Abstract:
:The greatest health threat from malignant melanoma is death due to metastatic disease. Consequently, the identification of markers predictive of metastatic disease is essential for identifying new therapeutic targets. EphA2, a protein tyrosine kinase receptor commonly expressed in epithelial cells, has been found to be overexpressed and constitutively active in melanoma tumor cells having a metastatic phenotype as characterized by increased invasion, proliferation and vasculogenic mimicry (VM). Based on this observation, we hypothesized that increased expression of EphA2 by melanoma tumor cells could promote these characteristics of a metastatic phenotype in addition to promoting tumorigenicity as a whole. We analyzed a panel of human melanoma tumor cell lines derived from patient tissues classified as primary (either radial growth phase or vertical growth phase) and/or metastatic for the expression of EphA2 and found a correlation between increased EphA2 expression and metastatic potential. Experiments using the most metastatic of the human melanoma cell lines demonstrated that downregulation of EphA2 results in a significant decrease in invasion, proliferation, clonogenicity and VM in vitro, in addition to suppressed tumorigenicity in an orthotopic mouse model. Lastly, utilization of a human phospho-kinase array revealed increased phosphorylation of several different protein kinases involved in mediating various aspects of cellular proliferation. To the best of our knowledge these results provide the first direct in vivo evidence demonstrating a role for EphA2 in promoting melanoma tumorigenicity and suggest EphA2 as a significant molecular target for the therapeutic intervention of malignant melanoma.
journal_name
Cancer Biol Therjournal_title
Cancer biology & therapyauthors
Margaryan NV,Strizzi L,Abbott DE,Seftor EA,Rao MS,Hendrix MJ,Hess ARdoi
10.4161/cbt.8.3.7485subject
Has Abstractpub_date
2009-02-01 00:00:00pages
279-88issue
3eissn
1538-4047issn
1555-8576pii
7485journal_volume
8pub_type
杂志文章abstract::Docetaxel is an important anti-microtubule agent used to treat a variety of solid tumors, including breast cancer; notably, docetaxel-containing regimens improve outcomes for patients in metastatic, adjuvant, and neoadjuvant settings. However, the effectiveness of docetaxel in clinical practice can be compromised by s...
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journal_title:Cancer biology & therapy
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