Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-associated macrophages are major infiltrates of human solid malignancies and play an important role in tumor angiogenesis by production of angiogenic factors. In the present study, we examined whether macrophage- melanoma cell interaction regulates vascular endothelial cell growth factor-A (VEGF-A) expression in macrophages. We analyzed the expression of mediators of monocyte recruitment and differentiation, such as monocyte chemotactic protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) in malignant melanoma specimens and tumor cells with different metastatic potential. Our data demonstrate that MCP-1 and M-CSF are differentially expressed in human malignant melanomas from different thickness and depth of invasion and cell lines. Next, we examined the effect of MCP-1 and M-CSF on modulation of VEGFA expression in monocytes/macrophages. Treatment of human monocytes with M-CSF and MCP-1 enhanced VEGF-A expression by increased hypoxia-inducible factor-1alpha (HIF-1alpha) expression and enhanced activation of the hypoxia response element (HRE). Further activation of monocytes and monocyte-derived macrophages (MDM) by lipopolysaccharide (LPS) caused an increase in VEGF-A expression. We demonstrate that coculture of melanoma cells with monocytes enhanced VEGF-A secretion, and conditioned medium from MDMs enhanced melanoma cell expression of VEGF-A. Furthermore, conditioned medium from melanoma cells enhanced VEGF-A expression in human monocytes, which was abrogated by anti-M-CSF neutralizing antibody. In summary, we demonstrate that MCP-1 and M-CSF, critical for monocyte recruitment, activation, and differentiation, differentially regulate VEGF-A expression and may play an important role in monocyte/macrophage- mediated tumor angiogenesis.
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PMID:Paracrine regulation of vascular endothelial growth factor--a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. 1631 81

The Ets transcription factors regulate a wide variety of biologic processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1 is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression is also enriched in tumor blood vessels, and have identified a short peptide, 34 amino acids in length, corresponding to the terminal portion of the highly conserved ETS domain that potently blocks the function of ELF-1. A tailored ELF-1 blocking peptide, containing a 12-amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets including Tie2 and endothelial nitric oxide synthase. Furthermore, the ELF-1 blocking peptide potently inhibits angiopoietin-1-mediated endothelial cell migration. Systemic administration of this peptide markedly attenuates B16 melanoma tumor growth and tumor-associated angiogenesis in nude mice. These results support the function of ELF-1 in the regulation of Tie2 gene expression during the development of tumor angiogenesis.
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PMID:Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. 1635 13

"Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-beta) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
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PMID:mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. 1646 4

Targeting the vascular endothelial growth factor (VEGF) in combination with standard chemotherapy has recently proved successful in the treatment of different types of advanced cancer. The achievements of combinatorial anti-VEGF monoclonal antibody bevacizumab (BEV) renewed the confidence in targeted antiangiogenic approaches to constitute a complementary therapeutic modality in addition to surgery, radiotherapy and chemotherapy. While several second-generation multitargeted tyrosine kinase inhibitors show promise in defined tumor entities, these novel antiangiogenic compounds have yet to meet or exceed the efficacy of combinatorial BEV therapy in ongoing clinical trials. Current developments of targeted antiangiogenic agents include their use in the adjuvant setting and the combination of different antiangiogenesis inhibitors to take a more comprehensive approach in blocking tumor angiogenesis. The identification of surrogate markers that can monitor the activity and efficacy of antiangiogenic drugs in patients belongs to the most critical challenges to exploit the full potential of antiangiogenic therapies. The opportunities and obstacles in further development of growth factor- and growth factor receptor-targeted antiangiogenic approaches for advanced cancer, including malignant melanoma, will be discussed herein with particular reference to selected ongoing clinical trials.
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PMID:Antiangiogenic cancer therapies get their act together: current developments and future prospects of growth factor- and growth factor receptor-targeted approaches. 1648 Apr 25

The mechanism of thrombin-induced angiogenesis is poorly understood. Using a gene chip array to investigate the pro-malignant phenotype of thrombin-stimulated cells, we observed that thrombin markedly up-regulates growth-regulated oncogene-alpha (GRO-alpha) in several tumor cell lines as well as endothelial cells by mRNA and protein analysis. Thrombin enhanced the secretion of GRO-alpha from tumor cells 25- to 64-fold. GRO-alpha is a CXC chemokine with tumor-associated angiogenic as well as oncogenic activation following ligation of its CXCR2 receptor. GRO-alpha enhanced angiogenesis in the chick chorioallantoic membrane assay 2.2-fold, providing direct evidence for GRO-alpha as an angiogenic growth factor. Anti-GRO-alpha antibody completely inhibited the 2.7-fold thrombin-induced up-regulation of angiogenesis, as well as the 1.5-fold thrombin-induced up-regulation of both endothelial cell cord formation in Matrigel and growth in vitro. Thrombin as well as its PAR-1 receptor activation peptide [thrombin receptor activation peptide (TRAP)] as well as GRO-alpha all markedly increased vascular regulatory proteins and growth factors: matrix metalloproteinase (MMP)-1, MMP-2, vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), CD31, and receptors KDR and CXCR2 in human umbilical vein endothelial cells. All of the thrombin/TRAP gene up-regulations were completely inhibited by anti-GRO-alpha antibody and unaffected by irrelevant antibody. Similar inhibition of gene up-regulation as well as thrombin-induced chemotaxis was noted with small interfering RNA (shRNA) GRO-alpha KD 4T1 breast tumor and B16F10 melanoma cells. In vivo tumor growth studies in wild-type mice with shRNA GRO-alpha KD cells revealed 2- to 4-fold impaired tumor growth, metastasis, and angiogenesis, which was not affected by endogenous thrombin. Thus, thrombin-induced angiogenesis requires the up-regulation of GRO-alpha. Thrombin up-regulation of GRO-alpha in tumor cells as well as endothelial cells contributes to tumor angiogenesis.
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PMID:Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. 1661 33

A mutual spatial and functional relationship occurs between mast cells (MCs) and endothelial cells and the density of MCs is highly correlated with the extent of tumor angiogenesis. The aim of this study was to investigate the pattern of MCs around the blood vessels in melanoma samples by means of an approach derived from spatial statistics, based on the analysis of the distribution of the distances of MCs from vessels to objectively establish if the two structures (MCs and vessels) are distributed independently over the studied area or if they displayed any kind of spatial association. Results showed that a higher number of vessels and MCs can be observed in melanoma as compared with samples from common acquired nevi (control group). The percent of area covered by vessel profiles was significantly higher in the melanoma group than the control group and the MC density was also significantly different; the melanoma group showing a number of MCs per unit area twice as high as the number measured in the control group. Furthermore, in the melanoma group, MCs were closer to each other and to the vessels. In fact, both the mean distance from vessels and the mean distance from the nearest cell profile were significantly lower than in the control group. This close association between MCs and the endothelium does not necessarily imply a participation of MCs in angiogenic processes, but might rather indicate that MCs are involved in the maintenance reaction necessary for the long lasting functional integrity of the endothelium.
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PMID:An image analysis of the spatial distribution of perivascular mast cells in human melanoma. 1668 5

The inhibition of angiogenesis is a promising avenue for cancer treatment. Although some angiostatic compounds are in the process of development and testing, these often prove ineffective in vivo or have unwanted side effects. We have designed, synthesized, and evaluated a small library of nonpeptidic, calixarene-based protein surface topomimetics that display chemical substituents to approximate the molecular dimensions and amphipathic features (hydrophobic and positively charged residues) of the antiangiogenic peptide anginex, which, like many antiangiogenic proteins, consists primarily of an antiparallel beta-sheet structure as the functional unit. Two of the topomimetics (0118 and 1097) were potent angiogenesis inhibitors in vitro, as determined by endothelial cell proliferation, migration, and chick embryo chorioallantoic membrane assays. Moreover, both compounds were highly effective at inhibiting tumor angiogenesis and growth in two mouse models (MA148 human ovarian carcinoma and B16 murine melanoma). Our results demonstrate the feasibility of designing nonpeptidic protein surface topomimetics as novel pharmaceutical agents for clinical intervention against cancer through angiostatic or other mechanisms.
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PMID:Design of nonpeptidic topomimetics of antiangiogenic proteins with antitumor activities. 1681 57

Placenta growth factor (PlGF), a member of the vascular endothelial growth factor family, plays an important role in adult pathological angiogenesis. To further investigate PlGF functions in tumor growth and metastasis formation, we used transgenic mice overexpressing PlGF in the skin under the control of the keratin 14 promoter. These animals showed a hypervascularized phenotype of the skin and increased levels of circulating PlGF with respect to their wild-type littermates. Transgenic mice and controls were inoculated intradermally with B16-BL6 melanoma cells. The tumor growth rate was fivefold increased in transgenic animals compared to wild-type mice, in the presence of a similar percentage of tumor necrotic tissue. Tumor vessel area was increased in transgenic mice as compared to controls. Augmented mobilization of endothelial and hematopoietic stem cells from the bone marrow was observed in transgenic animals, possibly contributing to tumor vascularization. The number and size of pulmonary metastases were significantly higher in transgenic mice compared to wild-type littermates. Finally, PlGF promoted tumor cell invasion of the extracellular matrix and increased the activity of selected matrix metalloproteinases. These findings indicate that PlGF, in addition to enhancing tumor angiogenesis and favoring tumor growth, may directly influence melanoma dissemination.
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PMID:Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. 1687 62

Heparanase is an endo-beta-D-glucuronidase that degrades heparan sulfate glycosaminoglycan side chains of the proteoglycans in extracellular matrix and basement membrane. Heparanase enzymatic activity is important in the promotion of tumor angiogenesis, primary tumor growth, invasion, and metastasis. Expression of heparanase in many tumor types conversely correlates with prognosis. Much progress has been made in studying the regulation of heparanase expression, processing and activation. The interaction between heparanase and its substrate heparan sulfate has been well characterized. The fact that heparanase was identified as the single predominant heparan sulfate-degrading enzyme in human cancer sparked considerable interest in developing heparanase inhibitors for potential therapeutic applications. Recent progress in drug development led to several classes of heparanase inhibitors, including chemically modified natural products, small molecule inhibitors, and antibodies. Some of these inhibitors have demonstrated potent activities to inhibit tumor angiogenesis, tumor progress, or tumor metastasis. A leading compound, PI-88, is currently being evaluated in clinical phase II trials in patients with melanoma, liver, or lung cancers. This review summarizes the recent progress in heparanase biochemical research and the development of heparanase antagonists as novel anti-cancer therapeutics.
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PMID:Development of heparanase inhibitors for anti-cancer therapy. 1691 40

Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor-bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization.
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PMID:Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. 1709 30


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