Cervical cancer is the leading cause of cancer morbidity and mortality in women worldwide. (1) In United States, precancerous changes, known as cervical dysplasia, are detected on Pap tests in approximately 2 million women annually. Serious limitations of the Pap test are: (1) It is too expensive and labor-intensive for use in developing nations. (2) Although it is successfully at detecting invasive cancer and cancer precursors, it also detects 2.5 million minor abnormalities annually in the USA that are for the most part clinically insignificant. The availability of prognostic markers to distinguish patients with clinically benign atypical changes from those with cancer and high grade dysplasia would be extremely useful. The goal of this proposal is to characterize novel molecular markers of dysplasia that can be identified in cells scraped from the cervix. Work performed in her laboratory and others has established that molecular markers of angiogenesis are upregulated progressively in the different grades of cervical dysplasia, and between neoplastic cervical disease and normal cervix (4-12). The research outlined in this grant proposal is based upon the following hypothesis: Factors mediating angiogenesis in cervical dysplasia can be detected in exfoliated cervical cells and can be exploited to assist in more effective cervical cancer screening.
Specific Aim 1. Determine the association between the relative mRNA levels of angiogenic factors with the clinical cytological diagnosis in cells scraped from the cervix. 1A: Determine relative mRNA levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), angiopoitin-1 (ang-1) and angiopoitin-2 (ang-2) in a cohort of 60 cytologically verified cervical samples representing 20 with normal cytology, 20 with low grad squamous intrepithalial lesions (SIL), and 20 with high grade SIL. 1B: Determine the sensitivity, specificity, and positive and negative predictive values of BEGF/VPF, ang-1 and ang-2 mRNA levels as markers for low grade and high grade SIL.
Specific Aim 2. Determine the association between VEGF/VPF protein levels with the clinical cytological diagnoses in cells scraped from the cervix. 2A: Determine relative protein levels of VEGF/VPF in a cohort of 60 cytologically verified cervical samples representing 20 with normal cytology, 20 with low grade SIL, and 20 with high grade SIL. 2B: Determine the sensitivity, specificity, and positive and negative predictive values of VEGF/VPF protein expression as a marker for low grade and high grade SIL.
