Clinical and Biological Significance of Vascular Endothelial Growth Factor in Endometrial Cancer

• Published in: Clinical cancer research Vol. 13; no. 24; pp. 7487 - 7495
• Main Authors: KAMAT, Aparna A, MERRITT, William M, CHUNHUA LU, COLEMAN, Robert L, GERSHENSON, David M, SOOD, Anil K, COFFEY, Donna, LIN, Yvonne G, PATEL, Pooja R, BROADDUS, Russell, NUGENT, Elizabeth, HAN, Liz Y, LANDEN, Charles N, SPANNUTH, Whitney A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2007
• Subjects: Adult; Aged; Aged, 80 and over; angiogenesis; Angiogenesis Inhibitors - administration & dosage; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Endometrial cancer; Endometrial Neoplasms - blood supply; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - metabolism; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Medical sciences; Mice; Middle Aged; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; orthotopic model; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - biosynthesis; Prognosis; Survival Analysis; Taxoids - administration & dosage; Tumors; Vascular Endothelial Growth Factor A - biosynthesis; VEGF; Uterine diseases; Endometrium cancer; Vascular endothelium growth factor; Malignant tumor; Cancer; Female genital diseases
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1017

Purpose: Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial cancer is not fully known. Therefore, we examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model. Experimental Design: Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation. Results: Of 111 endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation between VEGF expression and MVD ( P < 0.001). On multivariate analysis, stage ( P = 0.04), grade ( P = 0.003), VEGF levels ( P = 0.03), and MVD ( P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97% inhibition over controls; P < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls; P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001). Conclusions: Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.