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)

The majority of human malignancies are believed to have epithelial origin, and the progression of cancer is often associated with a transient process named epithelial-mesenchymal transition (EMT). EMT is characterized by the loss of epithelial markers and the gain of mesenchymal markers that are typical of "cancer stem-like cells," which results in increased cell invasion and metastasis in vivo. Therefore, it is important to uncover the mechanistic role of factors that may induce EMT in cancer progression. Studies have shown that platelet-derived growth factor (PDGF) signaling contributes to EMT, and more recently, PDGF-D has been shown to regulate cancer cell invasion and angiogenesis. However, the mechanism by which PDGF-D promotes invasion and metastases and whether it is due to the acquisition of EMT phenotype remain elusive. For this study, we established stably transfected PC3 cells expressing high levels of PDGF-D, which resulted in the significant induction of EMT as shown by changes in cellular morphology concomitant with the loss of E-cadherin and zonula occludens-1 and gain of vimentin. We also found activation of mammalian target of rapamycin and nuclear factor-kappaB, as well as Bcl-2 overexpression, in PDGF-D PC3 cells, which was associated with enhanced adhesive and invasive behaviors. More importantly, PDGF-D-overexpressing PC3 cells showed tumor growth in SCID mice much more rapidly than PC3 cells. These results provided a novel mechanism by which PDGF-D promotes EMT, which in turn increases tumor growth, and these results further suggest that PDGF-D could be a novel therapeutic target for the prevention and/or treatment of prostate cancer. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. 1840 54

Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 (fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control-transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS.
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PMID:Frzb, a secreted Wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of Met signaling. 1845 Nov 62

A significant proportion of prostate cancer patients treated with curative intent go on to develop advanced disease. At a fundamental biological level, very little is known about what makes the disease aggressive and metastatic. Observational pathology reports and experimental data suggest that epithelial-mesenchymal transition is involved in prostate cancer invasiveness. Here, we investigated vimentin expression of prostate cancer cells, and explored the potential mechanism of vimentin promoting prostate cancer cells invasion. Vimentin expression was not detected in well differentiated tumors or in moderately differentiated tumors, but the majority of poorly differentiated cancers (5/11 with negative bone scan, 11/14 bone with positive scan) and bone metastases (8/8) had high vimentin expression in tumor cells. Downregulation of vimentin expression in PC-3 cells by transfection with antisense-vimentin led to a significant decrease in tumor cells motility and invasive activity. Furthermore, the expression of E-cadherin was inversely associated with expression of vimentin. Our results suggest that vimentin affects prostate cancer cells motility and invasiveness.
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PMID:Vimentin affects the mobility and invasiveness of prostate cancer cells. 1846 97

Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor beta1 (TGFbeta1) and transcription factors including Snail and Slug. We utilized the ARCaP(E)/ARCaP(M) prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaP(E) cells, the highly tumorigenic mesenchymal ARCaP(M) and ARCaP(M1) variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaP(M) and ARCaP(M1) expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-kappaB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFbeta1 treatment and Snail overexpression induced EMT in ARCaP(E) and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.
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PMID:Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. 1864 83

Calcitonin, a neuroendocrine peptide, and its receptor are localized in the basal epithelium of benign prostate but in the secretory epithelium of malignant prostates. The abundance of calcitonin and calcitonin receptor mRNA displays positive correlation with the Gleason grade of primary prostate cancers. Moreover, calcitonin increases tumorigenicity and invasiveness of multiple prostate cancer cell lines by cyclic AMP-dependent protein kinase-mediated actions. These actions include increased secretion of matrix metalloproteinases and urokinase-type plasminogen activator and an increase in prostate cancer cell invasion. Activation of calcitonin-calcitonin receptor autocrine loop in prostate cancer cell lines led to the loss of cell-cell adhesion, destabilization of tight and adherens junctions, and internalization of key integral membrane proteins. In addition, the activation of calcitonin-calcitonin receptor axis induced epithelial-mesenchymal transition of prostate cancer cells as characterized by cadherin switch and the expression of the mesenchymal marker, vimentin. The activated calcitonin receptor phosphorylated glycogen synthase kinase-3, a key regulator of cytosolic beta-catenin degradation within the WNT signaling pathway. This resulted in the accumulation of intracellular beta-catenin, its translocation in the nucleus, and transactivation of beta-catenin-responsive genes. These results for the first time identify actions of calcitonin-calcitonin receptor axis on prostate cancer cells that lead to the destabilization of cell-cell junctions, epithelial-to-mesenchymal transition, and activation of WNT/beta-catenin signaling. The results also suggest that cyclic AMP-dependent protein kinase plays a key role in calcitonin receptor-induced destabilization of cell-cell junctions and activation of WNT-beta-catenin signaling.
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PMID:Cadherin switching and activation of beta-catenin signaling underlie proinvasive actions of calcitonin-calcitonin receptor axis in prostate cancer. 1900 80

Because stroma in tumor tissues can promote prostate cancer development, modulation of tumor-stromal cell interactions may represent an attractive new strategy for cancer treatment. Here, we report that phthoxazolin A and its analog inthomycin B inhibit the growth of human prostate cancer DU-145 cells by modulating tumor-stromal cell interactions. Using an in vitro coculture system, in which prostate cancer cell growth is upregulated by prostate stromal cells (PrSC), we found that phthoxazolin A and inthomycin B strongly inhibited the growth of DU-145 cells when in coculture with PrSC compared to DU-145 cells cultured alone. Although PrSC consist of both fibroblasts and myofibroblasts, phthoxazolin A and inthomycin B inhibited the expression of smooth muscle alpha-actin, a myofibroblast marker, without affecting vimentin and beta-actin expression. Because myofibroblasts secrete various factors that can promote tumor cell growth, we examined whether the inhibitory compounds affected the secretion of such factors from PrSC. Proteomic analysis and reverse transcription-polymerase chain reaction revealed that phthoxazolin A and inthomycin B inhibited the expression of several insulin-like growth factor binding proteins and insulin-like growth factor (IGF)-I by PrSC. Transforming growth factor-beta1 increased myofibroblast numbers and IGF-I levels in PrSC. Phthoxazolin A inhibited transforming growth factor-beta1 activity without altering phosphorylation of the downstream molecule smad2. Furthermore, conditioned medium from phthoxazolin A-treated PrSC failed to increase the phosphorylation of IGF-IR and Akt in DU-145 cells. Taken together, our results suggested that phthoxazolin A acts as a small-molecule modulator of tumor-stromal cell interactions that can indirectly suppress prostate cancer cell growth through inhibition of IGF-I production by PrSC.
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PMID:Phthoxazolin A inhibits prostate cancer growth by modulating tumor-stromal cell interactions. 1901 64

Endo180 (CD280; MRC2; uPARAP) regulates collagen remodelling and chemotactic cell migration through cooperation with membrane type-1 matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator receptor (uPAR) and urokinase-type plasminogen activator (uPA). One hundred and sixty nine prostate tissue sections clinically graded as benign prostatic hyperplasia (BPH) (n=29) or prostate cancer (PCA) with Gleason scores indicating low (< or =7(3+4); n=26), intermediate (7(4+3)-8; n=96) or high (9-10; n=19) clinical risk were immunofluorescently stained for Endo180, pan-cytokeratin (pCk), vimentin, MT1-MMP and uPAR-uPA. Quantification of % Endo180(+)/pCk(-) and Endo180(+)/pCk(+) cells in entire tissue cores revealed stromal (p=0.0001) and epithelial (p=0.0001) upregulation of Endo180 in PCA compared to BPH. Epithelial Endo180 expression was significantly different between the three clinical risk groups of PCA (p<0.05). Correlations with MT1-MMP and uPAR-uPA confirmed the functionality of Endo180 during PCA progression. This molecular evaluation is the first step in the exploration of Endo180 in PCA diagnosis and therapy.
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PMID:Endo180 expression with cofunctional partners MT1-MMP and uPAR-uPA is correlated with prostate cancer progression. 1911 15

Prostatic carcinoma is an important cancer in both men and dogs. Dogs have been a valuable animal model for investigating prostate cancer, but their relevance is unclear as the origin of canine prostatic carcinomas is unknown. We hypothesized that a proteomic approach for diagnosis of these neoplasms might provide quantitative data useful for more complete characterization of their origin. Protein expression profiles were prepared from normal canine prostate glands and bladders. The normal protein profiles were then compared with protein expression profiles of three canine prostatic carcinomas. Two-dimensional differential in-gel electrophoresis (2-D DIGE) was used to analyse an average of approximately 1000 proteins per carcinoma. When compared with normal prostate tissue, the carcinomas exhibited greater than 2.5-fold difference in expression for an average of 230 proteins. Similar proteomic comparisons between the carcinomas and the normal bladder revealed a greater than 2.5-fold difference in expression for an average of 208 proteins. Mass spectrometry and protein database homology were used to identify nine proteins (alpha-enolase, vimentin, GRP78, endoplasmin (GRP94), albumin, keratins 7 and 8, haptoglobin, and transferrin) overexpressed by the carcinomas. Statistical testing demonstrated that keratin 7, GRP78, and endoplasmin were significantly overexpressed in the carcinomas compared with normal prostate or bladder. Principal components analysis revealed that the carcinomas formed a unique cluster distinct from either the normal prostate or normal bladder. In conclusion, proteomic analysis revealed that whereas the majority of proteins expressed by canine prostatic carcinomas are also expressed by normal and neoplastic bladder and prostate tissue, the carcinomas contained unique protein components that allowed their segregation as a distinct group separate from normal canine prostate and bladder. Additionally, several proteins uniquely expressed by canine prostatic carcinomas were also identified.
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PMID:Protein expression profiling of normal and neoplastic canine prostate and bladder tissue. 1975 95

We tracked the extracellular fate of proteins of pulmonary origin using the technique of stable isotope labeling of amino acids in cell culture (SILAC) in cell-impermeable Transwell culture systems. We find that irradiation to murine lung and lung-derived cells induces their release of proteins that are capable of entering neighboring cells, including primary murine bone marrow cells as well as prostate cancer and hematopoietic cell lines. The functional classification of transferred proteins was broad and included transcription factors, mediators of basic cellular processes and components of the nucleosome remodeling and deacetylase complex, including metastasis associated protein 3 and retinoblastoma-binding protein 7. In further analysis we find that retinoblastoma-binding protein 7 is a transcriptional activator of E-cadherin and that its intercellular transfer leads to decreased gene expression of downstream targets such as N-cadherin and vimentin. SILAC-generated data sets offer a valuable tool to identify and validate potential paracrine networks that may impact relevant biologic processes associated with phenotypic and genotypic signatures of health and disease.
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PMID:Intercellular transfer of proteins as identified by stable isotope labeling of amino acids in cell culture. 2002 4

Tumor and stromal interactions in the tumor microenvironment are critical for oncogenesis and cancer progression. Our understanding of the molecular events by which reactive stromal fibroblasts-myofibroblast or cancer-associated fibroblasts (CAF)-affect the growth and invasion of prostate cancer remains unclear. Laser capture microdissection and cDNA microarray analysis of CAFs in prostate tumors revealed strong upregulation of phosphoglycerate kinase-1 (PGK1), an ATP-generating glycolytic enzyme that forms part of the glycolytic pathway and is directly involved in CXCL12-CXCR4 signaling. Normal fibroblasts overexpressing PGK1 resembled myofibroblasts in their expression of smooth muscle alpha-actin, vimentin, and high levels of CXCL12. These cells also displayed a higher proliferative index and the capability to contribute to prostate tumor cell invasion in vitro, possibly through expression of MMP-2 and MMP-3 and activation of the AKT and ERK pathways. Coimplantation of PGK1-overexpressing fibroblasts with prostate tumor cells promoted tumor cell growth in vivo. Collectively, these observations suggest that PGK1 helps support the interactions between cancer and its microenvironment.
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PMID:Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. 2006 85


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