Abstract
Enhanced or altered epidermal growth factor receptor (EGFR) activity has been reported in many
human cancers and several molecular targeting therapies has been developed. However, despite
intense research, therapies targeting EGFR have shown conflicting results in clinical studies,
indicating the involvement of other important molecular players.
Several different EGFR mutations have been reported in cancer, one of which is the cancer specific
type III EGFR deletion mutant (EGFRvIII, de2-7EGFR, ΔEGFR). In a global search for EGFR and
EGFRvIII regulated genes we identified the receptor tyrosine kinase (RTK) EphA2. EphA2 belongs
to the large Eph-receptor family, which has mainly been associated with neuronal development.
More recently, expression of several Eph-receptors has been detected in many different cancer
types. Elevated EphA2 expression has been reported in a broad range of human cancer including
those originating from the brain, breast, cervix, colon, head and neck, kidney, lung, esophagus,
ovary, prostate, skin and stomach. Moreover, high EphA2 expression has been correlated with
increased tumor volume, short overall survival and increasing evidence also suggest that EphA2 is
involved in tumor metastasis and angiogenesis.
The aim of the PhD-project was to study the EGFR-induced EphA2 expression in mammalian
cancer cells, and to evaluate the role of EphA2 expression on EGFR regulated cell signaling and
functional effects using different in vitro models.
The results have shown that ligand activated EGFR and constitutive activated EGFRvIII induce
expression of EphA2 in human cancer cell lines. The regulation was shown to be mediated by
activation of specific signaling pathways and activation of the EphA2 promoter that regulates the
transcription of the EphA2 gene. Moreover, we have shown that EphA2 expression in in vitro
cultured cells is restricted to cells growing adherently.
EphA2 and EGFR are both cell surface trans-membrane proteins and we have found that the two
receptors co-localize on human cancer cells. EGFR and EphA2 co-immunoprecipitates and their
interactions affects receptor phosphorylation and activation of downstream signaling pathways.
Importantly, EphA2 downregulation inhibits EGF-induced cancer cell migration and viability. The
EGFR regulated EphA2 expression and functional cross-talk between the two receptor–ligand
systems could be very important when targeting either receptor in cancer.
human cancers and several molecular targeting therapies has been developed. However, despite
intense research, therapies targeting EGFR have shown conflicting results in clinical studies,
indicating the involvement of other important molecular players.
Several different EGFR mutations have been reported in cancer, one of which is the cancer specific
type III EGFR deletion mutant (EGFRvIII, de2-7EGFR, ΔEGFR). In a global search for EGFR and
EGFRvIII regulated genes we identified the receptor tyrosine kinase (RTK) EphA2. EphA2 belongs
to the large Eph-receptor family, which has mainly been associated with neuronal development.
More recently, expression of several Eph-receptors has been detected in many different cancer
types. Elevated EphA2 expression has been reported in a broad range of human cancer including
those originating from the brain, breast, cervix, colon, head and neck, kidney, lung, esophagus,
ovary, prostate, skin and stomach. Moreover, high EphA2 expression has been correlated with
increased tumor volume, short overall survival and increasing evidence also suggest that EphA2 is
involved in tumor metastasis and angiogenesis.
The aim of the PhD-project was to study the EGFR-induced EphA2 expression in mammalian
cancer cells, and to evaluate the role of EphA2 expression on EGFR regulated cell signaling and
functional effects using different in vitro models.
The results have shown that ligand activated EGFR and constitutive activated EGFRvIII induce
expression of EphA2 in human cancer cell lines. The regulation was shown to be mediated by
activation of specific signaling pathways and activation of the EphA2 promoter that regulates the
transcription of the EphA2 gene. Moreover, we have shown that EphA2 expression in in vitro
cultured cells is restricted to cells growing adherently.
EphA2 and EGFR are both cell surface trans-membrane proteins and we have found that the two
receptors co-localize on human cancer cells. EGFR and EphA2 co-immunoprecipitates and their
interactions affects receptor phosphorylation and activation of downstream signaling pathways.
Importantly, EphA2 downregulation inhibits EGF-induced cancer cell migration and viability. The
EGFR regulated EphA2 expression and functional cross-talk between the two receptor–ligand
systems could be very important when targeting either receptor in cancer.
| Originalsprog | Engelsk |
|---|
| Antal sider | 117 |
|---|---|
| Status | Udgivet - jun. 2010 |