Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alteration in the expression of growth factors is widely accepted as being one of several critical defects in the generation of the malignant cell. In the present study, 19 human metastatic melanoma cell lines were compared to 14 normal human foreskin melanocyte cell lines for the production of RNA transcripts specific for 11 different growth factors. Using the extremely sensitive technique of polymerase chain reaction to amplify growth factor-specific complementary DNAs, we analyzed the following: transforming growth factor (TGF) types alpha, beta 1, beta 2, and beta 3, acidic (a) fibroblast growth factor (FGF), basic (b) FGF, FGF-5, keratinocyte growth factor (KGF), HST, and platelet-derived growth factor (PDGF) types A and B. There were clear distinctions among the patterns of growth factor RNA expression by normal melanocytes and malignant melanoma cells. The prototypic melanocyte pattern of expression included TGF beta 1, TGF beta 3, and KGF. A subset of melanocyte cell lines also expressed PDGFA transcripts. In contrast, melanoma cells characteristically expressed RNA transcripts of TGF beta 1, TGF beta 2, TGF beta 3, TGF alpha, bFGF, KGF, and PDGFA. Subsets of melanoma cell lines also expressed aFGF, FGF-5, and PDGFB. The results presented indicated that TGF beta 2, TGF alpha, and bFGF may be particularly important in melanomagenesis and that these, as well as FGF-5, aFGF, and PDGFB, can be used as markers of transformation in this tumor type.
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PMID:Induction of growth factor RNA expression in human malignant melanoma: markers of transformation. 171 14

Normal human cells, cells from nonmalignant proliferative lesions, and primary and metastatic tumor cells can be maintained in vitro and analyzed for requirements for growth in chemically defined media. The human melanocytic cell system with normal melanocytes, precursor nevus cells, and primary and metastatic melanoma cells has been extensively studied for the phenotypic properties of the cells, including their requirements for exogenous growth factors and other mitogens. In high calcium-containing W489 medium, normal melanocytes require four supplements: IGF-I (or insulin); bFGF, TPA, and alpha-MSH. Nevus cells are largely independent of bFGF. Depletion of TPA from medium is not as detrimental to nevus cells as it is to melanocytes, but the phorbol ester is still essential for maintenance of the typical nevic phenotype. Primary melanoma cells require at least one growth factor, IGF-I (or insulin), for continuous proliferation. On the other hand, metastatic cells of melanoma as well as of carcinomas of colon and rectum, bladder, ovary, and cervix are able to proliferate after a short adaptation period in medium depleted of any growth factors and other proteins. Doubling times of metastatic tumor cells in protein-free medium are only 30-60% longer than in FCS-containing medium. The growth autonomy of human tumor cells is apparently due to the endogenous production of growth factors. Likely candidates for autocrine growth stimulation of human tumor cells are TGF-alpha, TGF-beta, and PDGF. Melanoma and colorectal carcinoma cells express functional EGF/TGF-alpha receptors, and produce TGF-alpha, indicating that this growth factor is produced for autocrine stimulation. In addition to the use of anti-growth factor antibodies, other strategies for the inhibition of autocrine growth stimulation include mAbs to growth factor receptors, soluble receptors, receptor-mimicking antiidiotype antibodies, and active immunization against growth factors. Whether any of these therapeutic approaches is clinically feasible will need to be determined in extensive preclinical investigations.
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PMID:Growth-regulatory factors for normal, premalignant, and malignant human cells in vitro. 240 78

Based on the clinicopathological delineation of distinct steps of tumor progression in the melanocytic system, the in vitro behavior of melanocytes with increasing malignant potential has been investigated. Tumor progression in melanocytes is characterized by an increasing growth autonomy and decreased requirement but enhanced utilization of exogenously provided polypetide growth factors (EGF, IGF-I). The endogenous production of growth factors such as alpha-TGF, PDGF, and bFGF by metastatic melanoma cells might contribute to their independence from exogenously provided factors. Although expression of some melanoma-associated antigens in vivo is detectable only on malignant cells, propagation of normal melanocytes in tissue culture leads to expression of the majority of these antigens. Many of these antigens can be grouped into functionally defined categories, including growth factor receptors, extracellular matrix proteins, and cell-substrate interacting antigens. One cell-substrate interacting antigen, the GD2/GD3 ganglioside, appears to play a critical role in the metastatic process of melanoma cells. The successful propagation and characterization of melanocytic cells of all stages of tumor progression in tissue culture provide a unique human experimental model for the study of mechanisms of malignant transformation.
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PMID:Characteristics of cultured human melanocytes from different stages of tumor progression. 290 75

The brain is a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. To metastasize to the brain malignant tumor cells must attach to microvessel endothelial cells, respond to brain-derived invasion factors, invade the blood-brain barrier and respond to survival and growth factors. Trophic factors are important in brain invasion because they can act to stimulate this process. In responsive malignant cells trophic factors such as neurotrophins can promote invasion by enhancing the production of basement membrane-degradative enzymes (such as type IV collagenase/gelatinase and heparanase) capable of locally destroying the basement membrane and the blood-brain barrier. We examined human melanoma cell lines that exhibit varying abilities to form brain metastases. These melanoma lines express low-affinity neurotrophin receptor p75NTR in relation to their brain-metastatic potentials but the variants do not express trkA, the gene encoding a high affinity nerve growth factor (NGF) tyrosine kinase receptor p140trkA. Melanoma cells metastatic to brain also respond to paracrine factors made by brain cells. We have found that a paracrine form of transferrin is important in brain metastasis, and brain-metastatic cells respond to low levels of transferrin and express high levels of transferrin receptors. Brain-metastatic tumor cells can also produce autocrine factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for the following autocrine growth factors: TGF beta, bFGF, TGF alpha and IL-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain cells, such as oligodendrocytes and astrocytes. Increased amounts of NGF were found in tumor-adjacent tissues at the invasion front of human melanoma tumors in brain biopsies. Trophic factors, autocrine growth factors, paracrine growth factors and other factors may determine whether metastatic cells can successfully invade, colonize and grow in the central nervous system.
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PMID:The role of trophic factors and autocrine/paracrine growth factors in brain metastasis. 788 17

Basic Fibroblast Growth Factor (bFGF/FGF2) is thought to play a decisive role in malignant progression. Aberrant expression of bFGF causes constitutive autocrine activation of its cognate receptor and autonomous growth of human melanoma cells or bFGF transformed fibroblasts in culture. It remains to be determined, however, whether the endogenous bFGF confers growth advantage to tumors and what are the downstream targets of the activated FGF receptor critical for its transforming capacity. We therefore transfected metastatic melanoma cells and bFGF transformed mouse fibroblasts with a dominant-negative mutant of the murine FGF receptor 1 (fgfr1/flg), comprising the extracellular and transmembrane domains but lacking the intracellular kinase domain (dnflg). Reverse transcriptase-PCR, 125I-bFGF binding and affinity labeling analyses show that the truncated receptor is targeted to the membrane and is expressed at much higher levels than the endogenous receptor in all of the selected clones. Expression of the dnflg dramatically reduces the basal as well as bFGF induced growth of these cells in vitro and also suppresses their tumorigenic potential in nude mice. The expression of the dnflg does not significantly alter the general level of tyrosyl-phosphorylated proteins in the trunsduced melanoma cells. Rather, a major downstream affected target is a Src-family kinase, whose activity, determined by an in vitro immune kinase assay, is stimulated in normal melanocytes by exogenous bFGF, and is markedly reduced in the dnflg-expressing melanoma cells. The present study demonstrates that direct interference with the activity of FGF receptors has a deleterious effect on cell proliferation and survival in vitro and in vivo leading to the suppression of melanoma tumor progression possibly through the inactivation of a Src-family kinase.
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PMID:Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: evidence for the involvement of Src-family kinases. 922 63

Caveolae have been indicated as a center of cytoskeleton regulation for Src kinase/Rho GTPase signaling. In addition, Src recruitment on intact cortical actin cytoskeleton appears to be required for bFGF/FGFR signal activation. Recently, we established a relationship between caveolin-1 (Cav-1) expression and cell migration in human malignant melanoma, constitutively activated by a bFGF autoregulatory loop. This work intends to investigate whether caveolae's asset, through bFGF/FGFR/c-Src/Rho signaling, could be related to melanoma cell anchorage. Accordingly, we revealed the existence of a FGFR/Src kinase pathway in Cav-1 enriched detergent-resistant membranes (DRMs) of Me665/1 metastatic melanoma cells, as confirmed by FGFR silencing. Moreover, we determined the expression and phosphorylation levels of Cav-1/Src/Erk signal pathway as a function of FGFR activation and cell density. A sucrose density gradient ultracentrifugation was employed to monitor Cav-1 membrane association and buoyancy in Me665/1 cells treated for actin fragmentation or for altered phosphorylation signals. As a result, melanoma cells show remarkable resistance to Cav-1 disassembly, together with persisting cell signal activity, being Src and Cav-1 crucial modulators of Rho GTPases. In conclusion, our study primarily highlights, in a metastatic melanoma cell line expressing caveolin, the circumstances whereby caveola structural and functional endurance enables the FGFR/Src/Rho GTPases pathway to keep on cell progression.
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PMID:Human melanoma cells express FGFR/Src/Rho signaling that entails an adhesion-independent caveolin-1 membrane association. 2144 70