Absence of Classical MAP Kinase Pathway Signalling in Merkel Cell Carcinoma

Houben, Roland; Michel, Barbara; Vetter-Kauczok, Claudia S.; Pföhler, Claudia; Laetsch, Barbara; Wolter, M.; Leonard, J. Helen; Trefzer, Uwe; Ugurel, Selma; Schrama, David; Becker, Juergen C.

doi:10.1038/sj.jid.5700170

Cited by 55 publications

(52 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, Swick et al determined that although eight of nine MCC tumors were positive for c-kit by immunohistochemical staining, no activating mutations were present in the four exons commonly found to have mutations in this gene [28]. Similarily, the analysis of MCC samples did not reveal presence of any activating B-Raf mutations [29,30]. Moreover, immunohistochemical studies revealed that despite high proliferation indices and existing expression of ERK, the ERK protein generally occurs in the non-phosphorylated form and is thus inactive [29].…”

Section: Pathogenesismentioning

confidence: 81%

Merkel cell carcinoma

Becker

Schrama

Houben

2008

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. More than one-third of MCC patients will die from this cancer, making it twice as lethal as malignant melanoma. Despite the fact that MCC is still a very rare tumor, its incidence is rapidly increasing; the American Cancer Society estimates for 2008 almost 1,500 new cases in the USA. These clinical observations are especially disturbing as the pathogenesis of MCC is not yet fully understood; however, a number of recent reports contribute to a better understanding of its pathogenesis. Here we describe findings regarding the role of Wnt, MAPK and Akt signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor network in MCC. Most important, and possibly with high impact on future therapeutic approaches is the demonstration that a polyomavirus has frequently integrated in the genome of the MCC cells prior to tumor development.

show abstract

Section: Pathogenesismentioning

confidence: 81%

Merkel cell carcinoma

Becker

Schrama

Houben

2008

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…The classical MAP kinase signaling pathway was also examined in this skin carcinoma, and found to be not necessarily important, as there were no activating mutations in the B-Raf gene. 31 In this study, we evaluated the expression and mutational status of receptor tyrosine kinases, KIT and PDGFRA, in 32 cases of Merkel cell carcinoma. Expression of KIT was observed in 17 of 32 cases (53%).…”

Section: Discussionmentioning

confidence: 99%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

View full text Add to dashboard Cite

Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

show abstract

“…35,36 Nevertheless, all three MAPK pathways seem to be involved in carcinogenesis and recent evidence suggests that P38l, one of the four P38 isoforms (P38a, P38b, P38k, and P38l), 36 is instrumental in malignant transformation linked to K-ras mutations. In a study of Merkel cell carcinoma, the ERK pathway was completely inactive in 42 of 44 cases, 37 but no information on the P38 pathway was provided. In the present study, there was immunopositivity for phosphorylated P38 in 26 of 31 cases of Merkel cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

et al. 2007

View full text Add to dashboard Cite

Primary neuroendocrine carcinoma of the skin, or Merkel cell carcinoma, is the most aggressive cutaneous neoplasm. In spite of its similarities to small cell carcinomas from other locations, Merkel cell carcinoma shows many peculiarities probably related to its epidermal origin and the etiologic role of UV radiation. We have immunohistochemically investigated 43 markers on a tissue microarray in which 31 surgically resected Merkel cell carcinomas were represented. Of these, 15 patients remained free of disease after removal, whereas 16 developed metastases. Immunoreactivity was scored according to staining intensity and the percentage of positive cells. We found statistically significant correlations between metastatic tumor spread and overexpression of matrix metalloproteinase (MMP) 7, MMP10/2, tissue inhibitor of metalloproteinase 3, vascular endothelial growth factor (VEGF), P38, stromal NF-kappaB, and synaptophysin. Also detected were statistically significant correlations between the expression levels of MMP7 and VEGF, MMP7 and P21, MMP7 and P38, MMP10/2 and VEGF, P38 and synaptophysin, P38 and P53, and P21 and stromal NF-kappaB. These findings may be helpful in predicting the clinical course of Merkel cell carcinoma and are potentially useful for the development of targeted therapies.

show abstract

Absence of Classical MAP Kinase Pathway Signalling in Merkel Cell Carcinoma

Cited by 55 publications

References 41 publications

Merkel cell carcinoma

Merkel cell carcinoma

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

Contact Info

Product

Resources

About