Suppression of tumorigenicity in an aggressive cervical carcinoma induced by protein zero, a nervous system IgCAM.

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.