Bates R C, Elith C A, Thorne R F, Burns G F
Cancer Research Unit, Faculty of Medicine, University of Newcastle, New South Wales, Australia.
Cell Adhes Commun. 1998 Jun;6(1):21-38. doi: 10.3109/15419069809069758.
The LIM 1863 colon carcinoma cell line grows as structured organoids around a central lumen, and we have previously demonstrated that the three-dimensional arrangement protects the individual cells from apoptosis induced by an anti-alpha v integrin antibody, 23C6 (Bates et al., 1994). Here we show that the intercellular forces which drive spheroid formation can be overcome by exposure of the cells to a collagen substrate, or more specifically through ligation of the CD44 receptor by a monoclonal antibody. Binding to immobilized anti-CD44 antibody induced a monolayer morphology which is accompanied by fibronectin production and secretion, and expression of the integrin alpha v beta 6. Significantly, the cells of the monolayer acquired resistance to 23C6 antibody-mediated apoptosis over time and this property was sustained even after removal from the monolayer. We provide data to show that this resistance is not dependent on monolayer morphology, constant engagement of the CD44 receptor, loss of the 23C6 antigen, or elevation of Bcl-2 or Bcl-XL protein. The CD44 expressed by LIM 1863 is shown to be the metastatic variant of the molecule therefore these results provide a possible explanation for the selective advantages conferred by expression of this variant for metastasizing colon cancer cells. Overall, the findings of this study support a model for the development of malignancy through the production of specific survival and growth signals as a direct consequence of a signaling event induced by stimulation of an epithelial variant of CD44.
LIM 1863结肠癌细胞系围绕中央管腔生长形成结构化类器官，我们之前已经证明这种三维排列可保护单个细胞免受抗αv整合素抗体23C6诱导的凋亡（Bates等人，1994年）。在此我们表明，驱动球体形成的细胞间力可通过将细胞暴露于胶原底物来克服，或者更具体地说，通过单克隆抗体连接CD44受体来克服。与固定化抗CD44抗体结合诱导形成单层形态，伴随纤连蛋白的产生和分泌以及整合素αvβ6的表达。值得注意的是，单层细胞随着时间的推移获得了对23C6抗体介导的凋亡的抗性，并且即使从单层中移除后这种特性仍能维持。我们提供的数据表明，这种抗性不依赖于单层形态、CD44受体的持续结合、23C6抗原的丧失或Bcl-2或Bcl-XL蛋白的升高。LIM 1863表达的CD44被证明是该分子的转移变体，因此这些结果为这种变体的表达赋予转移结肠癌细胞的选择性优势提供了一种可能的解释。总体而言，本研究结果支持一种恶性肿瘤发展模型，即通过刺激CD44上皮变体诱导的信号事件直接产生特定的存活和生长信号。
