循环肿瘤细胞在血管内膜的粘附和孕卵在子宫内膜的着床的相似性：预防肿瘤转移的新思路

The cancer death rates were not significantly reduced although the total number of the global cancer survivors multiplied in the past 50 years. This fact suggests the hopelessness of the current cancer treatments once cancer metastasizes over the body. To circumvent the incurability of the late metastases, we have to propose a novel conception, i.e., cancer pre-metastasis chemoprevention following cancer surgery. Inspired by the large epidemiological survey that concluded that using oral abortion pills for a long term could reduce the cancer risks, and by our experimental findings that abortifacients (including the Chinese abortion herbs) could indeed prevent cancer metastasis induced by the circulating tumor cells (CTC), we hypothesize some similarities in cell/microenvironment interplay between the adhesion of circulating tumor cells to vascular endothelium and the implantation of blastocyst to endometrium. The present application aims at interdisciplinarily investigating the molecular and cellular similarities between reproduction system and tumor system after establishing the reproduction models of blastocyst implantation to endometrium and mouse gestation, as well as CTC adhesion to endothelium and mouse cancer metastasis; identifying the common proteins secreted from the two systems after hetero-cellular adhesions; studying the mechanisms underlying the effects of related factors and abortifacients on the hetero-cellular adhesion process; demonstrating in parallel the effects of abortifacients on the two mouse models; clarifying our novel strategy that if we interrupt the starting point of cancer metastasis cascade, i.e., CTC adhesion to vascular endothelium, we could prevent the metastasis from happening. The study will open a new avenue by interdisciplinarily studying cancer pre-metastasis chemoprevention and pregnancy control, and re-purpose abortifacients.

50年来肿瘤手术后幸存者的总数成倍增长，但肿瘤死亡率未见显著下降，提示肿瘤再转移的极难治愈性。欲破解这一难题，我们提出在肿瘤手术后提前用药预防再转移的新思路。在国外大规模普查得出口服避孕药可降低癌症风险的启迪下，在我们前期证明避孕药可预防循环肿瘤细胞（CTC）诱发的肿瘤转移的基础上，我们假设孕卵在子宫内膜着床和CTC在血管内膜粘附之间存在细胞/微环境互动的生物相似性。本课题拟通过构建孕卵在子宫内膜着床与动物妊娠的生殖体系，和癌细胞在血管内膜粘附与癌转移动物模型的肿瘤体系，跨学科地研究二大体系的分子细胞学共性，发现细胞着床后二大体系的共性分泌蛋白，研究各种相关因子和避孕药对着床过程的调控，在二类动物模型上同步研究避孕药的药理作用，阐明我们提出的干预CTC粘附血管内膜的起始步骤即可遏制肿瘤转移级联反应的战略思路。本课题可开启肿瘤转移药物预防和生育调控二大领域交叉融合的新篇章，挖掘避孕药宝库。

项目背景：如何安全、有效地干预CTC诱发的肿瘤转移是一项全球性的理论、技术和产品的空白。在国外大规模普查得出口服避孕药可降低癌症风险的启迪下，在我们前期证明避孕药可预防CTC诱发的肿瘤转移的基础上，我们假设孕卵在子宫内膜着床和CTC在血管内膜粘附之间存在细胞分子生物学的相似性。本课题拟证明这2个体系、过程的生物相似性。.主要研究内容：1. 研究孕卵在子宫内膜的着床和癌细胞在血管内皮的粘附之间的细胞形态学的异同。2. 研究孕卵和子宫内膜共孵育、癌细胞和血管内皮共孵育时二个体系共同产生的具有共性的分泌蛋白及其生物学功能。3.在孕卵着床和癌细胞粘附二类动物模型上同步研究避孕药的药理作用。.重要结果和关键数据：用细胞显微镜、激光共聚焦显微镜、扫描电子显微镜观察、比较孕卵在子宫内膜的着床和癌细胞在血管内皮的粘附之间的细胞形态学的异同。对比了2个系统中15余种细胞分子表达的水平，结果显示人的孕卵细胞JEG-3和人的乳腺癌细胞MCF-7细胞均表达高sLex、CD47和细胞粘附分子，而子宫内膜细胞RL95-2和人内皮细胞HUVEC均显著高表达整合素和细胞粘附分子ICAM-1。接近生理浓度的17β-雌二醇和孕酮通过上调整合素、MMP促进JEG-3和MCF-7细胞的迁移和侵袭。而避孕药米非司酮和美她司酮显著抑制JEG-3和MCF-7的迁移和侵袭，并分别抑制JEG-3和MCF-7与细胞基质、与子宫内膜细胞RL95-2和人内皮细胞HUVEC的粘附。抑制作用是通过下调JEG-3和MCF-7细胞中的sLex和MMP，和下调RL95-2和HUVEC中的整合素而实现的。米非司酮和米非司酮对小鼠胚胎着床和癌细胞转移动物模型均有同样的抑制作用。.科学意义：系统地解析和诠释这二个不同体系生物微环境的相似性，可奠定将避孕药用于预防 CTC 诱导的肿瘤转移的药理学基础，开创性地解决基础研究和应用研究的共性问题。