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)

Pituitary adenylate cyclase-activating peptide (PACAP), a cAMP-activating agent, is highly expressed in the hypothalamus during the period when many neuroendocrine cells become differentiated from the neural stem cells (NSCs). Activation of the cAMP system in rat hypothalamic NSCs differentiated these cells into beta-endorphin (BEP)-producing neurons in culture. When these in vitro differentiated neurons were transplanted into the paraventricular nucleus (PVN) of the hypothalamus of an adult rat, they integrated well with the surrounding cells and produced BEP and its precursor gene product, proopiomelanocortin (POMC). Animals with BEP cell transplants demonstrated remarkable protection against carcinogen induction of prostate cancer. Unlike carcinogen-treated animals with control cell transplants, rats with BEP cell transplants showed rare development of glandular hyperplasia, prostatic intraepithelial neoplasia (PIN), or well differentiated adenocarcinoma with invasion after N-methyl-N-nitrosourea (MNU) and testosterone treatments. Rats with the BEP neuron transplants showed increased natural killer (NK) cell cytolytic function in the spleens and peripheral blood mononuclear cells (PBMCs), elevated levels of antiinflammatory cytokine IFN-gamma, and decreased levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in plasma. These results identified a critical role for cAMP in the differentiation of BEP neurons and revealed a previously undescribed role of these neurons in combating the growth and progression of neoplastic conditions like prostate cancer, possibly by increasing the innate immune function and reducing the inflammatory milieu.
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PMID:Cyclic adenosine monophosphate differentiated beta-endorphin neurons promote immune function and prevent prostate cancer growth. 1856 81

The absence of curative treatment strategies for metastatic prostate cancer requires further development of novel, more effective treatment regimens. Because of recent advances in immunologic and translational research, therapeutic vaccines are becoming important as promising treatment modalities against prostate cancer. Immunizing patients who have hormone-refractory prostate cancer with an allogenic IL-2 and IFN-gamma secreting tumor cell vaccine is safe and feasible with no dose-limiting toxicity; it has been shown to reduce the progression of prostate-specific antigen in treated subjects and to induce vaccine-specific immune responses. Despite these results, current vaccine strategies have shown only limited success in clinical settings. There is ample evidence that multiple immunosuppressive mechanisms, such as regulatory T cells and myeloid suppressor cells, exist that considerably dampen antitumor responses and weaken the activity of current immunotherapeutic regimens. Recent insights into the characteristics of the regulatory elements of the immune system have provided new opportunities to enhance vaccine-mediated antitumor immunity by reversing tumor-mediated immunosuppression before immunotherapies can be used successfully for cancer patients.
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PMID:[Active immunotherapy of urologic malignancies and tumor-mediated immunosuppression]. 1870 62

Immunotherapy by vaccination represents a novel method for treatment of cancer. In this regard, vaccines with the broadest possible menu of relevant antigens stand the greatest chance of success. Tissue vaccines are composed of material harvested directly from tumors and contain not only antigens associated with neoplastic epithelium, but also those that may be unique to in vivo growth and antigens associated with the tumor stroma. To test the hypothesis that a tissue vaccine, produced by glutaraldehyde fixation of harvested syngeneic prostate tumors (GFT vaccine), could be used for treatment of prostate cancer, male Lobund-Wistar (LW) rats were treated with methylnitrosourea (MNU) and testosterone propionate to induce autochthonous prostate tumors. Tumor-bearing rats were randomly assigned to one of three treatment groups: no treatment (11 rats); vaccination with media (10 rats); or vaccination with the GFT vaccine (19 rats). Vaccination was given initially with Freund's complete adjuvant and booster doses were given with incomplete Freund's adjuvant every week until the time of euthanasia. There were no significant differences in mean tumor weight between groups; however, GFT-vaccinated rats had a prolonged survival time; and 4/19 (21%) GFT-vaccinated rats were found to be tumor-free compared to none of the untreated or media-treated controls. Further, pulmonary metastasis occurred in only 5/15 (33%) of GFT-vaccinated rats compared to 10/11 (91%) and 10/10 (100%) of untreated and media-vaccinated controls, respectively. Supernatants of cultured splenocytes from similarly media- and GFT-vaccinated rats demonstrated significant (P < 0.001) increases in IFN-gamma and TNF-alpha from splenocytes of GFT-vaccinated rats, suggesting that GFT vaccination stimulates a Th1 response. In summary, treatment of tumor-bearing rats with a tissue vaccine stimulated a protective immune response that resulted in complete tumor regression in 21% of animals and reduced the number of animals with any evidence of metastasis by nearly 70%. These results suggest that tissue vaccines may be useful for the treatment of prostate cancer.
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PMID:Inhibition of prostate cancer metastasis by administration of a tissue vaccine. 1882 Oct 60

We conducted a clinical trial of peptide prostate specific antigen (PSA): 154-163 (155L) vaccination in human leukocyte antigen (HLA)-A2 patients with detectable and rising serum PSA after radical prostatectomy for prostate cancer (Clinicaltrials.gov identifier NCT00109811). The trial was a single dose-level, phase 2 pilot trial of 1 mg of PSA: 154-163 (155L) emulsified with adjuvant (Montanide ISA-51). The primary endpoint was the determination of immunogenicity of the vaccine; secondary outcomes were determination of toxicity and effect on serum PSA. The vaccine was given subcutaneously 7 times on weeks 0, 2, 4, 6, 10, 14, and 18. Peptide-specific CD8 T-cell responses in the peripheral blood mononuclear cells (PBMC) of patients were measured by interferon (IFN)-gamma enzyme-linked immunosorbent spot assay. CD8 T-cell cultures were also established by in vitro stimulation with the peptide presented by autologous dendritic cells. Five patients were enrolled and completed all vaccinations. No IFN-gamma response to PSA: 154-163 (155L) was detected in unfractioned PBMC in any patient either before or after vaccination. Three of 5 patients demonstrated strong IFN-gamma responses to PSA: 154-163 (155L) and native PSA: 154-163 peptides in CD8 T-cell cultures derived from postvaccination PBMC. However, peptide-specific T cells failed to recognize HLA-A2 positive targets expressing endogenous PSA. There were no significant changes in serum PSA level in any subject. No serious adverse events were observed. PSA: 154-163 (155L) is not an effective immunogen when given with Montanide ISA-51. The PSA: 154-163 peptide is poorly processed from endogenous PSA and therefore represents a cryptic epitope of PSA in HLA-A2 antigen-presenting cells.
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PMID:Vaccination with agonist peptide PSA: 154-163 (155L) derived from prostate specific antigen induced CD8 T-cell response to the native peptide PSA: 154-163 but failed to induce the reactivity against tumor targets expressing PSA: a phase 2 study in patients with recurrent prostate cancer. 1948 44

We recently reported that hormone therapy induces antigen-specific autoantibody responses in prostate cancer patients. However, the contribution of autoantibody responses to clinical outcomes is unknown. We used an animal model to test the hypothesis that hormone therapy-induced immune responses may be associated with delayed tumor recurrence. Male DD/S mice bearing established tumors from the androgen-dependent Shionogi carcinoma line were castrated to induce tumor regression. Tumor-specific autoantibody responses were measured by immunoblot, and the underlying antigen was identified by serological screening of a cDNA expression library. T cell responses were assessed by immunohistochemistry and IFN-gamma ELISPOT. Following castration, 97% of mice underwent complete tumor regression. Of these, 72% experienced tumor recurrence 18-79 days postcastration, whereas the remaining 28% remained tumor-free for the duration of the experiment. In 55% of mice, castration induced autoantibody responses to an antigen identified as poly(A) binding protein nuclear 1 (PABPN1). Castration also induced PABPN1-specific T cell responses, which were highly correlated to autoantibody responses, and this was accompanied by dense infiltration of tumors by CD3+ T cells 1-2 weeks after castration. Unexpectedly, mice that developed autoantibody and T cell responses to PABPN1 showed a higher rate and shorter latency of tumor recurrence. In mice with recurrent tumors, T cell responses to PABPN1 were still detectable; however, T cell infiltrates were restricted to the peripheral stroma of tumors. In conclusion, castration-induced immune responses are associated with inferior outcomes in the Shionogi carcinoma model, raising concerns about the influence of treatment-induced immune responses on clinical outcomes in humans.
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PMID:Castration induces autoantibody and T cell responses that correlate with inferior outcomes in an androgen-dependent murine tumor model. 1955 30

Defects in HLA class I antigen processing machinery (APM) component expression often have a negative impact on the clinical course of tumors and on the response to T cell-based immunotherapy. Since only scant information is available about the frequency and clinical significance of HLA class I APM component abnormalities in prostate cancer, the APM component expression pattern was analyzed in 59 primary prostate carcinoma, adjacent normal tissues, as well as in prostate carcinoma cell lines. The IFN-gamma inducible proteasome subunits LMP2 and LMP7, TAP1, TAP2, calnexin, calreticulin, ERp57, and tapasin are strongly expressed in the cytoplasm of normal prostate cells, whereas HLA class I heavy chain (HC) and beta(2)-microglobulin are expressed on the cell surface. Most of the APM components were downregulated in a substantial number of prostate cancers. With the exception of HLA class I HC, TAP2 and ERp57 not detectable in about 0.5% of tumor lesions, all other APM components were not detected in at least 21% of lesions analyzed. These APM component defects were associated with a higher Gleason grade of tumors and an early disease recurrence. Prostate carcinoma cell lines also exhibit a heterogeneous, but reduced constitutive APM component expression pattern associated with lack or reduced HLA class I surface antigens, which could be upregulated by IFN-gamma. Our results suggest that HLA class I APM component abnormalities are mainly due to regulatory mechanisms, play a role in the clinical course of prostate cancer and on the outcome of T cell-based immunotherapies.
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PMID:Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. 1982 Sep 34

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous cytokine that induces apoptosis in malignant tumor cells. Here, we show for the first time that lactobacilli induce TRAIL production in human peripheral blood mononuclear cells (PBMC). Treatment with lactobacilli induced TRAIL on the cell surface of PBMC and in culture medium. The TRAIL production induced by lactobacilli partially depends on IFN-alpha and IFN-gamma. Lactobacilli treatment facilitated NK activity of PBMC against prostate cancer cells. Moreover, TRAIL neutralization antibody efficiently prevented the NK activity. Our results indicate that lactobacilli facilitate NK activity through TRAIL production, and raise the possibility of a new TRAIL-based strategy against malignant tumors.
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PMID:Lactobacillus strains induce TRAIL production and facilitate natural killer activity against cancer cells. 1999 62

Up-regulation of receptor-ligand pairs during interaction of a peptide-bound MHC complex on dendritic cells (DCs) with cognate TCR may amplify, sustain, and drive diversity in the ensuing T cell immune response. Members of the TNF ligand superfamily and the TNFR superfamily contribute to this costimulatory molecule signaling. In the present study, we used replication deficient adenoviruses to introduce a tumor-associated Ag (a truncated human prostate-specific membrane antigen (tPSMA)) and the T cell costimulatory molecule 4-1BBL into murine DCs, and observed the ability of these recombinant DCs to elicit tPSMA-directed T-cell responses in vitro and anti-tumor immunity to RM-1-tPSMA in a murine tumor model. Infection of DCs with Ad-tPSMA-IRES-m4-1BBL induced tPSMA-specific proliferative responses and up-regulated CD80 and CD86 s signaling molecules. The cytotoxic T lymphocytes activated by the Ad-tPSMA-IRES-m4-1BBL-transfected DCs showed significantly higher IFN-gamma production and cytotoxicity against the RM-1 cells transfected with tPSMA. Moreover, vaccination of mice with Ad-tPSMA-IRES-m4-1BBL-transfected DCs induced a potent protective and therapeutic anti-tumor immunity to RM-1-tPSMA in a tumor model. These results demonstrated that development of DCs engineered to express tPSMA and 4-1BBL by recombinant adenovirus-mediated gene transfer may offer a new strategy for prostate cancer immunotherapy.
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PMID:Anti-tumor immune response induced by dendritic cells transduced with truncated PSMA IRES 4-1BBL recombinant adenoviruses. 2014 24

The goal of this study was to evaluate cytokine secretion capacity in a mouse model of prostate cancer, both with and without metalloporphyrin antioxidant and radiation treatment. C57BL/6 mice with subcutaneous RM-9 tumors were treated daily for 12 days with MnTE-2-PyP(5+) [Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin], beginning 1 day after injection of RM-9 cells; a 10-Gy tumor-localized dose of (60)Co gamma rays was administered in a single fraction on day 7. Spleen, tumors and plasma were collected on day 12. T cells in the spleen were activated with anti-CD3 antibody and supernatants were collected. Twenty-two cytokines were quantified in spleen supernatants, five in tumor homogenates, and three in plasma using multiplex bead array technology and ELISA. The presence of a tumor had significant effects on many of the cytokines quantified (P < 0.05). Tumor-induced depression was evident for eight spleen cytokines (TNF-alpha, G-CSF, GM-CSF, IFN-gamma, IL10, IP-10, MIP-1alpha and mKC), whereas only three were enhanced (IL1beta, IL6 and MCP-1). Radiotherapy resulted in enhanced splenocyte capacity to produce IL4 and IL13 and increased IL4, MCP-1 and VEGF in tumors (P < 0.05). Addition of MnTE-2-PyP(5+) to radiation decreased the concentrations of IL4, IL13 and TGF-beta1 in spleen supernatants and IL4 and VEGF in tumors (P < 0.05 compared to radiation alone). Some differences were also noted in plasma cytokines. Overall, the findings suggest that administration of MnTE-2-PyP(5+) together with radiotherapy may enhance anti-tumor immune responsiveness and decrease the risk for radiation-induced normal tissue toxicities.
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PMID:A metalloporphyrin antioxidant alters cytokine responses after irradiation in a prostate tumor model. 2033 16

The effect of radiation therapy (RT) to the pelvis on circulating T cells was studied in prostate cancer (PCa) patients to provide a baseline for a more informed design of combination radioimmunotherapy. Peripheral blood samples taken from 12 PCa patients with locally advanced tumor before, during, and after hypofractionated RT were analyzed for T cell phenotype and function. There was significantly more loss of naive and early memory compared with more differentiated T cells during RT. The proportions of annexin-V(+) and Fas-expressing T cells were elevated in patients during RT and in PBMC irradiated in vitro (< or = 5.0 Gy), with preferential increases in CD45RA(+) T cells. The baseline level of apoptosis of CD45RA(-) T cells increased > 2-fold in the presence of an IkappaB-kinase inhibitor, indicating a protective effect via this pathway. T cell proliferation was impaired during RT with IL-2-dependent recovery post-RT. Recall T cell responses to common viral Ags, measured by IFN-gamma production, were little affected by RT. In vitro irradiation of healthy donor PBMCs resulted in a significantly increased frequency of responding T cells, due at least partly to the preferential elimination of CD45RA(+) T cells. Most importantly, antitumor CD4(+) and CD8(+) T cell responses were detectable after, but not before or during RT. The results indicate that generating tumor-specific T cell responses before RT and boosting their activity post-RT are ways likely to amplify the frequency and function of antitumor T cells, with implications for scheduling immunotherapy in PCa.
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PMID:Resistance of CD45RA- T cells to apoptosis and functional impairment, and activation of tumor-antigen specific T cells during radiation therapy of prostate cancer. 2054 27


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