Expression of SCF splice variants in human melanocytes and melanoma cell lines: potential prognostic implications

Welker, Pia; Schadendorf, Dirk; Artuc, Metin; Grabbe, Jürgen; Henz, Beate M.

doi:10.1054/bjoc.1999.1076

Cited by 27 publications

(19 citation statements)

References 40 publications

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“…As tumor aggressiveness increased, a shift in alternative splicing towards the 'readthrough' transcript was noticed in tumor cells but not in near-by endothelial cells, suggesting modified control over the splicing factors leading to AChE-R production in malignant, as opposed to benign cells. Shifted splicing is often associated with tumorogenicity; for example, metastatic melanoma cell lines lose their ability to express stem cell factor (SCF)-2 but retain their ability to express its alternatively spliced SCF-1 variant (Welker et al, 2000). Also, the VEGF 121 variant, when over-expressed in breast carcinoma cells, increased angiogenicity and tumorogenicity more than other VEGF splice variants (Zhang et al, 2000).…”

Section: Tumor Versus Vascular Cellsmentioning

confidence: 99%

Complex regulation of acetylcholinesterase gene expression in human brain tumors

et al. 2002

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To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3' splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3b nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 coactivator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP 67 , a peptide composed of the 67 Cterminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 Cterminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.

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Section: Tumor Versus Vascular Cellsmentioning

confidence: 99%

Complex regulation of acetylcholinesterase gene expression in human brain tumors

et al. 2002

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“…Simultaneous expression of c-kit and SCF has been reported in colon, gastric, and lung cancer cell lines, in which a growth/migrationstimulating autocrine loop has been demonstrated (Bellone et al, 1997;DiPaola et al, 1997;Hassan et al, 1998). On the other hand, in melanomas and in breast and thyroid carcinomas a loss of expression of these molecules, in comparison with normal melanocytes and mammary or thyroid epithelium, has been described (Moretti et al, 1999;Natali et al, 1992Natali et al, , 1995Welker et al, 2000). The introduction of a c-kit expression vector in melanoma and breast cancer cell lines caused growth inhibition (Huang et al, 1996;Nishida et al, 1996).…”

Section: Esposito Et Almentioning

confidence: 99%

The Stem Cell Factor–c-kit System and Mast Cells in Human Pancreatic Cancer

Espósito

Kleeff

Bischoff

et al. 2002

Laboratory Investigation

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SUMMARY:Stem cell factor (SCF) and its receptor c-kit take part in the regulation of developmental processes of mast cells, hematopoietic stem cells, and melanocytes, as well as in the growth control of human malignancies. To explore the possible role of the SCF-c-kit system and of mast cells in pancreatic cancer, the concomitant expression and distribution of the two molecules were examined in 17 normal and 26 cancerous human pancreatic tissues and in 6 cultured pancreatic cancer cell lines. Mast cell distribution was also evaluated in the same tissue samples. In addition, the effects of SCF and of the c-kit tyrosine-kinase inhibitor STI571 on the growth of the cancer cell lines and of the normal pancreatic ductal cell line TAKA-1 were assessed. SCF immunoreactivity was absent in acinar, ductal, and islet cells of the normal pancreas and faint in pancreatic cancer tissues and cell lines. In contrast, c-kit was clearly present in some normal and hyperplastic ducts of the normal pancreas, in the cancer cells of 73% of the tumor samples, and in all the cell lines tested. Mast cells, identified by tryptase and chymase immunostaining on consecutive tissue sections, showed immunoreactivity for SCF and c-kit in both normal and cancerous specimens and their number was significantly increased (p ϭ 0.03) in pancreatic cancer compared with the normal pancreas. SCF showed a dose-dependent growth inhibitory effect on TAKA-1 cells (p Ͻ 0.001), whereas pancreatic cancer cells were resistant to the SCF-induced growth inhibition. Nonetheless, the growth of TAKA-1 cells and pancreatic cancer cells was inhibited by the c-kit tyrosine kinase inhibitor STI571. In conclusion, the SCF-c-kit system, possibly with the contribution of mast cells, may have a growth-regulating role in the normal pancreas, which is altered during malignant transformation. (Lab Invest 2002, 82:1481-1492.

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“…Melanoma cells are known to express c-kit, PDGF-R and Abl (Worm et al, 1993;Montone et al, 1997;Welker et al, 2000;Potti et al, 2003;Shen et al, 2003). Moreover, based on experimental in vitro data gained from melanoma cell lines, autocrine growth loop mechanisms were postulated for the receptor -ligand interaction of PDGF-R and PDGF, as well as of Kit and stem cell factor (SCF) (Harsh et al, 1990;DiPaola et al, 1997).…”

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confidence: 99%

Lack of clinical efficacy of imatinib in metastatic melanoma

et al. 2005

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This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day À1. In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ra and -Rb expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ra in seven out of 12 cases (58%) and for PDGF-Rb in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.

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Expression of SCF splice variants in human melanocytes and melanoma cell lines: potential prognostic implications

Cited by 27 publications

References 40 publications

Complex regulation of acetylcholinesterase gene expression in human brain tumors

Complex regulation of acetylcholinesterase gene expression in human brain tumors

The Stem Cell Factor–c-kit System and Mast Cells in Human Pancreatic Cancer

Lack of clinical efficacy of imatinib in metastatic melanoma

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