卵巢癌早期血管生成拟态的靶向超声造影研究

The mortality of ovarian cancer is high and its prognosis depends on early diagnosis. Its early diagnosis is still a worldwide problem today, now various imaging techniques and serological tests are applied to its early diagnosis , but its accuracy and specificity are not high. Researches have shown that early growth of ovarian cancer is related to vascularmimicry (VM) , vascular mimicry(VM) is one of a blood supply structures to malignant tissue which appears prior to tumor angiogenesis ,meanwhile VM is is a new tumor microcirculation mode which is independent of tumor angiogenesis, Early diagnostic purposes can be achieved if we can detect the VM structure within ovarian cancer by targeting ultrasound imaging technique. But so far there is no ultrasound method that can detect tumor VM.VM-targeted contrast agents can be made for the early diagnosis of ovarian cancer by means of matrix metalloproteinase-2 (MMP-2) which specifically expressed in tumor VM structure as the sites of action of tumor VM-targeted contrast agent. Based on the Progress achieved from the preliminary experiments in this study, by means of preparation of targeted contrast agent carrying MMP-2 antibody to observe the targeted ultrasound contrast imaging characteristics of vm at different growth stages of transplanted ovarian carcinoma with common contrast agent and targeted contrast agent through comparing respectively,and compared with VM number which CD31/PAS immune histochemical double staining detects to explore the application of targeted ultrasound contrast agent in ovarian cancer VM furthermore , to provide experimental evidence for improving the mortality and specificity of early diagnosis of ovarian cancer and to make contribution for reducing the mortality of ovarian cancer.

卵巢癌的死亡率高，其预后取决于早诊断早治疗；其早期诊断仍是当今世界性难题，现各种影像技术及血清学检查用于其早期诊断，但准确性及特异性均不高。研究表明卵巢癌的早期生长与血管生成拟态（VM）相关，VM是先于肿瘤新生血管出现的恶性肿瘤组织供血结构，是独立于肿瘤新生血管的一种新的肿瘤微循环模式。但至今尚无检测肿瘤VM的超声方法，根据基质金属蛋白酶-2（MMP-2）在肿瘤VM结构中特异性的表达，将其做为肿瘤VM靶向作用位点，可制作VM的靶向造影剂，用于卵巢癌的早期诊断。基于本研究预实验取得的进展，拟通过制作携MMP-2抗体靶向剂探测卵巢癌早期VM结构，对比观察普通及靶向造影剂在不同生长时期卵巢癌移植瘤VM的造影特征，并与CD31/PAS免疫组化双染法检测VM数目相关比较，进一步探讨靶向超声造影剂在卵巢癌VM中的应用，为提高卵巢癌早期诊断的准确性及特异性提供实验依据，为降低卵巢癌死亡率做贡献

卵巢癌的死亡率高，其预后取决于早诊断、早治疗，其早期诊断仍是当今世界性难题。研究表明卵巢癌的早期生长与血管生成拟态（VM）相关,VM是先于肿瘤新生血管出现的恶性肿瘤组织供血结构，是独立于肿瘤新生血管的一种新的肿瘤微循环模式。但在此之前尚无检测肿瘤VM的超声探查方法，本课题根据基质金属蛋白酶-2（MMP-2）在肿瘤VM结构中特异性的表达，将其做为肿瘤VM靶向作用位点，成功制备制备携MMP-2抗体靶向造影剂，并建立裸鼠卵巢癌移植瘤模型，将此靶向造影剂通过周围静脉注射，按移植瘤不同生长时期随机分为5组，对比观察普通造影剂和此靶向超声造影剂在裸鼠卵巢癌移植瘤VM内的造影特征：我们发现此靶向造影剂在不同时期均表现快进慢出，持续时间长并且造影强度高;在移植瘤早期（14d、21d、28d）此靶向超声造影剂的造影参数PI（峰值强度）、TTP（达峰时间） 较普通造影组更具有优势其差异具有统计学意义（P＜0.05）；14d、21d组肿瘤组织靶向造影参数的PI与MMP-2呈正相关（r=0.86、0.76，P＜0.01、P=0.02），TTP与MMP-2呈负相关（r=-0.84、-0.87，P=0.01、P＜0.01）；结果显示携MMP-2抗体的靶向超声造影剂有助于卵巢癌的早期诊断；进一步采用CD31/PAS免疫组化双染法观察移植瘤不同病理分期VM数目与靶向造影结果的相关比较，发现不同分期卵巢癌血管生成拟态（VM）密度差异有统计学意义（P＜0.01），II期表达最高，I期卵巢癌移植瘤VM与靶向造影参数PI、TTD呈显著正相关（rPI=0.865，rTTD=0.809，P＜0.01），II期也呈明显呈正相关（rPI=0.827,rTTD=0.675，P＜0.05），而III期均无相关性（P＞0.05），由此可见此靶向造影剂对开拓早期卵巢癌诊断具有潜在的应用前景。