Spiryda L B, Colman D R
Department of Cell Biology and Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
J Cell Sci. 1998 Nov;111 ( Pt 22):3253-60. doi: 10.1242/jcs.111.22.3253.
In mammals, protein zero (P0), a neural IgCAM, is expressed solely in the peripheral nervous system where it mediates self-adhesion of Schwann cell membranes as compact myelin is generated. We show that when P0 is expressed in HeLa, a cervical carcinoma cell line, cells regain adhesion-mediated growth control, including the acquisition of contact inhibition and loss of anchorage-independent growth. Additionally, P0-expressing HeLa cells lose the ability to invade an artificial matrix, which correlates with decreased secretion of matrix-degrading enzymes. Lastly, and of great interest, unlike the aggressively metastatic cell line from which they were derived, P0-HeLa cells are neither tumorigenic nor metastatic when injected into athymic nude mice. By all these criteria, P0 expression appears to efficiently suppress in the long term, the transformed state of this carcinoma cell line. N-cadherin and its intracellular partners plakoglobin, alpha- and beta-catenin were significantly upregulated in the P0-HeLa cells. It appears therefore that P0 induces epithelialization and suppression of tumorigenicity in HeLa through the activation of the cadherin/catenin signaling systems. We conclude that the forced expression of bona fide adhesion molecules, such as P0, may serve as 'upstream' inducers of an essentially dormant but undamaged adhesion program in carcinoma cells that ultimately triggers the re-acquisition of normal epithelial characteristics, thereby suppressing tumorigenicity. Therapeutically, it may be that intercellular adhesion, no matter how it is induced, may serve as a single master event that is able to induce reversion of the carcinomatous state.
在哺乳动物中，蛋白零（P0）是一种神经免疫球蛋白超家族细胞黏附分子（IgCAM），仅在外周神经系统中表达，在生成紧密髓鞘时介导施万细胞膜的自身黏附。我们发现，当P0在人宫颈癌HeLa细胞系中表达时，细胞恢复了黏附介导的生长控制，包括获得接触抑制和丧失不依赖贴壁的生长能力。此外，表达P0的HeLa细胞失去了侵入人工基质的能力，这与基质降解酶分泌减少有关。最后，也是非常有趣的是，与它们所源自的具有高度侵袭性的转移细胞系不同，将表达P0的HeLa细胞注射到无胸腺裸鼠中时，它们既不具有致瘤性也不具有转移性。根据所有这些标准，P0的表达似乎能长期有效地抑制该癌细胞系的转化状态。N-钙黏蛋白及其细胞内伴侣桥粒斑蛋白、α-连环蛋白和β-连环蛋白在表达P0的HeLa细胞中显著上调。因此，P0似乎通过激活钙黏蛋白/连环蛋白信号系统诱导HeLa细胞上皮化并抑制其致瘤性。我们得出结论，强制表达真正的黏附分子，如P0，可能作为癌细胞中基本处于休眠但未受损的黏附程序的“上游”诱导剂，最终触发重新获得正常上皮特征，从而抑制致瘤性。在治疗方面，可能无论细胞间黏附是如何诱导的，都可能作为一个单一的主要事件，能够诱导癌状态的逆转。
