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Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin‐B2 ligand
Author(s) -
Rutkowski Raphael,
MertensWalker Inga,
Lisle Jessica E.,
Herington Adrian C.,
Stephenson SallyAnne
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27392
Subject(s) - tumor progression , cancer research , biology , carcinogenesis , receptor tyrosine kinase , signal transduction , ligand (biochemistry) , ephrin , phenotype , microbiology and biotechnology , tumor promotion , phosphorylation , angiogenesis , receptor , cancer , biochemistry , genetics , gene
Overexpression of the receptor tyrosine kinase EphB4 is common in epithelial cancers and linked to tumor progression by promoting angiogenesis, increasing survival and facilitating invasion and migration. However, other studies have reported loss of EphB4 suggesting a tumor suppressor function in some cancers. These opposing roles may be regulated by ( i ) the presence of the primary ligand ephrin‐B2 that regulates pathways involved in tumor suppression or ( ii ) the absence of ephrin‐B2 that allows EphB4 signaling via ligand‐independent pathways that contribute to tumor promotion. To explore this theory, EphB4 was overexpressed in the prostate cancer cell line 22Rv1 and the mammary epithelial cell line MCF‐10A. Overexpressed EphB4 localized to lipid‐rich regions of the plasma membrane and confirmed to be ligand‐responsive as demonstrated by increased phosphorylation of ERK1/2 and internalization. EphB4 overexpressing cells demonstrated enhanced anchorage‐independent growth, migration and invasion, all characteristics associated with an aggressive phenotype, and therefore supporting the hypothesis that overexpressed EphB4 facilitates tumor promotion. Importantly, these effects were reversed in the presence of ephrin‐B2 which led to a reduction in EphB4 protein levels, demonstrating that ligand‐dependent signaling is tumor suppressive. Furthermore, extended ligand stimulation caused a significant decrease in proliferation that correlated with a rise in caspase‐3/7 and ‐8 activities. Together, these results demonstrate that overexpression of EphB4 confers a transformed phenotype in the case of MCF‐10A cells and an increased metastatic phenotype in the case of 22Rv1 cancer cells and that both phenotypes can be restrained by stimulation with ephrin‐B2, in part by reducing EphB4 levels.