UMLS:C0025202 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

Recent reports of tumor regression following delivery of autologous tumor antigen-pulsed DCs suggest that defective antigen presentation may play a key role in tumor escape. Here we show in two different murine tumor models, CT26 (colon adenocarcinoma) and B16 (melanoma), that the number and activation state of intratumoral DCs are critical factors in the host response to tumors. We used CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) chemokine to increase the number of tumoral DCs and intratumoral injections of CG-rich motifs (CpGs) to activate such cells. Expression of CCL20 in the tumor site attracted large numbers of circulating DCs into the tumor mass and, in the case of CT26 tumors, led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 tumors. In this model CpG overcame tumor-mediated inhibition of DC activation and enabled tumoral DCs to cross-present tumor antigens to naive CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of the DC growth factor, Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs. These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor-bearing hosts to mount an effective antitumor immune response. Our results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell-mediated antitumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.
...
PMID:Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. 1499 Oct 63

Cells that display chemokine receptors are capable of responding to a gradient of chemokine with a motility response that can translate into a chemotactic response. This continuous response to the chemokine sometimes requires that the chemokine receptor be internalized and recycled back to the membrane. We have shown that ligand activation of the CXC chemokine receptor, CXCR2, results in movement of the receptor into clathrin coated pits, followed by movement into the early endosome, the sorting endosome, then on to the recycling endosome prior to trafficking back into the plasma membrane compartment. Prolonged exposure to saturating concentrations of the ligand results in movement of a large percentage of the receptor into the late endosome and on to the lysosome for degradation. Mutation of the receptor in a manner which impairs receptor internalization by altering the binding of adaptor proteins AP-2 or beta arrestin to CXCR2, results in a marked reduction in the chemotactic response. Chemokine receptors also activate multiple intracellular signals that lead to the activation of the transcription factor, nuclear factor kappa beta (NF-kappaB). Transformation is often associated with a constitutive activation of NF-kappaB, leading to endogenous expression of chemokines and their receptors. This creates an autocrine loop with NF-kappaB in the activated state, and altered cxpression of factors that promote tumour angiogenesis and escape from apoptosis. We have shown that the constitutive activation of NF-kappaB in human melanoma tumours is accompanied by constitutive activation of the NF-kappaB inducing kinase (NIK) as well as the constitutive activation of AKT. As these factors that modulate the expression of anti-apoptotic factors work together, the tumour cells exhibit enhanced survival and growth. This never ending cycle of activation of NF-kappaB, leading to enhanced production of chemokines, enhanced activation of AKT and NF-kappaB, and enhanced transcription of inhibitors of apoptosis and chemokines, is one that has been used to foster the growth of the tumour to the disadvantage of the host. Thus we propose that blocking CXCR2 and/or NF-kappaB offers potential therapeutic promise for a number of chronic inflammatory conditions and cancers, including malignant melanoma.
...
PMID:How do chemokine/chemokine receptor activations affect tumorigenesis? 1502 84

Tissue invasion by tumor cells involves their migration across basement membranes through activation of extracellular matrix degradation and cell motility mechanisms. Chemokines binding to their receptors provide chemotactic cues guiding cells to specific tissues and organs; they therefore could potentially participate in tumor cell dissemination. Melanoma cells express CXCR4, the receptor for the chemokine stromal cell-derived factor-1alpha (SDF-1alpha). Using Matrigel as a model, we show that SDF-1alpha promotes invasion of melanoma cells across basement membranes. Stimulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) activity by SDF-1alpha was necessary for invasion, involving at least up-regulation in the expression of this metalloproteinase, as detected in the highly metastatic BLM melanoma cell line. Moreover, SDF-1alpha triggered the activation of the GTPases RhoA, Rac1, and Cdc42 on BLM cells, and expression of dominant-negative forms of RhoA and Rac1, but not Cdc42, substantially impaired the invasion of transfectants in response to SDF-1alpha, as well as the increase in MT1-MMP expression. Furthermore, CXCR4 expression on melanoma cells was notably augmented by transforming growth factor-beta1, a Matrigel component, whereas anti-transforming growth factor-beta antibodies inhibited increases in CXCR4 expression and melanoma cell invasion toward SDF-1alpha. The identification of SDF-1alpha as a potential stimulatory molecule for MT1-MMP as well as for RhoA and Rac1 activities during melanoma cell invasion, associated with an up-regulation in CXCR4 expression by interaction with basement membrane factors, could contribute to better knowledge of mechanisms stimulating melanoma cell dissemination.
...
PMID:Stromal cell-derived factor-1alpha promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities. 1505 9

In general, metastases to the small intestine are rare, and mostly occur in melanoma. CCR9 has been shown to be the principal chemokine receptor for the thymus expressed chemokine (TECK), a chemokine selectively expressed in the small intestine and thymus. Here we show that CCR9 is highly expressed on melanoma cells and all melanoma cell lines isolated from small intestinal metastases, and on a proportion of cell lines from other sites. Only melanoma cells and cell lines from small intestinal metastases, however, were responsive to the CCR9 ligand TECK, as assessed by receptor downregulation and by actin polymerization. CCR9 expression was also found on the adenocarcinoma cell line CaCo-2 expressing characteristics of enterocytic differentiation, but not on any other cell line isolated from colorectal, breast, and lung cancer. Our data provide evidence that the aberrant functional cell surface expression of an organ-specific chemokine receptor is associated with metastasis to this site. The regulation of receptor function seems to be a critical step in the metastatic process.
...
PMID:Functional CCR9 expression is associated with small intestinal metastasis. 1508 89

Dendritic cells (DCs) are potent stimulators of immunity, and DCs pulsed with tumor antigen ex vivo have applications in tumor immunotherapy. However, DCs are a small population of cells, and their isolation and pulsing with antigen can be impractical. Here we show that a crude preparation of plasma membrane vesicles (PMV) from the highly metastatic murine melanoma (B16-OVA) and a surrogate tumor antigen (OVA) can be targeted directly to DCs in vivo to elicit functional effects. A novel metal-chelating lipid, 3(nitrilotriacetic acid)-ditetradecylamine, was incorporated into B16-OVA-derived PMV, allowing recombinant hexahistidine-tagged forms of single chain antibody fragments to the DC surface molecules CD11c and DEC-205, to be conveniently "engrafted" onto the vesicle surface by metal-chelating linkage. The modified PMV, or similarly engrafted synthetic stealth liposomes containing OVA or OVA peptide antigen, were found to target DCs in vitro and in vivo, in experiments using flow cytometry and fluorescence confocal microscopy. When used as vaccines in syngeneic mice, the preparations stimulated strong B16-OVA-specific CTL responses in splenic T cells and a marked protection against tumor growth. Protection was dependent on the simultaneous delivery of both antigen and a DC maturation or "danger signal" signal (IFN-gamma or lipopolysaccharide). Administration of the DC-targeting vaccine to mice challenged with B16-OVA cells induced a dramatic immunotherapeutic effect and prolonged disease-free survival. The results show that the targeting of antigen to DCs in this way is highly effective at inducing immunity and protection against the tumor, with protection being at least partially dependent on the eosinophil chemokine eotaxin.
...
PMID:Targeting dendritic cells with antigen-containing liposomes: a highly effective procedure for induction of antitumor immunity and for tumor immunotherapy. 1520 52

An important theme that is emerging in cancer research is the interaction between tumor cells and the host stroma. Because many types of human cancer are infiltrated by eosinophils that are believed to mediate an anti-tumor cytotoxic effect, we developed and studied a transfected B16 murine melanoma cell line that secretes high levels (510 pg/ml/100,000 cells/day) of eotaxin, a chemokine that recruits and activates primarily eosinophils. Here we report that there was increased inflammation (eosinophils, mast cells, mononuclear cells), blood clotting, and microvascular density within the tumors produced by subcutaneous implants of eotaxin-secreting tumor cells in 10 C57BL/6 compared to tumors produced by wild-type tumor cells. The extensive blood clotting in the eotaxin-transfected tumors was associated with significantly decreased blood flow to the tumors as measured by magnetic resonance imaging [(mean maximum signal enhancement of eotaxin-secreting tumors, 147 +/- 57 (n = 7) compared to 202 +/- 36 signal enhancement units (n = 8) for the wild-type melanoma cells; P = 0.04 by two-tailed, unpaired t-test]. Surprisingly, there was no significant difference between the growth rates or mean masses of the eotaxin-secreting tumors (750 +/- 280 mg, n = 10) and the wild-type tumors (780 +/- 290, n = 10) after 20 days of growth in vivo, despite the significantly slower growth rate in vitro of the eotaxin-secreting tumor cells. We conclude that eotaxin and the resultant tumor-infiltrating inflammatory cells are not likely to mediate a significant anti-tumor effect in vivo. Instead, elevated eotaxin is associated with increased inflammation, microvascular density, and blood clotting. Thus, eotaxin and eosinophils may play a more complex role in modulating the growth of tumors than the simple, anti-tumor cytotoxic effect that has been previously proposed.
...
PMID:Increased blood clotting, microvascular density, and inflammation in eotaxin-secreting tumors implanted into mice. 1527 19

The amino boronic dipeptide, PT-100 (Val-boro-Pro), a dipeptidyl peptidase (DPP) inhibitor, has been shown to up-regulate gene expression of certain cytokines in hematopoietic tissue via a high-affinity interaction, which appears to involve fibroblast activation protein. Because fibroblast activation protein is also expressed in stroma of lymphoid tissue and tumors, the effect of PT-100 on tumor growth was studied in mice in vivo. PT-100 has no direct cytotoxic effect on tumors in vitro. Oral administration of PT-100 to mice slowed growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, and mastocytoma cell lines. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 caused regression and rejection of tumors. The antitumor effect appeared to involve tumor-specific CTL and protective immunological memory. PT-100 treatment of WEHI 164-inoculated mice increased mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells. The role of innate activity was further implicated by observation of significant, although reduced, inhibition of WEHI 164 and A20/2J tumors in immunodeficient mice. PT-100 also demonstrated ability to augment antitumor activity of rituximab and trastuzumab in xenograft models of human CD20(+) B-cell lymphoma and HER-2(+) colon carcinoma where antibody-dependent cytotoxicity can be mediated by innate effector cells responsive to the cytokines and chemokines up-regulated by PT-100. Although CD26/DPP-IV is a potential target for PT-100 in the immune system, it appeared not to be involved because antitumor activity and stimulation of cytokine and chemokine production was undiminished in CD26(-/-) mice.
...
PMID:PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. 1528 57

Cancer metastasis is the end result of a complex series of biologic events that leads to the formation of clinically significant secondary tumors at distant sites. The sites of distant metastasis are not random since certain tumors show a tendency to develop metastases in specific organs. Human melanoma, for example, demonstrates frequent metastasis to brain, lungs, lymph nodes, and skin. Herein, we review the evidence that suggests that a limited number of chemokine receptors may play critical roles in determining organ-selective metastasis in melanoma by regulating diverse processes such as chemoattraction, adhesion, and survival. In particular, we describe roles for CC chemokine receptor 7 (CCR7) in lymph node metastasis, CXC chemokine receptor 4 (CXCR4) in pulmonary metastasis, and CCR10 in skin metastasis, using a mouse model of melanoma. Preliminary evidence in this preclinical model suggests that inhibiting the function of these receptors may decrease the ability of cancer cells to disseminate to other sites and/or block their ability to survive and form tumors. Therefore, manipulation of the chemokine network could have therapeutic potential in human malignancies.
...
PMID:Chemokine receptors and melanoma metastasis. 1551 36

Gene therapy is a novel therapy for melanoma. To date, however, there is still no powerful tumor specific promoter (TSP) to restrict the transgene expression in melanoma cells. In order to define a useful TSP for targeting in the context of melanoma gene therapy, four promoters, the cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (CXCR4), epithelial glycoprotein 2 (EGP-2), and survivin, were tested in both established melanoma cell lines and primary melanoma cells. We employed recombinant adenoviral vectors (reAds) each with a candidate TSP (the Cox-2, CXCR4, EGP-2, or survivin), a reporter luciferase gene, and a poly-A signal, all of which were inserted into the E1-deleted region. A reAdGL3Bcytomegalovirus (CMV), containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity. Luciferase activity was measured in multiple tumor cell lines and two primary melanoma cell cultures after infection with reAds. Human epithelial melanocytes, HEM, were used as normal control. In contrast to three other promoters, the survivin promoter exhibited the highest activities within both melanoma cell lines and primary melanoma cells, but not in HEMs. Additionally, the survivin promoter exhibited very low activities in major mouse organs including the liver, in vivo. EGP-2 is not active in melanoma; messenger RNA expressions were correlated to promoter activities both in melanoma cell lines and primary cell cultures. Thus, these data suggest that the survivin promoter achieved a 'tumor-on/liver-off' profile, and thus represents a potentially useful tumor-specific promoter with applications for transcriptional targeting of Ad vector-based cancer gene therapy or oncolysis to melanoma.
...
PMID:Evaluation of tumor-specific promoter activities in melanoma. 1569 77

Histone deacetylation and DNA methylation establish epigenetic modifications, which through chromatin remodeling may result in gene silencing. We hypothesized that chemokine receptors C-C chemokine receptor 7 (CCR7) and C-X-C chemokine receptor 4 (CXCR4) on melanoma cells undergo epigenetic regulation. We investigated whether a histone deacetylase inhibitor and a demethylating agent influence CCR7 and CXCR4 expression on melanoma cells. Initially, microarray analysis was done to screen changes in chemokine receptor expression on melanoma cells after treatment with trichostatin A (TSA) and 5-Aza-2-deoxycytidine (5-Aza). CCR7 and CXCR4 mRNA expression were uniformly altered and selected for further investigation. Quantitative real-time reverse transcription-PCR assay, immunohistochemistry, and Western blot analysis were used to assess changes in mRNA and protein expression induced by TSA and 5-Aza in melanoma lines. Cell migration assays were conducted to assess the effects of altered CCR7 and CXCR4 expression on cell function. Treatment with TSA or 5-Aza increased gene expression of both CCR7 and CXCR4 in melanoma lines. TSA was the strongest enhancer. With combined treatment, CCR7 and CXCR4 mRNA expression was also up-regulated. Immunohistochemistry after combined treatment showed enhanced staining of both CCR7 and CXCR4 compared with control cells. Melanoma cell migration in TSA- and 5-Aza-treated cells was 7- and 2-fold higher than control cells for CCR7 and CXCR4, respectively. In summary, a histone deacetylase inhibitor and a demethylating agent up-regulated CCR7 and CXCR4 expression on melanoma cells. This increase in chemokine receptor expression correlated with functional activity. Most importantly, we have identified an epigenetic mechanism that may endogenously regulate chemokine receptor expression on melanoma cells.
...
PMID:Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells. 1575 77

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>