Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer.
OBJECTIVE
EphA2 overexpression predicts poor prognosis in endometrial cancer. To explore mechanisms for this association and assess its potential as therapeutic target, the relationship of EphA2 expression to markers of angiogenesis was examined using patient samples and an orthotopic mouse model of uterine cancer.


METHODS
Expression of EphA2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was evaluated using immunohistochemistry in 85 endometrioid endometrial adenocarcinomas (EEC) by two independent investigators. Results were correlated with clinicopathological characteristics. The effect of EphA2- agonist monoclonal antibody EA5, alone or in combination with docetaxel was studied in vitro and in vivo. Samples were analyzed for markers of angiogenesis, proliferation and apoptosis.


RESULTS
Of 85 EEC samples, EphA2 was overexpressed in 47% of tumors and was significantly associated with high VEGF expression (p=0.001) and high MVD counts (p=0.02). High EphA2 expression, high VEGF expression and high MVD counts were significantly associated with shorter disease-specific survival. EA5 led to decrease in EphA2 expression and phosphorylation in vitro. In the murine model, while EA5 (33-88%) and docetaxel (23-55%) individually led to tumor inhibition over controls, combination therapy had the greatest efficacy (78-92%, p.
Merritt
William M
WM
Department of Gynecologic Oncology, Anderson Cancer Center, Houston, TX, USA.
Kamat
Aparna A
AA
Hwang
Jee-Young
JY
Bottsford-Miller
Justin
J
Lu
Chunhua
C
Lin
Yvonne G
YG
Coffey
Donna
D
Spannuth
Whitney A
WA
Nugent
Elizabeth
E
Han
Liz Y
LY
Landen
Charles N
CN
Nick
Alpa M
AM
Stone
Rebecca L
RL
Coffman
Karen
K
Bruckheimer
Elizabeth
E
Broaddus
Russell R
RR
Gershenson
David M
DM
Coleman
Robert L
RL
Sood
Anil K
AK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018269:Carcinoma, Endometrioid / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000077143:Docetaxel; D016889:Endometrial Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000648:ultrastructure; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013534:Survival; D043823:Taxoids / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D020794:Receptor Protein-Tyrosine Kinases; D036104:Receptor, EphA2