Induction of epithelialization and suppression of tumorigenicity in an aggressive carcinoma by protein zero, a nervous system IgCAM.
Item
-
Title
-
Induction of epithelialization and suppression of tumorigenicity in an aggressive carcinoma by protein zero, a nervous system IgCAM.
-
Identifier
-
AAI9908366
-
identifier
-
9908366
-
Creator
-
Spiryda, Lisa Beth.
-
Contributor
-
Adviser: David R. Colman
-
Date
-
1998
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Cell | Health Sciences, Medicine and Surgery | Biology, Neuroscience
-
Abstract
-
HeLa is an aggressive cervical carcinoma that lacks the features of a normal epithelium. It proliferates in an anchorage-independent manner, secretes high amounts of matrix degrading enzymes, and is highly invasive and tumorigenic. In the peripheral nervous system, Protein Zero (P{dollar}\sb0{dollar}), a homophilic IgCAM, mediates self-adhesion of Schwann cell membranes as they enwrap axons and generate compact myelin. P{dollar}\sb0{dollar} expression in HeLa led to ultrastructural rearrangements and biochemical changes consistent with epithelial junction formation suggestion that this carcinoma morphologically reverted to an epithelial-like phenotype.;My thesis was directly focused on determining the functional significance of these morphologic changes. I found that P{dollar}\sb0{dollar} expression not only triggered the normal morphological features found in epithelia, but also re-engaged the characteristic physiology of epithelia. Constitutive P{dollar}\sb0{dollar} expression in HeLa cells restores several important aspects of normal epithelial cell physiology, including functional tight functions, cell polarity, contact inhibition, and adhesion-mediated growth control. Of greatest interest, HeLa cells constitutively expressing P{dollar}\sb0{dollar} did not form tumors in athymic nude mice. This IgCAM elicits an inherent but dormant or "sluggish" intracellular pathways which, when activated, triggers epithelialization and the suppression of the tumorigenic and transformed properties of this cervical carcinoma cell line. Since N-cadherin, plakoglobin, {dollar}\alpha{dollar}-catenin and {dollar}\beta{dollar}-catenin were significantly upregulated in the P{dollar}\sb0{dollar}-HeLa cells, it appeared that P{dollar}\sb0{dollar} mediated epithelialization in HeLa through activation of N-cadherin/catenin signaling systems. I showed that the expression of N-cadherin in HeLa also restored the morphological and physiologic characteristic of epithelia. Additionally, in this cervical carcinoma, E-cadherin expression could substitue for N-cadherin and elicited an identical sequence of events leading to complete reversion of tumorigenicity.;By all these criteria, P{dollar}\sb0{dollar} expression appears to augment functional epithelial junction formation and efficiently suppress long term, the transformed state of this carcinoma cell line. It can be concluded that the forced expression of bona fide adhesion molecules, such as P{dollar}\sb0{dollar}, may serve as "upstream" inducers of an essentially dormant but undamaged cadherin-based adhesion program in carcinoma cells that ultimately triggers them to regain and maintain normal epithelial characteristics thereby suppressing tumorigenicity.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
