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Prostate Cancer Progression (prostate + cancer_progression)
Selected AbstractsDevelopment of recombinant inhibitors specific to human kallikrein 2 using phage-display selected substratesFEBS JOURNAL, Issue 3 2004Sylvain M. Cloutier The reactive site loop of serpins undoubtedly defines in part their ability to inhibit a particular enzyme. Exchanges in the reactive loop of serpins might reassign the targets and modify the serpin,protease interaction kinetics. Based on this concept, we have developed a procedure to change the specificity of known serpins. First, reactive loops are very good substrates for the target enzymes. Therefore, we have used the phage-display technology to select from a pentapeptide phage library the best substrates for the human prostate kallikrein hK2 [Cloutier, S.M., Chagas, J.R., Mach, J.P., Gygi, C.M., Leisinger, H.J. & Deperthes, D. (2002) Eur. J. Biochem. 269, 2747,2754]. Selected substrates were then transplanted into the reactive site loop of ,1-antichymotrypsin to generate new variants of this serpin, able to inhibit the serine protease. Thus, we have developed some highly specific ,1-antichymotrypsin variants toward human kallikrein 2 which also show high reactivity. These inhibitors might be useful to help elucidate the importance of hK2 in prostate cancer progression. [source] Chromosome 18 suppresses tumorigenic properties of human prostate cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 3 2006Audrey Gagnon Although prostate cancer is still the most diagnosed cancer in men, most genes implicated in its progression are yet to be identified. Chromosome abnormalities have been detected in human prostate tumors, many of them associated with prostate cancer progression. Indeed, alterations (including deletions or amplifications) of more than 15 human chromosomes have been reported in prostate cancer. We hypothesized that transferring normal human chromosomes into human prostate cancer cells would interfere with their tumorigenic and/or metastatic properties. We used microcell-mediated chromosome transfer to introduce human chromosomes 10, 12, 17, and 18 into highly tumorigenic (PC-3M-Pro4) and highly metastatic (PC-3M-LN4) PC-3-derived cell lines. We tested the in vitro and in vivo properties of these hybrids. Introducing chromosome 18 into the PC-3M-LN4 prostate cancer cell line greatly reduced its tumorigenic phenotype. We observed retarded growth in soft agar, decreased invasiveness through Matrigel, and delayed tumor growth into nude mice, both subcutaneously and orthotopically. This phenotype is associated with a marker in the 18q21 region. Combined with the loss of human chromosome 18 regions often seen in patients with advanced prostate cancer, our results show that chromosome 18 encodes one or more tumor-suppressor genes whose inactivation contributes to prostate cancer progression. © 2005 Wiley-Liss, Inc. [source] Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostateINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2010Flávia K. Delella Summary The safety of using finasteride as a prevention of prostate cancer is still under debate. In this study, we investigated the effects of finasteride on the location, gene expression and activities of matrix metalloproteinases -2 and -9, which are involved in the degradation of extracellular matrix components during tissue remodelling and prostate cancer progression, invasion and metastasis. Ventral prostates (VP) from Wistar rats treated with finasteride (25 mg/kg/day) for 7 and 30 days and age-matched controls were evaluated using histology, immunohistochemistry, semi-quantitative RT-PCR and gelatin zymography. Finasteride treatment reduced the epithelial immunostaining of MMP-2 but increased MMP-9 immunostaining in the epithelial cells and in the stroma. The mRNA expression of both MMP-2 and MMP-9 were significantly increased on day 7 of finasteride treatment, mainly for MMP-9 and returned to the control levels by day 30. However, gelatin zymography showed that MMP-9 activity was significantly increased on day 7 of finasteride treatment and remained elevated on day 30 (p < 0.05), while MMP-2 activity was reduced after 30 days of treatment. Finasteride increases MMP-9 and reduces MMP-2 activities in the prostate, which may affect negatively and positively both normal and tumoural prostatic cell behaviour during the treatment. Studies on expression of MMPs in the prostate during different androgen manipulation or cancer chemoprevention strategies can contribute to understand the tissue's overall response and clinical data. [source] TIP30 is associated with progression and metastasis of prostate cancerINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Hui Zhang Abstract Tat-interacting protein 30 (TIP30), a transcriptional repressor for ER,-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis. © 2008 Wiley-Liss, Inc. [source] The role of the disintegrin metalloproteinase ADAM15 in prostate cancer progressionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Neali Lucas Abstract The metalloproteinase ADAM15 is a multi-domain disintegrin protease that is upregulated in a variety of human cancers. ADAM15 mRNA and protein levels are increased in prostate cancer and its expression is significantly increased during metastatic progression. It is likely that ADAM15 supports disease progression differentially through the action of its various functional domains. ADAM15 may downregulate adhesion of tumor cells to the extracellular matrix, reduce cell,cell adhesion, and promote metastasis through the activity of its disintegrin and metalloproteinase domains. Additionally, ADAM15 can influence cell signaling by shedding membrane-bound growth factors and other proteins that interact with receptor tyrosine kinases, leading to receptor activation. There is also evidence supporting a role for ADAM15 in angiogenesis and angioinvasion of tumor cells, which are critical for unrestrained tumor growth and metastatic spread. Given its diverse functions, ADAM15 may represent a pivotal regulatory component of tumor progression, an important target for therapeutic intervention, or emerge as a biomarker of disease progression. J. Cell. Biochem. 106: 967,974, 2009. © 2009 Wiley-Liss, Inc. [source] Apoptosis evasion: The role of survival pathways in prostate cancer progression and therapeutic resistanceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Shaun McKenzie Abstract The ability of a tumor cell population to grow exponentially represents an imbalance between cellular proliferation and cellular attrition. There is an overwhelming body of evidence suggesting the ability of tumor cells to avoid programmed cellular attrition, or apoptosis, is a major molecular force driving the progression of human tumors. Apoptotic evasion represents one of the true hallmarks of cancer and appears to be a vital component in the immunogenic, chemotherapeutic, and radiotherapeutic resistance that characterizes the most aggressive of human cancers [Hanahan and Weinberg, 2000]. The challenges in the development of effective treatment modalities for advanced prostate cancer represent a classic paradigm of the functional significance of anti-apoptotic pathways in the development of therapeutic resistance. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Ras signaling in prostate cancer progressionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Michael J. Weber Abstract When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post-translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen. © 2003 Wiley-Liss, Inc. [source] Shepherding AKT and androgen receptor by Ack1 tyrosine kinaseJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Kiran Mahajan Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kinase domain of AKT is essential for mitotic progression and positively correlates with breast cancer progression. In contrast to AR and AKT, Ack1-mediated phosphorylation of the tumor suppressor Wwox at Tyr287 lead to rapid Wwox polyubiquitination followed by degradation. Thus, by its ability to promote tumor growth by negatively regulating tumor suppressor such as Wwox and positively regulating pro-survival factors such as AKT and AR, Ack1 is emerging as a critical player in cancer biology. In this review, we discuss recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers. J. Cell. Physiol. 224: 327,333, 2010. © 2010 Wiley-Liss, Inc. [source] Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemopreventionJOURNAL OF PINEAL RESEARCH, Issue 2 2007Chun W. Tam Abstract:, There is an unmet clinical demand for safe and effective pharmaceuticals/nutraceuticals for prostate cancer prevention and hormone-refractory prostate cancer treatment. Previous laboratory and human studies of our laboratory demonstrated an association between the antiproliferative action of melatonin and melatonin MT1 receptor expression in prostate cancer. The aim of this study was to determine, using a pharmacological approach, the signaling mechanisms of melatonin in hormone-refractory 22Rv1 human prostate cancer cell antiproliferation. Both immunoreactive MT1 and MT2 subtypes of G protein-coupled melatonin receptor were expressed in 22Rv1 cells. Melatonin inhibited, concentration dependently, cell proliferation, upregulated p27Kip1 gene transcription and protein expression, and downregulated activated androgen signaling in 22Rv1 cells. While the effects of melatonin were mimicked by 2-iodomelatonin, a high-affinity nonselective MT1 and MT2 receptor agonist, melatonin effects were blocked by luzindole, a nonselective MT1 and MT2 receptor antagonist, but were unaffected by 4-phenyl-2-propionamidotetraline, a selective MT2 receptor antagonist. Importantly, we discovered that the antiproliferative effect of melatonin exerted via MT1 receptor on p27Kip1 gene and protein upregulation is mediated by a novel signaling mechanism involving co-activation of protein kinase C (PKC) and PKA in parallel. Moreover, we also showed that a melatonin/MT1/PKC mechanism is involved in melatonin-induced downregulation of activated androgen signal transduction in 22Rv1 cells. Taken together with the known molecular mechanisms of prostate cancer progression and transition to androgen independence, our data provide strong support for melatonin to be a promising small-molecule useful for prostate cancer primary prevention and secondary prevention of the development and progression of hormone refractoriness. [source] Arachidonic acid activation of intratumoral steroid synthesis during prostate cancer progression to castration resistanceTHE PROSTATE, Issue 3 2010Jennifer A. Locke Abstract BACKGROUND De novo androgen synthesis and subsequent androgen receptor (AR) activation has recently been shown to contribute to castration-resistant prostate cancer (CRPC) progression. Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells. METHODS Tumoral FA and steroid levels were assessed by GC,MS and LC,MS, respectively. Profiles of genes and proteins involved in FA activation of steroidogenesis were assessed by fluorescence microscopy, immunohistochemistry, microarray expression profiling and Western blot analysis. RESULTS In human CaP tissues the levels of proteins responsible for FA activation of steroid synthesis were observed to be altered during progression to CRPC. Further investigating this mechanism in LNCaP cells, we demonstrate that specific FA, arachidonic acid, is synthesized in an androgen-dependent and AR-mediated manner. Arachidonic acid is known to induce steroidogenic acute regulatory protein (StAR) in steroidogenic cells. When bound to hormone sensitive lipase (HSL), StAR shuttles free cholesterol into the mitochondria for downstream conversion into androgens. We show that arachidonic acid induces androgen production in steroid starved LNCaP cells coincidently in the same conditions that HSL and StAR are predominantly localized in the mitochondria. Furthermore, their activities are verified by a functional increase in mitochondrial uptake of cholesterol in this steroid starved environment. CONCLUSIONS We propose that this characterized arachidonic acid induced steroidogenesis mechanism significantly contributes to the activation of AR in CRPC progression and therefore recommend that fatty acid pathways be targeted therapeutically in progressing CaP. Prostate 70: 239,251, 2010. © 2009 Wiley-Liss, Inc. [source] Over-expression of I,B-kinase-, (IKK,/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell linesTHE PROSTATE, Issue 7 2009Benjamin Péant Abstract BACKGROUND Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that I,-B kinase-epsilon (IKK,/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6. RESULTS In this study, we report that over-expression of IKK, in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKK, knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKK, over-expression does not induce the activation of the IKK, classical targets NF-,B and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKK, expression results in its nuclear translocation, a phenomena that is TBK1-independent. CONCLUSIONS This study identifies IKK, as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer. Prostate 69: 706,718, 2009. © 2009 Wiley-Liss, Inc. [source] The polycomb group protein EZH2 regulates actin polymerization in human prostate cancer cellsTHE PROSTATE, Issue 3 2008R.J. Bryant Abstract BACKGROUND The Polycomb Group protein EZH2 is implicated in prostate cancer progression. EZH2 promotes prostate cancer cell proliferation and invasiveness. We describe a link between EZH2 function and actin polymerization in prostate cancer cells. METHODS Nuclear and cytoplasmic EZH2 expression in benign and malignant prostate tissue samples was assessed. An association between EZH2 function and actin polymerization in prostate cancer cells was investigated using siRNA-mediated knock-down of EZH2. Effects of EZH2 knock-down on actin polymerization dynamics were analyzed biochemically using immunoblot analysis of cell lysate fractions, and morphologically using immunocytochemistry. RESULTS Cytoplasmic EZH2 is expressed at low levels in benign prostate epithelial cells and over-expressed in prostate cancer cells. Cytoplasmic EZH2 expression levels correlate with nuclear EZH2 expression in prostate cancer samples. Knock-down of EZH2 in PC3 prostate cancer cells increases the amount of F-actin polymerization, cell size, and formation of actin-rich filaments. CONCLUSIONS Cytoplasmic EZH2 is over-expressed in prostate cancer cells. EZH2 function promotes a reduction in the pool of insoluble F-actin in invasive prostate cancer cells. EZH2 may regulate actin polymerization dynamics and thereby promote prostate cancer cell motility and invasiveness. Prostate 68: 255,263, 2008. © 2007 Wiley-Liss, Inc. [source] Regulation of global gene expression in the bone marrow microenvironment by androgen: Androgen ablation increases insulin-like growth factor binding protein-5 expressionTHE PROSTATE, Issue 15 2007Chang Xu Abstract BACKGROUND Prostate cancer frequently metastasizes to bone. Androgen suppression treatment is initially highly effective, but eventually results in resistant cancer cells. This study evaluates the effects of androgen suppression on the bone and bone marrow (BM). In particular we questioned whether the androgen therapy could adversely facilitate prostate cancer progression through an increase growth factor secretion by the bone microenvironment. METHODS Global gene expression is analyzed on mPEDB DNA microarrays. Insulin-like growth factor binding protein-5 (IGFBP5) is detected by immunohistochemistry in mouse tissues and its regulation measured by qPCR and Western blotting in human BM stromal cells. Effects of extracellular matrix-associated IGFBP5 on human prostate epithelial cells are tested in an MTS cell-growth assay. RESULTS Castration increases expression of 159 genes (including 4 secreted cytokines) and suppresses expression of 84 genes. IGFBP5 is most consistently increased and the increase in expression is reversed by testosterone administration. IGFBP5 protein is detected in vivo in osteoblasts, BM stromal cells, and endothelial cells. Primary human stromal cell cultures secrete IGFBP5. In vitro, treatment of immortalized human marrow stromal cells with charcoal-stripped serum increases IGFBP5 mRNA expression, which is reversed by androgen supplementation. IGFBP5 is incorporated into the extracellular matrix. Further, IGFBP5 immobilized on extracellular matrices of stromal cells enhances the growth of immortalized prostate epithelial cells. CONCLUSIONS Androgen suppressive therapy increases IGFBP5 in the BM microenvironment and thereby may facilitate the progression of prostate cancer. Prostate 67: 1621,1629, 2007. © 2007 Wiley-Liss, Inc. [source] Relaxin becomes upregulated during prostate cancer progression to androgen independence and is negatively regulated by androgensTHE PROSTATE, Issue 16 2006Vanessa C. Thompson Abstract BACKGROUND Relaxin is a potent peptide hormone normally secreted by the prostate. This study characterized relaxin expression during prostate cancer progression to androgen independence (AI), and in response to androgens. METHODS The prostate cancer cell line, LNCaP, was assayed by microarrays and confirmatory Northern analysis to assess changes in relaxin levels due to androgen treatment and in LNCaP xenografts following castration. Relaxin protein levels were examined by immunohistochemistry (IHC) in tissue microarrays of human prostate cancer samples following androgen ablation. RESULTS Relaxin levels decreased in a time and concentration-dependent manner due to androgens in vitro, and increased in xenografts post-castration. Relaxin increased in radical prostatectomy specimens after 6 months of androgen ablation and in AI tumors, was highest in bone metastases. CONCLUSIONS Relaxin is negatively regulated by androgens in vitro and in vivo, which correlates to clinical prostate cancer specimens following androgen ablation. The role of relaxin in angiogenesis and tissue remodeling suggests it may contribute to prostate cancer progression. Prostate © 2006 Wiley-Liss, Inc. [source] Changes in gap junctional connexin isoforms during prostate cancer progressionTHE PROSTATE, Issue 1 2006Amanda W. Tate Abstract BACKGROUND Connexins have their traditional function as part of gap junction (GJ) structures, but have recently been shown to have GJ-independent roles. Although GJs and their connexin subunits are thought to be down-regulated in cancer, depending on the connexin examined, many times the expression level is preserved or even increased. This is further apparent by the importance of GJs in "by-stander effects" of radiation and viral targeting treatments. METHODS We surveyed connexin isoforms in prostate cancer cell lines and tissue with RT-PCR and immunohistochemistry. Upon modulating GJ function, we observed prostate epithelial cell behaviors. RESULTS Advanced cells within PC-3 and LNCaP prostate cancer progression models exhibit elevated connexin 26 (Cx26) levels,a trend validated in clinical samples. When GJs were inhibited, adhesion was not affected, but invasion and migration were strikingly decreased. A link between the expression of Cx26 and integrin adhesion-linked functions are suggested by Cx26's direct interaction with focal adhesion kinase (FAK). CONCLUSIONS These results suggest a novel mechanism for adhesion regulation by a GJ-independent Cx26 function that correlates with prostate disease progression. The increased Cx26 expression during prostate cancer progression plays a role in adhesion regulation possibly through its interaction with FAK. © 2005 Wiley-Liss, Inc. [source] Constitutive activation of PI3K-Akt and NF-,B during prostate cancer progression in autochthonous transgenic mouse modelTHE PROSTATE, Issue 3 2005Sanjeev Shukla Abstract BACKGROUND Cancer progression is usually facilitated by independent growth signals that may lead to increased cell survival and evasion of apoptosis. Phosphatidylinositol 3,-OH kinase (PI3K)-Akt and transcription factor NF-,B are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis, and oncogenesis. Although PI3K-Akt and NF-,B have been implicated in the development and progression of prostate cancer, expression of these molecules during progression of autochthonous disease has not been elucidated. METHODS Prostate cancer growth and progression in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and male non-transgenic littermates were observed by magnetic resonance imaging (MRI). Expression patterns of PI3K-Akt, NF-,B, I,B, and associated signaling molecules during different stages of cancer progression in these mice were examined by Western blot analysis, electrophoretic mobility shift assay (EMSA), enzyme-linked immunoabsorbent assay (ELISA), kinase assay, and immunohistochemistry. RESULTS Sequential MRI and gross analysis of prostate gland exhibited increasing prostate volume associated with the development and progression of prostatic adenocarcinoma in TRAMP mice, compared to male non-transgenic littermates. Differential protein expression of PI3K, phosphorylated-Akt (Ser473), I,B, and its phosphorylation, IKK kinase activity, NF-,B/p65, p50, DNA binding, and transcriptional-regulated genes, viz., Bcl2, cyclin D1, MMP-9, and VEGF were observed during prostate cancer progression in TRAMP mice, compared to male non-transgenic littermates. Expressions of these molecules were significantly increased during cancer progression observed at 24 and 32 weeks of age. CONCLUSIONS Differential expression pattern of PI3K-Akt, NF-,B and I,B during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention. © 2005 Wiley-Liss, Inc. [source] Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression,THE PROSTATE, Issue 3 2004Lisa G. Horvath Abstract BACKGROUND The role of the bone morphogenetic protein (BMP) pathway in prostate cancer (PC) is unclear. This study aimed to characterize aspects of the BMP pathway in PC by assessing BMP2, Smad8, and Smad4 expression in normal, hyperplastic, and malignant prostate tissue, and to correlate findings with progression to PC. METHODS Radical prostatectomy (RP) specimens from 74 patients with clinically localized PC (median follow-up 51 months, range 15,152), 44 benign prostatic hypertrophy (BPH) lesions, and 4 normal prostates (NPs) were assessed for BMP2, Smad8, and Smad4 expression using immunohistochemistry. RESULTS Both BMP2 (P,<,0.001) and nuclear Smad4 (P,<,0.0001) expression were significantly decreased in PC compared to benign prostate tissue. Nuclear Smad8 was present in normal/benign prostate tissue but absent in PC and adjacent hyperplasia. Furthermore, loss of BMP2 (P,<,0.001) and decreased nuclear Smad4 (P,=,0.05) expression correlated with increasing Gleason score. CONCLUSIONS These data suggest that decreased BMP2, nuclear smad8 and nuclear Smad4 expression are associated with the progression to PC, and in particular loss of BMP2 and Smad4 are related to progression to a more aggressive phenotype. © 2004 Wiley-Liss, Inc. [source] YB-1 is upregulated during prostate cancer tumor progression and increases P-glycoprotein activityTHE PROSTATE, Issue 3 2004Pepita Giménez-Bonafé Abstract BACKGROUND Currently, the main obstacle to curing advanced prostate cancer is development of androgen independence (AI), where malignant cells acquire the ability to survive in the absence of androgens. Our initial experimental approach used cDNA microarrays to characterize changes in gene expression in the LNCaP human prostate tumor model during progression to AI. The transcription factor Y-box binding protein (YB-1) was shown to be one of the genes upregulated. We focused on increased YB-1 expression during progression in clinical specimens, and further examined one of its downstream targets, P-glycoprotein (P-gp). METHODS Northern blot analysis was performed on LNCaP tumor series, as well as immunohistochemical analyses of human prostate cancer tissue samples. YB-1 was transiently transfected and transport analysis were performed to analyze P-gp efflux activity. RESULTS YB-1 expression is markedly increased during benign to malignant transformation and further following androgen ablation. In addition, increased YB-1 expression after castration in the LNCaP model is linked to upregulation of P-gp. We demonstrate that YB-1 upregulates P-gp activity resulting in a 40% intracellular decrease in the P-gp substrate vinblastine. We have also found that P-gp increases the efflux of the endogenous androgen, dihydrotestosterone (DHT), from prostate cells and leads to decreased androgen regulated gene expression. CONCLUSIONS We hypothesize that early in prostate cancer progression, increased expression of YB-1 may increase P-gp activity which may in turn lower androgen levels in the prostate tumor cells. Suppression of androgen levels may activate cell survival pathways and lead to an adaptive survival advantage of androgen independent prostate cancer cells following androgen ablation therapy. © 2004 Wiley-Liss, Inc. [source] Group IIA phospholipase A2 as a prognostic marker in prostate cancer: relevance to clinicopathological variables and disease-specific mortalityAPMIS, Issue 3 2009TUOMAS MIRTTI Group IIA Phospholipase A2 (PLA2-IIA), a key enzyme in arachidonic acid and eicosanoid metabolism, participates in a variety of inflammatory processes but possibly also plays a role in tumor progression in vivo. Our aim was to determine the mRNA and protein expression of PLA2-IIA during prostate cancer progression in localized and metastatic prostate tumors. We evaluated the prognostic significance of PLA2-IIA expression in biochemical recurrence, clinical recurrence and disease-specific survival after surgical treatment. The expression of PLA2-IIA was examined by immunohistochemistry and chromogenic in situ hybridization in tissue microarrays of radical prostatectomy specimens and advanced/metastatic carcinomas. The expression data were analyzed in conjunction with clinical follow-up information and clinicopathological variables. The mRNA and protein expression of PLA2-IIA was significantly increased in Gleason pattern grade 2,4 carcinomas compared with benign prostate (p-values 0.042,0.001). In metastases, the expression was significantly lower than in local cancers (p=0.001). The PLA2-IIA expression correlated positively with Ki-67 and ,-methylacyl CoA racemase (AMACR) expression. The prognostic evaluation revealed decreased PLA2-IIA protein expression among patients who had died of prostate cancer. In conclusion, PLA2-IIA expression is increased in carcinoma when compared with benign prostate. However, metastatic carcinoma showed decreased expression of PLA2-IIA when compared with primary carcinomas. PLA2-IIA may serve as a marker for highly proliferating, possibly poorly differentiated prostate carcinomas. The protein expression of PLA2-IIA may be diminished in patients who consequently die of prostate cancer. [source] Differential Expression and Network Inferences through Functional Data ModelingBIOMETRICS, Issue 3 2009Donatello Telesca Summary Time course microarray data consist of mRNA expression from a common set of genes collected at different time points. Such data are thought to reflect underlying biological processes developing over time. In this article, we propose a model that allows us to examine differential expression and gene network relationships using time course microarray data. We model each gene-expression profile as a random functional transformation of the scale, amplitude, and phase of a common curve. Inferences about the gene-specific amplitude parameters allow us to examine differential gene expression. Inferences about measures of functional similarity based on estimated time-transformation functions allow us to examine gene networks while accounting for features of the gene-expression profiles. We discuss applications to simulated data as well as to microarray data on prostate cancer progression. [source] Vascular endothelial growth factor receptor 1 expression in pelvic lymph nodes predicts the risk of cancer progression after radical prostatectomyCANCER SCIENCE, Issue 6 2009Kazutoshi Fujita Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) 1-positive hematopoietic progenitor cells precede the arrival of tumor cells and form clusters that may portend sites of future metastatic disease. The aim of the present study was to clarify whether VEGFR1 expression in pelvic lymph nodes predicts the risk of prostate cancer progression after radical prostatectomy. VEGFR1 expression in pelvic lymph nodes was examined by immunohistochemistry in 95 patients who underwent radical prostatectomy for prostate cancer. A cluster of VEGFR1-positive cells was considered positive. Expression of VEGFR1 in pelvic lymph nodes and biochemical recurrence after radical prostatectomy were examined by univariate survival analysis and multivariate Cox proportional hazards regression analysis. Thirty-seven of 79 lymph node-negative patients (46.8%) were found to have VEGFR1-positive cells in their pelvic lymph nodes, whereas 16 of 16 lymph node metastasis-positive patients (100%) had VEGFR1 clusters. There was a significant correlation between pathological stage and VEGFR1 staining (P = 0.002). Univariate analysis showed that pathological stage ,pT3 and VEGFR1 expression in pelvic lymph nodes were each significantly associated with biochemical recurrence after radical prostatectomy. Multivariate analysis showed VEGFR1 expression to be an independent predictor of biochemical recurrence after radical prostatectomy (risk ratio = 5.715, P = 0.010), as was preoperative prostate-specific antigen (PSA) level ,10 ng/mL. Although larger validation studies are required, our results suggest that VEGFR1 expression in pelvic lymph nodes predicts the risk of biochemical PSA recurrence after radical prostatectomy. (Cancer Sci 2009; 100: 1047,1050) [source] | ||||||||||||||||