Regulatory System of Anchorage-Dependent Cell Growth

癌症的核心特征是所谓的“细胞不受控制的生长”。癌细胞这种独特的生长特性在体外细胞培养系统中可以再现为“细胞的锚定非依赖性生长”。换句话说，这一特征表明存在高度组织化的细胞生长控制系统，该系统需要细胞附着在基质上。随着分子生物学的发展，人们逐渐了解了生长因子调控植物生长的主要机制。相比之下，区分癌细胞与其亲本正常细胞的“锚定非依赖性生长”的机制在很大程度上还不清楚。本项目旨在利用我们最初开发的材料和方法来确定对锚定非依赖性生长至关重要的信号通路。在贴壁或悬浮培养条件下，我们分析了正常和转化细胞生长信号特征的变化。针对这些重要的信号分子，我们开发了它们的显性负性形式和siRNA。利用这些工具，我们表征了肿瘤特异性细胞生长的独特性。通过我们的研究，几个重要的信号分子，如SHPS-1，Stat 3，Ras和FAK参与肿瘤特异性生长。此外，我们还发现SHPS-1/SHP-2信号通路能够促进正常细胞在贴壁条件下的生长，并激活癌细胞的侵袭能力。此外，我们发现正常细胞在悬浮状态下发生凋亡需要caspase系统的参与。锚定依赖性细胞凋亡的信号转导机制是一个亟待解决的问题。

The core feature of cancer is so-called "uncontrolled growth of cell". This unique growth property of cancer cells can be reproduced as "the anchorage-independent growth of cell" in the in vitro cell culture system. This feature, in other word, suggests the presence of highly organized control system of cell growth that requires the attachment of cells to the substratum. The progress of molecular biology enabled us to understand the principal mechanism of growth control by the growth factors. In contrast, the mechanism of "the anchorage-independent growth" that distinguishes cancer cells from its parental normal cells is yet largely unclear. This project aimed to identify the signaling pathways critical for the anchorage-independent growth with our originally developed materials and methods. With normal and transformed cells cultured in attached or suspended conditions, we analyzed the change in the feature of growth signaling. Focusing on the important signaling molecules, we developed their dominant negative forms and siRNAs. With these tools, we characterized the uniqueness of tumor-specific cell growth. By our study, involvement of several important signaling molecules such as SHPS-1, Stat3, Ras and FAK in tumor-specific growth was demonstrated. In addition, we showed that SHPS-1/SHP-2 signaling positively drived the growth of normal cells in attached condition, and activated the invasiveness of cancer cells. Moreover, we found that normal cells in suspended condition were undergone apoptosis that required caspase system. Identification of signaling that control the anchorage-dependent apoptosis is an important problem to be clarified.