c-Met Mediated Ovarian Cancer Cell Motility

描述（由申请人提供）： 在卵巢癌中，与大多数其他实体瘤一样，转移性疾病而不是原发性病变是大多数患者死亡的最常见原因。细胞迁移的HGF/c-Met信号转导失调已被认为有助于肿瘤侵袭和转移。因此，针对HGF/c-Met信号传导的特异性抑制剂对于治疗其中Met活性促成侵袭性/转移性表型的癌症可能具有重要的治疗潜力。最近，已经开发了几种c-Met受体拮抗剂。本研究的目的是研究c-Met特异性ATP竞争性小分子SU 11274对人卵巢癌细胞运动和跨内皮侵袭的影响。我们假设c-Met介导的信号通过改变提供运动实际手段的特定物理过程来影响细胞运动。此外，我们怀疑虽然c-Met的作用因细胞类型而异，但抑制c-Met可能会显著抑制表达高水平活化c-Met的卵巢癌细胞的运动性和侵袭性。该项目将通过使用电细胞基质阻抗传感（ECIS）来促进，ECIS是一种新型的基于细胞的生物传感器，可以监测粘附在小金电极上的细胞的形态变化。该方法将与我们在荧光成像、ECM包被的聚丙烯酰胺底物和数字图像分析方面的既定能力相结合，以表征对SU 11274的各种细胞反应。具体目标是：1.确定活化的c-Met对细胞迁移速度和/或方向持久性的影响。2.确定激活的c-Met对细胞收缩力和形态的影响。3.确定SU 11274灭活c-Met对卵巢癌细胞跨内皮侵袭的影响。这项研究将为激活的c-Met在人卵巢癌细胞转移行为中的功能作用提供新的信息。这些结果将有助于更广泛的目标，即开发一种新的针对卵巢癌和其他形式癌症的分子靶向抗癌疗法。

DESCRIPTION (provided by applicant): In ovarian cancer, as in most other solid tumor, metastatic disease rather than the primary lesion is the most common cause of death of the majority of patients. Dysregulated HGF/c-Met signaling of cell migration has been suggested to contribute to tumor invasion and metastasis. Specific inhibitors against HGF/c-Met signaling, therefore, may have important therapeutic potential for the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype. Recently, several c-Met receptor antagonists have been developed. The goal of the proposed research is to investigate the effects of a c-Met specific ATP-competitive small-molecule SU11274 on human ovarian carcinoma cell motility and transendothelial invasion. We hypothesize that c-Met- mediated signals affect cell motility by altering specific physical processes which provide the actual means for movement. Moreover, we suspect that although the role of c-Met varies from cell type to cell type, inhibition of c-Met may significantly inhibit motility and invasive activity in ovarian cancer cells expressing high levels of activated c-Met. The project will be facilitated by the use of electric cell-substrate impedance sensing (ECIS), a novel cell-based biosensor that monitors morphological changes of cells adherent on small gold electrodes. This approach will be combined with our established ability in fluorescence imaging, ECM coated polyacrylamide substrate, and digital image analysis to characterize a variety of cellular responses to SU11274. The specific aims are: 1. To determine the effect of activated c-Met on cell migration speed and/or directional persistence. 2. To determine the effect of activated c-Met on cell contractile force and morphology. 3. To determine the effect of c-Met inactivation by SU11274 on the transendothelial invasion of ovarian cancer cells. The proposed research will provide new information regarding the functional role of activated c- Met in metastatic behaviors of human ovarian carcinoma cells. The results will contribute to a broader goal of developing a new molecularly targeted anti-cancer therapy for ovarian cancer and possibly other forms of cancer.