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)

Locally advanced prostate carcinoma (PCa) can involve adjacent colorectal tissue. In such cases, accurate assignment of primary source may prove difficult. Given the difference in treatment and prognosis between PCa and colorectal carcinoma (CRCa), an accurate diagnosis is crucial. Surgical pathology files were searched for all cases with a diagnosis of PCa on colorectal biopsy between 1987 and 2006. Histologic and clinical data were available in 23 of the 30 found cases. The diagnosis of PCa was made for the first time at the time of the colorectal presentation in 4 men. Three of the 4 underwent colectomy. Among the remaining 19 men with a previously documented diagnosis of PCa, the overall clinical and endoscopic impression still favored a second primary CRCa in 12 patients. The latter was due in part to the chronologically distant prior PCa diagnosis (mean, 6.9 years; range, 2-18 years). None of the colorectal biopsies demonstrated carcinoma in situ or dysplastic colonic mucosa. PCa architecture in the colonic biopsies was that of Gleason score of 9 to 10 in 20 cases and Gleason score of 8 in the remaining 3. Cribriform or microacinar architecture typical of PCa was seen in 6 cases. Immunostains were positive for prostate-specific antigen, P501S (prostein), prostate-specific membrane antigen, and prostate-specific acid phosphatase, in 16 of 20, 9 of 11, 10 of 11, and 10 of 20 cases, respectively. Three cases lacked immunohistochemical evidence of prostatic differentiation. Caudal-type homebox transcription factor 2 (CDX2) and beta-catenin were negative in all tested cases (0/11 for both). Although relatively rare, initial presentation of PCa as a rectal lesion may lead to an erroneous clinical and or histologic impression of CRCa. Because history of prostate cancer is often remote, clinical findings may be misleading. Pathologists should consider the possibility of prostatic origin in poorly differentiated carcinoma encountered on colorectal biopsy when features such as lack of an in situ component, extrinsic pattern of involvement, microacinar or solid architecture, and/or prominent nucleoli, are noted, especially in the absence of nuclear pleomorphism and mitotic activity. Immunohistochemical studies could help establish the diagnosis.
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PMID:Prostatic adenocarcinoma in colorectal biopsy: clinical and pathologic features. 1823 78

Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.
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PMID:Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells. 1828 40

This review summarizes the recent advancements that have improved our understanding of the functions of prostatic stem/progenitor cells in maintaining homeostasis of the prostate gland. We also describe the oncogenic events that may contribute to their malignant transformation into prostatic cancer stem/progenitor cells during cancer initiation and progression to metastatic disease stages. The molecular mechanisms that may contribute to the intrinsic or the acquisition of a resistant phenotype by the prostatic cancer stem/progenitor cells and their differentiated progenies with a luminal phenotype to the current therapies and disease relapse are also reviewed. The emphasis is on the critical functions of distinct tumorigenic signaling cascades induced through the epidermal growth factor system, hedgehog, Wnt/beta-catenin, and/or stromal cell-derived factor-1/CXC chemokine receptor-4 pathways as well as the deregulated apoptotic signaling elements and ATP-binding cassette multidrug transporter. Of particular therapeutic interest, we also discuss the potential beneficial effects associated with the targeting of these signaling elements to overcome the resistance to current treatments and prostate cancer recurrence. The combined targeted strategies toward distinct oncogenic signaling cascades in prostatic cancer stem/progenitor cells and their progenies as well as their local microenvironment, which could improve the efficacy of current clinical chemotherapeutic treatments against incurable, androgen-independent, and metastatic prostate cancers, are also described.
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PMID:Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies. 1829 64

delta-Catenin is upregulated in human carcinomas. However, little is known about the potential transcriptional factors that regulate delta-catenin expression in cancer. Using a human delta-catenin reporter system, we have screened several nuclear signaling modulators to test whether they can affect delta-catenin transcription. Among beta-catenin/LEF-1, Notch1, and E2F1, E2F1 dramatically increased delta-catenin-luciferase activities while beta-catenin/LEF-1 induced only a marginal increase. Rb suppressed the upregulation of delta-catenin-luciferase activities induced by E2F1 but did not interact with delta-catenin. RT-PCR and Western blot analyses in 4 different prostate cancer cell lines revealed that regulation of delta-catenin expression is controlled mainly at the transcriptional level. Interestingly, the effects of E2F1 on delta-catenin expression were observed only in human cancer cells expressing abundant endogenous delta-catenin. These studies identify E2F1 as a positive transcriptional regulator for delta-catenin, but further suggest the presence of strong negative regulator(s) for delta-catenin in prostate cancer cells with minimal endogenous delta-catenin expression.
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PMID:Identification of E2F1 as a positive transcriptional regulator for delta-catenin. 1830 37

Androgen and androgen receptor (AR) are involved in growth of normal prostate and development of prostatic diseases including prostate cancer. Androgen deprivation therapy is used for treating advanced prostate cancer. This therapeutic approach focuses on suppressing the accumulation of potent androgens, testosterone and 5alpha-dihydrotestosterone (5alpha-DHT), or inactivating the AR. Unfortunately, the majority of patients with prostate cancer eventually advance to androgen-independent states and no longer respond to the therapy. In addition to the potent androgens, 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), reduced from 5alpha-DHT through 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs), activated signaling may represent a novel pathway responsible for the progression to androgen-independent prostate cancer. Androgen sensitive human prostate cancer LNCaP cells were used to compare 5alpha-DHT and 3alpha-diol activated androgenic effects. In contrast to 5alpha-DHT, 3alpha-diol regulated unique patterns of beta-catenin and Akt expression as well as Akt phosphorylation in parental and in AR-silenced LNCaP cells. More significantly, 3alpha-diol, but not 5alpha-DHT, supported AR-silenced LNCaP cells and AR negative prostate cancer PC-3 cell proliferation. 3alpha-diol-activated androgenic effects in prostate cells cannot be attributed to the accumulation of 5alpha-DHT, since 5alpha-DHT formation was not detected following 3alpha-diol administration. Potential accumulation of 3alpha-diol, as a result of elevated 3alpha-HSD expression in cancerous prostate, may continue to support prostate cancer growth in the presence of androgen deprivation. Future therapeutic strategies for treating advanced prostate cancer might need to target reductive 3alpha-HSD to block intraprostatic 3alpha-diol accumulation.
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PMID:5alpha-androstane-3alpha,17beta-diol supports human prostate cancer cell survival and proliferation through androgen receptor-independent signaling pathways: implication of androgen-independent prostate cancer progression. 1832 May 93

SOX9 is a transcription factor that plays a critical role in the development of multiple tissues. We previously reported that SOX9 in normal human adult prostate was restricted to basal epithelium. SOX9 was also expressed in a subset of prostate cancer (PCa) cells and was increased in relapsed hormone-refractory PCa. Moreover, SOX9 expression in PCa cell lines enhanced tumor cell proliferation and was beta-catenin regulated. Here we report additional in vivo results showing that SOX9 is highly expressed during fetal prostate development by epithelial cells expanding into the mesenchyme, suggesting it may contribute to invasive growth in PCa. Indeed, SOX9 overexpression in LNCaP PCa xenografts enhanced growth, angiogenesis, and invasion. Conversely, short hairpin RNA-mediated SOX9 suppression inhibited the growth of CWR22Rv1 PCa xenografts. These results support important functions of SOX9 in both the development and maintenance of normal prostate, and indicate that these functions contribute to PCa tumor growth and invasion.
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PMID:SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. 1833 40

Wnt proteins are a large family of secreted glycoproteins that activate signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity. Wnts are capable of signaling through several pathways, the best-characterized being the canonical beta-catenin/Tcf-mediated pathway. Canonical Wnts stabilize beta-catenin protein, which has implications in the genesis of many human cancers like non-small cell lung cancer, colorectal carcinoma, prostate cancer, breast cancer and many others. In all of these cancers the common denominator is the activation of target genes. Although detailed mechanisms are not well understood of why Wnts are overexpressed in one tumor and down regulated in another, the pleiotropism of Wnt signaling is evident. The pathway itself offers ample targeting nodal points for cancer drug development. The identification of many important regulatory genes and the mechanism of their function offer an opportunity to develop new therapies targeting this pathway. In this review, we describe the roles of several oncogenes of the Wnt/beta-catenin signaling pathway in the development of tumorigenesis and discuss few strategies that are already developed or can be explored to target key components of the Wnt/ beta-catenin signaling pathway in finding of anti-cancer drugs.
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PMID:Wnt signaling and cancer development: therapeutic implication. 1834 48

A significant proportion of prostate cancer patients treated with curative intent 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 an epithelial-mesenchymal transition (EMT) is involved in prostate cancer invasiveness. The mechanism by which vimentin promotes prostate cancer cell invasion and metastasis was examined. The highly metastatic human prostate epithelial cell line PC-3M-1E8 (1E8-H) and the low metastatic line PC-3M-2B4 (2B4-L) were used for comparative proteomic analysis by two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/time of flight mass spectrometry (MALDI-TOF-MS). A transwell assay was performed to test cell migration and invasion and immunoblotting was used to analyze the relative expression of proteins. High vimentin expression was detected in 1E8-H compared to 2B4-L cells. Down-regulation of vimentin in 1E8-H by antisense-vimentin transfection led to a significant inhibition of invasiveness, and selective stimulation of vimentin activity in 2B4-L by delivery of recombinant vimentin promoted cell invasiveness. Vimentin activity was associated with C-src, beta-catenin and E-cadherin expression. PP2, a specific inhibitor of src family kinases, reduced phospho-beta-catenin expression and induce E-cadherin expression. Vimentin promotes tumor cell invasiveness and the targeting of vimentin/C-src may be a promising strategy for preventing or blocking prostate cancer metastasis.
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PMID:Overexpression of vimentin contributes to prostate cancer invasion and metastasis via src regulation. 3201 73

Although Wnt signaling has been shown to be important for embryonic morphogenesis and cancer pathogenesis of several tissues, its role in prostatic development and tumorigenesis is not well understood. Here we show that Wnt signaling regulated prostatic epithelial branching morphogenesis and luminal epithelial cell differentiation in developing rat prostate organ cultures. Specifically, Wnt signaling regulated the proliferation of prostate epithelial progenitor cells. Assessment of the expression levels of a Wnt pathway transcriptional target gene, Axin2, showed that the Wnt pathway was activated in the developing prostate, but was down-regulated in the adult. Castration resulted in an upregulation of Axin2 whereas androgen replacement resulted in a down regulation of Axin2. Such dynamic changes of Wnt activity was also confirmed in a BAT-gal transgenic mouse line in which beta-galactosidase reporter is expressed under the control of beta-catenin/T cell factor responsive elements. Furthermore, we evaluated the role of Wnt signaling in prostate tumorigenesis. Axin2 expression was found upregulated in the majority of human prostate cancer cell lines examined. Moreover, addition of a Wnt pathway inhibitor, Dickkopf 1 (DKK1), into the culture medium significantly inhibited prostate cancer cell growth and migration. These findings suggest that Wnt signaling regulates prostatic epithelial ductal branching morphogenesis by influencing cell proliferation, and highlights a role for Wnt pathway activation in prostatic cancer progression.
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PMID:Regulation of epithelial branching morphogenesis and cancer cell growth of the prostate by Wnt signaling. 1847 98

Loss of alpha-catenin is one of the characteristics of prostate cancer. The catenins (alpha and beta) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, beta-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of beta-catenin invariably are altered in cancer. Although a wealth of information is available about beta-catenin deregulation during oncogenesis, much less is known about how or whether alpha-catenin regulates beta-catenin functions. In this study, we show that alpha-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of beta-catenin. In alpha-catenin-null prostate cancer cells, reexpression of alpha-catenin increased cell-cell adhesion and decreased beta-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of beta-catenin is a major mechanism for decreased beta-catenin interaction with E-cadherin in alpha-catenin-null cells. alpha-Catenin attenuated the effect of Src phosphorylation by increasing beta-catenin association with E-cadherin. We also show that alpha-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that alpha-catenin is a key regulator of beta-catenin transcriptional activity and that the status of alpha-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.
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PMID:alpha-Catenin overrides Src-dependent activation of beta-catenin oncogenic signaling. 1856 11


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