Clinical and biological significance of vascular endothelial growth factor in endometrial cancer

Aparna A. Kamat, William M. Merritt, Donna Coffey, Yvonne G. Lin, Pooja Patel, Russell Broaddus, Elizabeth Nugent, Liz Y. Han, Charles N. Landen, Whitney A. Spannuth, Chunhua Lu, Robert L. Coleman, David M. Gershenson, Anil K. Sood

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7487-7495
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number24
DOIs
StatePublished - Dec 15 2007
Externally publishedYes

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Endometrial Neoplasms
docetaxel
Vascular Endothelial Growth Factor A
Microvessels
Neoplasms
Therapeutics
Research Ethics Committees
Research Design
Multivariate Analysis
Animal Models
Immunohistochemistry
Research Personnel
Clinical Trials
Cell Line
Survival
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. / Kamat, Aparna A.; Merritt, William M.; Coffey, Donna; Lin, Yvonne G.; Patel, Pooja; Broaddus, Russell; Nugent, Elizabeth; Han, Liz Y.; Landen, Charles N.; Spannuth, Whitney A.; Lu, Chunhua; Coleman, Robert L.; Gershenson, David M.; Sood, Anil K.

In: Clinical Cancer Research, Vol. 13, No. 24, 15.12.2007, p. 7487-7495.

Research output: Contribution to journalArticle

Kamat, AA, Merritt, WM, Coffey, D, Lin, YG, Patel, P, Broaddus, R, Nugent, E, Han, LY, Landen, CN, Spannuth, WA, Lu, C, Coleman, RL, Gershenson, DM & Sood, AK 2007, 'Clinical and biological significance of vascular endothelial growth factor in endometrial cancer', Clinical Cancer Research, vol. 13, no. 24, pp. 7487-7495. https://doi.org/10.1158/1078-0432.CCR-07-1017
Kamat, Aparna A. ; Merritt, William M. ; Coffey, Donna ; Lin, Yvonne G. ; Patel, Pooja ; Broaddus, Russell ; Nugent, Elizabeth ; Han, Liz Y. ; Landen, Charles N. ; Spannuth, Whitney A. ; Lu, Chunhua ; Coleman, Robert L. ; Gershenson, David M. ; Sood, Anil K. / Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 24. pp. 7487-7495.
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abstract = "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.",
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AU - Kamat, Aparna A.

AU - Merritt, William M.

AU - Coffey, Donna

AU - Lin, Yvonne G.

AU - Patel, Pooja

AU - Broaddus, Russell

AU - Nugent, Elizabeth

AU - Han, Liz Y.

AU - Landen, Charles N.

AU - Spannuth, Whitney A.

AU - Lu, Chunhua

AU - Coleman, Robert L.

AU - Gershenson, David M.

AU - Sood, Anil K.

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