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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The AP-2 transcription factor plays a pivotal role in regulating the expression of several genes involved in tumor growth and progression of melanoma. We determined, by Western blot, variation in the level of expression of AP-2 and three of its downstream targets, c-kit, E-cadherin, and p21 in several human melanoma cell lines and, by immunohistochemistry, in a group of 99 histological samples including benign and malignant melanocytic lesions. A significant negative correlation between AP-2 expression level and tumor thickness was found. Moreover, AP-2 expression was positively associated with E-cadherin and c-kit expression. In contrast, there was a significant negative association between AP-2 and p21 expression levels. These findings suggest that p21 is independent of AP-2 transactivator function during the latest phases of melanoma progression. Finally, AP-2, c-kit, E-cadherin, and p21 expression levels did not show to be able to distinguish between dysplastic nevi and nevi without dysplasia. We conclude that changes in the expression of these proteins are involved in the later phases of melanoma progression, and may be responsible for the transition from local invasive melanoma to metastasis.
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PMID:Expression of AP-2 transcription factor and of its downstream target genes c-kit, E-cadherin and p21 in human cutaneous melanoma. 1159 5

There has been considerable variability in the reported results of immunohistochemical staining for some diagnostically relevant antigens. Our objectives in this study were to (1) use a multitumor tissue microarray with tissue from 351 cases received in our department, representing 16 normal tissues and 47 different tumor types, to compare immunohistochemical staining results in our laboratory with published data, using a panel of 22 antibodies; (2) assess interlaboratory variability of immunohistochemical staining for S-100 using this microarray; and (3) test the ability of hierarchical clustering analysis to group tumors by primary site, based on their immunostaining profile. Tissue microarrays consisting of duplicate 0.6-mm cores from blocks identified in the hospital archives were constructed and stained according to our usual protocols. Antibodies directed against the following antigens were used: B72.3, bcl-2, carcinoembryonic antigen, c-kit, pankeratin, CD 68, CD 99, CK 5/6, CK 7, CK 8/18, CK19, CK 20, CK 22, epithelial membrane antigen, estrogen receptor, melan-A, p53, placental alkaline phosphatase, S-100, synaptophysin, thyroid transcription factor-1, and vimentin. Staining results on the array cases were compared with published results, and hierarchical clustering analysis was performed based on the immunohistochemical staining results. Unstained slides of the multitumor tissue microarray were sent to five other diagnostic immunohistochemistry laboratories and stained for S-100 protein. The staining results from the different laboratories were compared. Staining results using our current methods and samples from our laboratory were compatible with those described in the literature for most antigens. Placental alkaline phosphatase staining was not specific with our protocol, showing staining of a broad spectrum of different tumors; this finding initiated a review of our recent requests for placental alkaline phosphatase immunostaining and revealed two instances in which placental alkaline phosphatase positivity was incorrectly interpreted as evidence of a germ cell tumor. S-100 staining was less sensitive but more specific for the diagnosis of melanoma or neural tumor in our laboratory, compared to some published reports. Assessment of interlaboratory variability of S-100 immunostaining showed that there was more frequent staining of carcinomas in some laboratories, resulting in decreased specificity of S-100 staining in distinguishing melanoma from carcinoma. Hierarchical clustering analysis showed a strong trend for tumors to cluster by tissue of origin, but there were significant exceptions. We conclude that multiple-tumor microarrays are an efficient method for assessing the sensitivity and specificity of staining with any antibody used diagnostically. As a tool for quality assurance, they offer the advantage of taking into account local differences in tissue fixation, processing, and staining. They also allow cost-effective assessment of interlaboratory variability in immunohistochemical staining. Results of hierarchical clustering analysis show the potential for panels of immunohistochemical stains to identify the primary site of metastatic carcinomas but also confirm the limitations of currently available antibodies in giving unequivocal tissue-specific staining patterns.
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PMID:Tissue microarrays are an effective quality assurance tool for diagnostic immunohistochemistry. 1248 Oct 20

The KIT gene encodes c-kit, a transmembrane receptor that has tyrosine kinase activity and plays a role in haematopoiesis, gametogenesis and melanogenesis. The c-kit protein is found in normal cutaneous and choroidal melanocytes, and there is evidence that expression is lost in melanoma. Expression of c-kit was analysed in 57 paraffin-embedded sections of choroidal melanoma specimens and three choroidal melanoma cell lines using immunochemistry and Western blotting. Of the tumour specimens, 75% stained positively for c-kit with a membrane pattern of reactivity. Of the six patients who underwent proton beam therapy before enucleation, five tumours exhibited no c-kit immunoreactivity and the other tumour demonstrated weak staining. Of the three melanoma cell lines used, c-kit expression was observed in only one. No correlations between c-kit positivity and parameters such as cell type, largest macroscopic tumour dimension, scleral invasion or pigmentation were observed. In contrast, a significant positive association was found between c-kit staining and mitotic activity (P = 0.02). However, c-kit expression did not significantly influence survival when evaluated by univariate analysis. In conclusion, c-kit is expressed in most choroidal melanoma tumours. Further analysis should provide new insights into the mechanisms underlying the molecular and cellular changes in choroidal melanomas.
Melanoma Res 2003 Apr
PMID:Expression of the c-kit receptor in choroidal melanomas. 1269 Feb 99

Epithelioid gastrointestinal stromal tumors (GISTs) may cause significant diagnostic confusion on fine-needle aspiration (FNA) with carcinomas, neuroendocrine tumors, and melanoma, particularly when metastatic. This study characterizes the cytologic features of nine cases of epithelioid GISTs that were obtained by computerized tomographic guidance in five, by endoscopic ultrasound in three, and from an excised liver tumor in one. Six cases presented as liver masses, one as a perisplenic mass, one as an abdominal mass, and one as a gastric mass. The aspirates revealed mainly single or small clusters of epithelioid cells with a moderate amount of granular to clear cytoplasm, small uniform nuclei with mild to marked nuclear envelope irregularities. Binucleation and intranuclear inclusions were frequent findings. Collagenous stroma was seen in most cases. In three cases, a neuroendocrine tumor was the initial diagnosis. Immunocytochemical staining for c-kit (CD117) was performed on cellblocks in six cases and was positive in five cases. On the subsequent surgical specimen, CD117 was positive in the c-kit-negative cytology case. The diagnosis of GIST should be considered in aspirates of the gastrointestinal tract, liver, mesentery, or abdominal wall mass lesions when epithelioid cells are the predominant cell type. Ancillary studies such as immunohistochemical stains are usually helpful in making a definitive diagnosis.
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PMID:Epithelioid variant of gastrointestinal stromal tumor: Diagnosis by fine-needle aspiration. 1288 40

Progression of melanoma is associated with loss of the transcription factor AP-2alpha and tyrosine-kinase receptor c-kit. However, the mechanisms by which these two proteins are down-regulated have not been fully elucidated. Fifty non-selected melanomas comprising ten superficial spreading melanomas (five exhibiting a radial growth phase and five a vertical growth phase), ten primary nodular melanomas, 30 melanoma metastases, and 16 naevi were investigated by direct sequencing analysis of the AP-2alpha and c-kit genes and by immunohistochemistry for the respective proteins. Because it has recently been demonstrated that AP-2alpha is preferentially cleaved by caspase-6 and to a lesser extent by caspase-3, immunohistochemistry for the cleaved (activated) forms of caspase-6 (c-casp-6) and caspase-3 (c-casp-3) was carried out. No mutations were identified in the c-kit gene, but three different point mutations were demonstrated in the activation motif of AP-2alpha in four tumours: one vertical growth phase superficial spreading melanoma, one nodular melanoma, and two metastases. Immunohistochemistry revealed progressive loss of the AP-2alpha and c-kit proteins in primary melanomas and metastases when compared with naevi. The decrease of both markers was more accentuated in the dermal component of all primary tumours, with c-kit more affected than AP-2alpha. All invasive melanomas and metastases expressed c-casp-6. c-casp-3 was expressed by 83% of the metastases and in the dermal component of one nodular melanoma. These findings suggest that the loss of AP-2alpha protein expression during the progression of melanoma could be related to mutation of the gene in only a small number of tumours, whereas the expression and activation of caspases, most prominently caspase-6, may be an important factor for the down-regulation of AP-2alpha protein. Furthermore, this study supports recent data that the activation of caspases does not inevitably result in apoptosis, but may also contribute to tumour progression in melanomas.
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PMID:Expression of AP-2alpha, c-kit, and cleaved caspase-6 and -3 in naevi and malignant melanomas of the skin. A possible role for caspases in melanoma progression? 1451 45

BACKGROUND: HER-2/neu and c-kit (CD117) onco-protein are increasingly being recognized as targets for therapy in solid tumors, but data on their role in malignant melanoma is currently limited. We studied the prevalence of overexpression of HER-2/neu and c-Kit in 202 patients with malignant melanoma to evaluate a possible prognostic value of these molecular targets in malignant melanoma. METHODS: Overexpression of HER-2/neu and c-Kit was evaluated using immunohistochemical assays in 202 archival tissue specimens. RESULTS: Between 1991 and 2001, 202 subjects (109 males; 54% and 93 females; 46%) with malignant melanoma were studied with a mean age of 57 years (age range: 15-101 years). The most common histologic type was amelanotic melanoma (n = 62; 30.7%) followed by superficial spreading melanoma (n = 54; 26.7%). The depth of penetration of melanoma (Breslow thickness, pT Stage) ranged from 0.4 mm (stage pT1) to 8.0 mm (stage pT4A). Mean thickness was 2.6 mm (stage pT3A). The ECOG performance scores ranged from 0 to 3. Only 2 patients (0.9%) revealed HER-2/neu overexpression, whereas 46 (22.8%) revealed c-Kit overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit positive and negative groups (p = 0.36). Interestingly, not only was c-Kit more likely to be overexpressed in the superficial spreading type, a preliminary association between the presence or absence of c-Kit overexpression and the existence of another second primary tumor was also observed. CONCLUSIONS: The results of our large study indicate that the HER-2/neu onco-protein neither has a role in melanogenesis nor is a potential target for clinical trials with monoclonal antibody therapy. This indicates there is no role for its testing in patients with malignant melanoma. Although c-Kit, expressed preferentially in the superficial spreading type, may not have prognostic value, it does have significant therapeutic implications as a molecular target warranting further investigation.
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PMID:Immunohistochemical determination of HER-2/neu overexpression in malignant melanoma reveals no prognostic value, while c-Kit (CD117) overexpression exhibits potential therapeutic implications. 1461 73

Spindle cell melanoma is a rare and distinctive variant of malignant melanoma that is composed of spindled neoplastic cells and includes desmoplastic and neurotropic melanoma. The lack of expression of several melanoma markers may result in a delayed or wrong diagnosis. In this study, we have analyzed in detail the phenotype of the tumor cells in 9 spindle cell melanomas on both paraffin-embedded and frozen material, using melanocytic, neural, and mesenchymal markers. The neoplastic cells expressed the melanocytic markers S-100, Mel-CAM, and NKIC3, but lacked gp100 and Melan-A; tyrosinase and c-Kit were expressed in 2 of 7 cases. Most cases expressed the neural markers p75-nerve growth factor receptor, neural cell adhesion molecule, and NSE. All cases expressed vimentin but lacked the mesenchymal markers CD34 and alpha-smooth muscle actin. Remarkably, all spindle cell melanomas strongly and diffusely expressed the fibroblastic markers Thy1 (CD90) and aminopeptidase N (CD13) and variably expressed the enzyme prolyl-4-hydroxylase, involved in procollagen formation. The coexpression of melanocytic, neural, and fibroblastic markers suggests bidirectional differentiation of neoplastic melanocytes toward (myo)fibroblasts and Schwann cells, a feature that was confirmed by electron microscopy. Furthermore, the lack of CD90 and CD13 staining in a wide range of melanocytic lesions suggests specificity of these markers for spindle cell melanoma.
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PMID:New phenotypical and ultrastructural findings in spindle cell (desmoplastic/neurotropic) melanoma. 1466 57

The role of c-Kit in the development of melanoma was studied in line 304/B6 of RET-transgenic mice, in which melanoma spontaneously develops. In Wv/Wv-RET (304/B6)-transgenic mice, in which c-Kit function was severely impaired, development of melanoma was strongly suppressed. Although 31 of the 44 original RET-transgenic mice died of rapidly growing melanoma within 12 months after birth, only 8 of the 44 Wv/Wv-RET-transgenic mice developed slowly growing melanocytic tumors with a greatly prolonged mean tumor-free period, 2 of which died of melanoma at a late stage. Even Wv/+-RET-transgenic mice had a clearly prolonged tumor-free period and definitely reduced frequency (6 of 61) of tumor death within 12 months after birth. Melanin production in the skin of these mice was not strongly impaired, suggesting that c-Kit affects the development of melanomas in these mice with only minor effects in melanin production. c-Kit expression in skin soon after birth was promoted in RET-transgenic mice, and c-Kit was expressed at high levels at the benign but not malignant stage of the tumor. A single injection of anti-c-Kit antibody (ACK2) into RET-transgenic mice soon after birth caused a surprisingly long-lasting suppression of development of melanoma, greatly prolonging the tumor-free period, and none of the 28 ACK2-treated RET-transgenic mice died from tumors at 12 months of age. The c-Kit function needed for melanin production was also suppressed for an unusually long time in ACK2-treated, RET-transgenic mice. These results suggest that c-Kit can be a unique target molecule for melanoma treatment.
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PMID:c-Kit-targeting immunotherapy for hereditary melanoma in a mouse model. 1487 2

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-alpha and -beta were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-alpha were expressed on cells with higher metastatic potential, and higher levels of PDGFR-beta were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-alpha and PDGFR-beta in vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit.
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PMID:Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo. 1500 22

The B-Raf(V599E)-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409-42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of (V599E)B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of (V599E)B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.
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PMID:Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. 1514 34


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