Barua Animesh, Edassery Seby L, McNeal Sa'Rah, Bahr Janice M, Bitterman Pincas, Basu Sanjib, Sharma Sameer, Abramowicz Jacques S
Departments of *Pharmacology, †Obstetrics and Gynecology, and ‡Pathology, Rush University Medical Center, Chicago; §Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana; ∥Department of Preventive Medicine (Biostatistics), Rush University Medical Center, Chicago, IL; and ¶Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI.
Int J Gynecol Cancer. 2016 Oct;26(8):1375-85. doi: 10.1097/IGC.0000000000000784.
The lack of an effective early detection test leads to high case to death ratio of women with ovarian cancer (OVCA). To improve early detection, tumor-associated imaging targets need to be established and imaging agents to image these targets need to be developed. Targeted imaging agents offer potential for improvement of signal intensities from their targets. Expression of death receptor 6 (DR6) by ovarian malignant cells and tumor-associated microvessels increases during OVCA development and represents a novel target for ultrasound imaging. The goal of this study was to examine the feasibility of newly developed DR6-targeted ultrasound imaging agents in enhancing early detection of ovarian tumors in laying hen model of spontaneous OVCA.
The study was conducted in an exploratory cross-sectional design using 4-year-old laying hens (n = 130). DR6-targeted imaging agents were developed by conjugating microbubbles with rabbit anti-chicken DR6 antibodies. Changes in signal intensity of ultrasound imaging were determined before and after injection of targeted imaging agents in hens with or without spontaneous OVCA. Following targeted imaging, normal or tumor ovaries were processed for histopathological and immunohistochemical studies.
DR6-targeted imaging agents bound with their targets expressed by malignant cells and tumor-associated microvessels in the ovary. Compared with pretargeted imaging, targeted imaging is enhanced by approximately 40% ultrasound echo signal intensity (P < 0.001) from early- and late-stage OVCA. Differences in signal enhancement were not observed among different histological subtypes of OVCA at early or late stages. Higher imaging signal intensities were associated with enhancement in DR6 expression by ovarian malignant cells and increase in the frequency of DR6-expressing microvessels during OVCA development.
The results of this study suggest that DR6-targeted imaging agents enhance the visualization of ovarian tumors and tumor-associated microvessels in hens with early-stage OVCA and will form a foundation for clinical studies.
缺乏有效的早期检测方法导致卵巢癌（OVCA）女性患者的病死率较高。为了改善早期检测，需要确定肿瘤相关成像靶点，并开发针对这些靶点的成像剂。靶向成像剂有望提高其靶点的信号强度。卵巢恶性细胞和肿瘤相关微血管中死亡受体6（DR6）的表达在OVCA发展过程中增加，是超声成像的一个新靶点。本研究的目的是检测新开发的靶向DR6的超声成像剂在自发性OVCA蛋鸡模型中增强卵巢肿瘤早期检测的可行性。
本研究采用探索性横断面设计，使用4岁的蛋鸡（n = 130）。通过将微泡与兔抗鸡DR6抗体偶联，开发了靶向DR6的成像剂。在注射靶向成像剂前后，测定有无自发性OVCA的蛋鸡的超声成像信号强度变化。靶向成像后，对正常或肿瘤卵巢进行组织病理学和免疫组织化学研究。
靶向DR6的成像剂与卵巢中恶性细胞和肿瘤相关微血管表达的靶点结合。与预靶向成像相比，靶向成像使早期和晚期OVCA的超声回波信号强度增强约40%（P < 0.001）。在早期或晚期，不同组织学亚型的OVCA之间未观察到信号增强差异。较高的成像信号强度与卵巢恶性细胞DR6表达增强以及OVCA发展过程中表达DR6的微血管频率增加有关。
本研究结果表明，靶向DR6的成像剂可增强早期OVCA蛋鸡卵巢肿瘤和肿瘤相关微血管的可视化，为临床研究奠定基础。
