PCa progression by interrupting IL-8 signaling, which is required in tumor angiogenesis, and thus applying vitamin D in PCa treatment may be beneficial for controlling disease progression.
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PMID:1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. 1662 28

Human angiogenin is progressively up-regulated in the prostate epithelial cells during the development of prostate cancer from prostate intraepithelial neoplasia (PIN) to invasive adenocarcinoma. Mouse angiogenin is the most up-regulated gene in AKT-induced PIN in prostate-restricted AKT transgenic mice. These results prompted us to study the role that angiogenin plays in prostate cancer. Here, we report that, in addition to its well established role in mediating angiogenesis, angiogenin also directly stimulates prostate cancer cell proliferation. Angiogenin undergoes nuclear translocation in PC-3 human prostate cancer cells grown both in vitro and in mice. Thus, knocking down angiogenin expression in PC-3 human prostate adenocarcinoma cells inhibits ribosomal RNA transcription, in vitro cell proliferation, colony formation in soft agar, and xenograft growth in athymic mice. Blockade of nuclear translocation of angiogenin by the aminoglycoside antibiotic neomycin inhibited PC-3 cell tumor growth in athymic mice and was accompanied by a decrease in both cancer cell proliferation and angiogenesis. These results suggest that angiogenin has a dual effect, angiogenesis and cancer cell proliferation, in prostate cancer and may serve as a molecular target for drug development. Blocking nuclear translocation of angiogenin could have a combined benefit of antiangiogenesis and chemotherapy in treating prostate cancer.
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PMID:A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation. 1697 83

We have recently established a highly tumorigenic cell line, LNCaP-CR, derived from human androgen-dependent prostate cancer LNCaP cells. In the present study, we examined the genes responsible for the high tumorigenicity of LNCaP-CR cells. The cDNA microarray analysis and protein array of secreted factors indicated angiogenin (ANG), an angiogenic factor, as a candidate gene. Reverse transcription-polymerase chain reaction and immunoassay confirmed that LNCaP-CR cells expressed high levels of ANG but not vascular endothelial growth factor (VEGF), compared with the parental LNCaP cells. We also proved that another tumorigenic androgen receptor-positive prostate cancer cell line, 22Rv1, secretes higher levels of ANG than VEGF. To assess the contribution of ANG to the highly tumorigenic phenotype, we transfected the ANG gene into LNCaP cells in order to overexpress ANG, and also transfected ANG small interfering RNA-expressing constructs into LNCaP-CR cells to downregulate ANG. Overexpression of ANG in LNCaP cells did not affect their growth in vitro, but it significantly enhanced tumorigenicity and angiogenesis in vivo. In contrast, knockdown of ANG expression in LNCaP-CR cells also did not affect the growth in vitro, but it led to a significant decrease in tumorigenicity and angiogenesis. Taken together, ANG is one of the genes responsible for the high tumorigenicity of LNCaP-CR cells. Thus, our results support the idea that ANG is an attractive target for cancer therapy and show that LNCaP-CR cells are useful for studying ANG action and experimental therapeutic approaches targeting ANG.
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PMID:Highly tumorigenic human androgen receptor-positive prostate cancer cells overexpress angiogenin. 1727 24

Angiogenesis is a critical step for the tumor therapy. Many angiogenic factors are involved in the tumor angiogenesis. In the course of our screening for inhibitors of angiogenin secretion, one of angiogenic factors, we have isolated a new terrein glucoside (1) and terrein (2) from the fermentation broth of fungal strain Aspergillus sp. PF1381. The structure and absolute stereochemistry of 1 was determined to be (4S,5R)-5-[(alpha-D-glucopyranosyl)oxy]-4-hydroxy-3-(E-1-propenyl)-2-cyclopenten-1-one on the basis of spectral and enzymatic analyses. Compounds 1 and 2 equally inhibited angiogenin secretion from androgen-dependent prostate cancer cells, LNCaP-CR, with IC50 values of 13 microM. However, both compounds did not affect VEGF secretion, another angiogenic factor. Furthermore, both compounds inhibited tube formation of human umbilical vein endothelial cells (HUVEC). These results suggested that 1 and 2 act as angiogenesis inhibitors through the inhibition of angiogenin secretion.
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PMID:A new terrein glucoside, a novel inhibitor of angiogenin secretion in tumor angiogenesis. 1877 56

In this study, we aimed to investigate the angiogenic cytokine profiles of hormone- and drug-refractory prostate carcinoma cell lines, PC-3 and DU-145. We also studied the effect of gossypol, a natural polyphenolic cotton-seed extract, on the angiogenic cytokine profile of these cell lines. XTT cell proliferation assay was used for the assessment of cytotoxicity. For apoptosis, both histone-DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used. Angiogenic cytokine profiles of supernatants from both cell lines, before and after treatment with gossypol, were investigated using the human angiogenesis antibody array I. It was shown that the two different hormone- and drug-resistant prostate cancer cell lines, PC-3 and DU-145, constitutively express some important angiogenic cytokines, which are known to regulate tumorigenicity and angiogenesis in hormone-refractory prostate cancer. However, PC-3 and DU-145 cells have distinct angiogenic cytokine profiles. In addition, these two cells lines respond differently to gossypol treatment in terms of cytotoxicity and angiogenic cytokine secretion. After treatment with 10 microM of gossypol, there was a 1.5-fold decrease in angiogenin and IL-8 levels and a 1.7- and 1.8-fold decrease in ENA-78 and GRO-alpha levels respectively, in DU-145 cells. For PC-3 cells, there were 1.6- and 1.8-fold decreases in IL-8 and VEGF levels, respectively. We conclude that PC-3 and DU-145 cells secrete significant amounts of different angiogenic cytokines that may explain their aggressive nature and metastatic potential. Gossypol treatment affects angiogenic cytokine secretion from these two cell lines in a different manner. By expanding our knowledge of the heterogeneous biological behavior of these two cell lines, novel treatment approaches can be developed for the treatment of prostate cancer.
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PMID:Profiling of angiogenic cytokines produced by hormone- and drug-refractory prostate cancer cell lines, PC-3 and DU-145 before and after treatment with gossypol. 1910 23

Molecular imaging techniques used to detect the initiation of disease have the potential to provide the best opportunity for early treatment and cure. This report aimed at testing the possibility that Flk1+ (vascular endothelial growth factor receptor 2), a crucial angiogenesis factor of most tumor cells, could be a molecular targeted imaging marker for the diagnosis and prognosis of cancer. We performed Flk1-targeted microbubble-enhanced ultrasound (US) imaging of prostate cancer in a genetically engineered mouse model with normal-appearing intact US (negative) prostates and with three different tumor sizes (small, medium, and large). Higher levels of Flk1+ molecular signals were identified in the intact US (negative) prostate group by US-targeted imaging and immunohistochemical analysis. The increase in Flk1+ expression occurred prior to the angiogenesis switch-on phase and vascularity peak. After this peak accumulation stage of Flk1+ molecules, lower and stabilized levels of Flk1+ signals were maintained together with tumor growth from small, to medium, to large size. In a longitudinal observation in a subset (n = 5) of mice with established tumors, elevated Flk1+ signals were observed in tissues surrounding the prostate cancer, for example, the ipsilateral boundary zones between two developing tumor lobes, new tumor blood vessel recruits, the urethra border, and the pelvic node basin. The potential of Flk1-targeted US imaging as a predictive imaging tool was confirmed by correlation studies of three-dimensional US B-mode imaging, gross pathology, and histology analyses. The results of the application in a genetically engineered mouse model with prostate cancer of molecular Flk1-targeted US imaging support the contention that Flk1 can be used as a molecular imaging marker for small tumors undetectable by microimaging and as a molecular diagnostic and prognosis marker for tumor metastasis and progression.
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PMID:Molecular targeted enhanced ultrasound imaging of flk1 reveals diagnosis and prognosis potential in a genetically engineered mouse prostate cancer model. 1972 75

Prostate fibroblasts promote prostate cancer progression by secreting factors that enhance tumour growth and induce the migration and invasion of prostate cancer cells. Considering the role of fibroblasts in cancer progression, we hypothesized that prostate cancer cells recruit these cells to their vicinity, where they are most directly available to influence cancer cell behaviour. To test this hypothesis, we performed modified Boyden chamber assays assessing the migration and collagen I invasion of normal primary prostate fibroblasts (PrSCs) and prostate cancer-associated fibroblasts (PCAFs) in response to media conditioned by the metastatic prostate cancer cell lines PC-3, LNCaP and DU145. During 4-hr incubations, PrSCs and PCAFs migrated and invaded in response to the conditioned media. To identify candidate proteins in the conditioned media that produced these effects, we performed cytokine antibody arrays and detected angiogenin in all three media. Angiogenin-blocked PC-3-conditioned medium, obtained using an anti-angiogenin polyclonal antibody or angiogenin siRNA, significantly reduced PC-3-induced PrSC and PCAF collagen I invasion. Furthermore, angiogenin alone at 1, 2 and 5 ng/ml significantly stimulated PCAF collagen I invasion. These results suggest that PC-3-derived angiogenin stimulates the invasion of normal prostate fibroblasts and PCAFs and is sufficient for invasion of the latter. Because prostate fibroblasts play key roles in prostate cancer progression, targeting their invasion using an anti-angiogenin-based therapy may be a strategy for preventing or treating advanced prostate cancer.
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PMID:Prostate cancer-derived angiogenin stimulates the invasion of prostate fibroblasts. 2135 72


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