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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and the first-in-class Hsp90 inhibitor, 17-allylamino-17 demethoxygeldanamycin (17AAG), is currently in phase II clinical trials. A fraction of Hsp90 has been identified at the cell surface and its presence has recently been shown to correlate with melanoma progression. Inhibition of cell-surface Hsp90 with antibodies or cell-impermeable Hsp90 inhibitors blocks cell motility and invasion in vitro and cancer metastasis in vivo. Thus, cell-surface Hsp90 may play a unique role in tumor metastasis, distinct from but perhaps overlapping with its intracellular function. In addition, because cell-surface Hsp90 may be the point of contact between some viruses and host cells, this pool of the chaperone may play a distinct role in initiation of infectious disease.
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PMID:Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. 1764 79

A vaccine is typically defined as any preparation used as a preventive inoculation to confer immunity against a specific disease. Vaccines for infectious diseases are highly effective, acting by inducing antigen-specific immunity that prevents subsequent infection. Unfortunately, the success of vaccines in infectious diseases has not been mirrored in oncology. This failure is the result of several challenges facing cancer vaccines, including the conceptual shift from disease prevention to disease treatment, tumor-induced immunosuppression and other mechanisms of immune escape, the similarity between tumor antigens and self antigens to which the patient is tolerant, unfavorable effector-to-target ratios in patients with established tumors, and financial and regulatory issues. Despite this, cancer remains a promising target for vaccine therapy. Melanoma in particular is known for its inherent immunogenicity on the basis of many anecdotal reports of spontaneous immune-based tumor regression, and thus has been the focus of immunotherapeutic approaches. Rare but significant vaccine-induced clinical regression of melanoma has spurred intensive investigations to augment vaccine efficacy. This review explores the many vaccine strategies that have been clinically tested for the treatment of melanoma and considers future approaches of cancer immunotherapy.
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PMID:Vaccine therapy for melanoma: current status and future directions. 1764 38

Infection by human papillomavirus (HPV) is extremely common and associated with the development of benign warts or malignant lesions of the skin and mucosa. Infection by a high-risk (oncogenic) anogenital HPV type, most often through sexual contacts, is the starting point of virtually all cases of cervical cancers and the majority of anal cancers. The same viral types are also increasingly being linked with a subset of head-and-neck and non-melanoma skin cancers. Although prophylactic vaccines are now available to protect against the four types most commonly found in cervical and anal cancers (HPV16 and HPV18) and anogenital warts (HPV6 and HPV11), these neither protect against all genital HPVs nor are of therapeutic utility for already infected patients. Thus, the need for antiviral agents to treat HPV-associated diseases remains great, but none currently exist. This article reviews the recent progress made towards the development of antiviral agents to treat HPV infections, from target identification and validation to the discovery of lead compounds with therapeutic potential. Emphasis has been placed on novel low-molecular-weight compounds that antagonize HPV proteins or, alternatively, inhibit cellular proteins which have been usurped by papillomaviruses and are mediating their pathogenic effects.
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PMID:Recent advances in the search for antiviral agents against human papillomaviruses. 1766 52

Invariant natural killer T (iNKT) cells are a subset of innate lymphocytes that recognize lipid antigens in the context of CD1d and mediate potent immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). We investigated whether diverse Toll-like receptor (TLR) signals in myeloid dendritic cells (DCs) could differentially stimulate iNKT cells. Together with the lipopolysaccharide-detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-gamma, but not IL-4. iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged beta-linked glycosphingolipid(s) by DCs. In addition, DCs stimulated via TLR9 activated both iNKT cells and NK cells in vivo and protected mice against B16F10-induced melanoma metastases. These data underline the role of TLR9 in iNKT cell activation and might have relevance to infectious diseases and cancer.
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PMID:Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. 1795 5

Adoptive therapy with antigen-specific T cells is a promising approach for the treatment of infectious diseases and cancer. However, cloning of antigen-specific T cells by the traditional approach of limiting dilution is a time-consuming, laborious, and inefficient process. Here, we describe a novel flow cytometric strategy for rapid isolation of human tumor antigen-specific T-cell clones by using T-cell receptor (TCR) Vbeta antibodies in combination with carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay. The CFSE dilution following antigen stimulation identified proliferating antigen-specific T cells, and the TCRVbeta antibodies allowed distinguishing T cells at the clonal level from a heterogeneous T-cell population. This method of TCRVbeta/CFSE dilution was used for the isolation of four different human lymphoma and melanoma-specific CD4(+) and CD8(+) T-cell clones reactive against defined and undefined tumor antigens. Isolated tumor-specific T-cell clones could be expanded to large numbers ex vivo while maintaining phenotype, function, and tumor antigen specificity. The method was simple, efficient, and reproducible, and may have potential application for the development of adoptive immunotherapeutic strategies.
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PMID:A novel strategy for rapid and efficient isolation of human tumor-specific CD4(+) and CD8(+) T-cell clones. 1795 94

To improve safety and specificity of oncolytic adenoviruses, we introduced T-cell receptors (TCR) specific for a unique class of truly tumor-specific antigens into the adenoviral fiber protein. The adenoviral fiber knob responsible for attachment to the coxsackie-adenoviral receptor (CAR) on target cells was replaced by a single-chain TCR (scTCR) molecule with specificity for the melanoma-associated cancer-testis antigen MAGE-A1, presented by HLA-A1, and an extrinsic trimerization motif in a replicating Ad5 vector (Ad5.R1-scTCR). The production of the recombinant virus was initiated in a novel producer cell line that expressed an antibody-based hexon-specific receptor (293T-AdR) in the cell membrane. This new production system allowed CAR-independent and target antigen-independent propagation of Ad5.R1-scTCR. Infection with adenovirus bearing the scTCR-based fiber resulted in an efficient killing of target tumor cells. The infection was cell type specific because only HLA-A1(+)/MAGE-A1(+) melanoma cells were killed, and thus, this retargeting strategy provides a versatile tool for future clinical application.
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PMID:An oncolytic adenovirus redirected with a tumor-specific T-cell receptor. 1805 57

CD4(+) Th1 type immunity is implicated in resistance to global infectious diseases. To improve the efficacy of T cell immunity induced by human immunodeficiency virus (HIV) vaccines, we are developing a protein-based approach that directly harnesses the function of dendritic cells (DCs) in intact lymphoid tissues. Vaccine proteins are selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. We find that polyriboinosinic:polyribocytidylic acid (poly IC) independently serves as an adjuvant to allow a DC-targeted protein to induce protective CD4(+) T cell responses at a mucosal surface, the airway. After two doses of DEC-targeted, HIV gag p24 along with poly IC, responder CD4(+) T cells have qualitative features that have been correlated with protective function. The T cells simultaneously make IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-2, and in high amounts for prolonged periods. The T cells also proliferate and continue to secrete IFN-gamma in response to HIV gag p24. The adjuvant role of poly IC requires Toll-like receptor (TLR) 3 and melanoma differentiation-associated gene-5 (MDA5) receptors, but its analog poly IC(12)U requires only TLR3. We suggest that poly IC be tested as an adjuvant with DC-targeted vaccines to induce numerous multifunctional CD4(+) Th1 cells with proliferative capacity.
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PMID:The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. 1825 87

The prognosis and response to conventional therapies of malignant melanoma inversely correlate with disease progression. With increasing thickness, melanomas acquire metastatic potential and become inherently resistant to radiotherapy and chemotherapy. These harsh realities mandate the design of improved therapeutic modalities, especially those targeting metastases. To develop an approach to effectively treat this aggressive disease, we constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV produces large quantities of MDA-7/IL-24 protein as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal human immortal melanocytes and human melanoma cells demonstrates cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for treating patients with advanced melanomas with metastases.
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PMID:A cancer terminator virus eradicates both primary and distant human melanomas. 1832 53

Listeria monocytogenes infection induces various types of immune responses. The Lm-induced immunity not only protects the hosts against Lm infection but also has a therapeutic effect on other diseases such as tumors and infectious diseases. In the present study, we sought to identify the cells and molecules that are primarily responsible for the Lm-induced antitumor immune response. We investigated the mechanism of the antitumor immune response induced by Lm infection using melanoma cells and various types of gene-manipulated mice and B16F10 melanoma cells. Melanoma cells were implanted into mice intrasplenically or intraperitoneally. Lm infection of mice remarkably suppressed the growth of transplanted melanoma. The suppression of melanoma growth was due to the augmented NK cytotoxicity. The Lm-induced NK activation against melanoma was type I interferon- and signal transducer and activator of transcription (STAT)1-dependent but independent of IL-12 and IFN-gamma. In contrast to avirulent Listeria innocua and hly(-) Lm failed to induce NK activation, a mutant Lm strain with minimal hemolytic activity and with normal accessibility to cytoplasm-induced NK activation. We demonstrated that the attenuated Lm entrance into the cytoplasm induces the production of type I IFN followed by the activation of NK cells, which is essential for the Lm-induced antitumor response.
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PMID:Attenuated Listeria infection activates natural killer cell cytotoxicity to regress melanoma growth in vivo. 1838 Aug 8

Measles is an acute febrile infectious disease with high morbidity and mortality. The genome of measles virus (MV), the causative agent, encodes two accessory products, V and C proteins, that play important roles in MV virulence. The V but not the C protein of the IC-B strain (a well-characterized virulent strain of MV) has been shown to block the Jak/Stat signaling pathway and counteract the cellular interferon (IFN) response. We have recently shown that a recombinant IC-B strain that lacks C protein expression replicates poorly in certain cell lines, and its growth defect is related to translational inhibition and strong IFN induction. Here, we show that the V protein of the MV IC-B strain also blocks the IFN induction pathway mediated by the melanoma differentiation-associated gene 5 product, thus actively interfering with the host IFN response at two different steps. On the other hand, the C protein per se possesses no activity to block the IFN induction pathway. Our data indicate that the C protein acts as a regulator of viral RNA synthesis, thereby acting indirectly to suppress IFN induction. Since recombinant MVs with C protein defective in modulating viral RNA synthesis or lacking C protein expression strongly stimulate IFN production, in spite of V protein production, both the C and V proteins must be required for MV to fully circumvent the host IFN response.
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PMID:Measles virus circumvents the host interferon response by different actions of the C and V proteins. 1856 42


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