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Dissertation
Angiogenesis, ovarian cancer and vascular endothelial growth factor
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Feb 1999
DOI:
https://doi.org/10.17918/00007544
Abstract
Angiogenesis, the formation of new capillaries from preexisting blood essels, plays an important role in the growth and progression of malignancies. This concept is particularly applicable to ovarian cancer, the growth of which is not sustainable without a concurrent increase in blood supply. We hypothesize that high expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, correlates with ovarian malignancy. We further postulate that VEGF may stimulate angiogenesis in ovarian cancer, thereby promoting the growth and metastatic spread of this neoplasm. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF in the cyst fluid of patients with ovarian cancer (n = 13), benign cysts and cystadenomas (n = 23), borderline tumors (n = 5) and functional cysts (n = 8). VEGF levels were markedly elevated in the fluid of malignant cysts (38.5 [special characters omitted] 8.2ng/ml) as compared to benign (1.6 [special characters omitted] 0.4ng/ml, p < 0.001), borderline (5.7 [special characters omitted] 1.5ng/ml, p < 0.001) or functional cysts (3.8 [special characters omitted] 2.0ng/ml, p < 0.001). Follow-up of patients with malignant and borderline lesions demonstrated a correlation between VEGF levels in cyst fluid and tumor recurrence (p < 0.03). Microvascular density of archival malignant ovarian tumors was three times higher (x = 29.6 [special characters omitted] 7.0, p < 0.02, n = 8) than that of benign lesions (x = 11.4 [special characters omitted] 1.8, n = 9). The cyst fluid from five patients with malignancies substantially stimulated the proliferation of human microvascular endothelial cells (x = 63.2 x 104 [special characters omitted] 7.2) as compared to the benign fluid (24.9 x 104 [special characters omitted] 4.6, p < 0.01, n = 4) or control growth medium (x = 26.4 x 104 [special characters omitted] 2.0, p < 0.01). VEGF RNA expression in twelve ovarian cancer cell lines ranged from undetectable to intense signal. ELISA of the conditioned media from six selected cell lines and Western analysis of cellular extracts confirmed the presence of VEGF protein. Actinomycin D experiments indicated that stabilization of VEGF mRNA occurred in cell line A2780. Conditioned medium from cell line SKOV-3 stimulated microvessel outgrowth in a dose-dependent manner in an in vitro model of angiogenesis. Conditioned medium from six cell lines stimulated vessel outgrowth to varying degrees, with A2780 producing the greatest response. These results support the idea that angiogenesis and VEGF are integrally involved in ovarian cancer pathology. They also indicate that ovarian cancers may exhibit heterogenous phenotypes with respect to VEGF expression and angiogenic activity.
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Details
- Title
- Angiogenesis, ovarian cancer and vascular endothelial growth factor
- Creators
- Darcie A. Hazelton
- Contributors
- Bruce A. Ruggeri (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- x, 145 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888862004721