Detection of tumor-associated neoangiogenesis by Doppler ultrasonography during early-stage ovarian cancer in laying hens: a preclinical model of human spontaneous ovarian cancer.

Ovarian cancer (OVCA) remains a fatal malignancy of women and is responsible for the third highest rate of mortality due to gynecological cancers, after breast and cervical cancers.1 In contrast to OVCA, the availability of early-detection tests for other gynecological malignancies including breast and cervical cancers, has contributed in part to the gradual decline in death rates due to these malignancies.1 Because of the lack of an effective screening tool or an early diagnostic method, it is difficult to detect OVCA at an early stage, and, in most cases, it is detected at late stages, when the 5-year survival rate of patients is less than10% as compared with greater than 90% when detected at early stages.2, 3 The non-specificity of OVCA symptoms at early stages reduces the accessibility to a patient’s specimens. It is therefore difficult to validate potential targets for early diagnosis and to establish an effective method to detect that targets.4 Consequently, this represents one of the main obstacles to the development of an early-detection test for OVCA. Substantial studies have been described, involving 3 different approaches to develop an effective early-detection test for OVCA, including a serum marker (Cancer Antigen 125[CA-125), traditional transvaginal ultrasounography(TVUS) and their combination. 5, 6 Although circulating levels of CA-125 have proven useful in determining prognosis and response to treatment for patient undergoing chemotherapy, elevated CA-125 levels are also associated with many benign gynecologic conditions. In addition to mucinous OVCA in which elevation of CA-125 level is less frequent, 20% patients with OVCA do not show elevated CA-125 levels. 7 On the other hand, the effectiveness of the Doppler indices (Resistive Index [RI and Pulsatility Index [PI]) from TVUS has been tested extensively to detect early-stage OVCA in humans without any success because of due to limited resolution and overlap between normal and abnormal indices. Improvement in the overall level of OVCA detection was not observed even with the use of TVUS together with CA-125 because no imaging target in the ovary (indicative of early OVCA-associated morphologic or cellular changes) corresponding to serum CA-125 level has been defined. Therefore, appropriate changes the in ovarian morphologic, cellular or molecular architecture associated with early stage OVCA need to be identified. Tumor- associated neoangiogenesis (TAN) is one of the earlier events in tumor development. Similar to cancer of other organs, neoangiogenesis is an early event in ovarian malignancy and is a critical determinant of tumor growth, invasion, progression and metastatic potential.8, 9 Therefore, ovarian TAN represents a potential target for early detection of OVCA and non-invasive diagnostic techniques to assess in vivo TAN are needed to detect OVCA at an early stage. Ultrasonography is the currently recommended non-invasive method for the evaluation of ovarian abnormalities, but the difficulty in diagnosing early-stage OVCA impedes conducting of studies to improve the ability of Doppler ultrasonography (DUS) to detect early-stage OVCA in humans. Animal models have been useful for preclinical testing of diagnostic paradigms 10 but the often used rodent models of OVCA do not develop OVCA spontaneously, and the histopathologic characteristics of induced OVCA differs from spontaneous OVCA in humans. 10, 11 Laying hens (Gallus domesticus) develop OVCA spontaneously 12, 13 with similarities to human OVCA in histopathologic characteristics 12, 13 and expression of several markers. The objective of this study was to examine the suitability of ovarian TAN as an in vivo detection target of early-stage OVCA by DUS and to further explore the feasibility of the laying hen as a preclinical model to elucidate the ovarian vascular changes relative to OVCA development.