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Role of E-cadherin in the progressio...

Margulis, Alexander.

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Role of E-cadherin in the progression of squamous cell carcinoma.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Role of E-cadherin in the progression of squamous cell carcinoma./
Author:	Margulis, Alexander.
Description:	136 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1634.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3131320
ISBN:	0496785621

Role of E-cadherin in the progression of squamous cell carcinoma.
Margulis, Alexander.

Role of E-cadherin in the progression of squamous cell carcinoma. - 136 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1634.

Thesis (Ph.D.)--State University of New York at Stony Brook, 2004.

The purpose of this dissertation was to determine how abrogation of E-cadherin-mediated adhesion influenced the earliest stages of cancer progression in tissues that mimic human, premalignant disease. To accomplish this, organotypic three-dimensional (3-D) cultures with a human cell line that represents an early stage of the transformation process (HaCaT-II-4 cells) were generated. Initial characterization of this cell line showed alterations in E-cadherin-mediated adhesion, as seen by a paucity of cell adhesion structures and decreased association of E-cadherin and beta-catenin with cortical actin, without diminishing the expression and association of E-cadherin and catenins. To further reduce functional E-cadherin, II-4 cells were infected with a recombinant adenovirus, expressing a dominant-negative (DN) form of E-cadherin that lacked its extracellular domain (Ad-ECadDeltaEC). This induced the loss of endogenous E-cadherin and complete disruption of II-4 cell adhesion, as seen by loss of beta-catenin from II-4 cell junctions in 2-D cultures. Three-dimensional tissues generated with these cells demonstrated disruption of tissue architecture, loss of cell-cell adhesion and the invasion of individual tumor cells into the underlying stroma that was associated with loss of basement membrane integrity, as seen by degradation of Type IV collagen and laminin 5. To conduct long-term studies on the response to loss of tumor cell adhesion, II-4 cells were transduced with a retroviral vector encoding chimeric protein consisting of an H-2Kd extracellular domain and cytoplasmic domain of E-cadherin (H-2Kd-Ecad). This generated a DN effect on E-cadherin function in 2-D and 3-D cultures of II-4 cells, as seen by loss of cell-cell adhesion, cytoplasmic redistribution of beta-catenin, increase in migratory and invasive properties, upregulation of MMP expression and MMP-dependent degradation of basement membrane. In contrast, these effects were not seen in cells transduced with an empty vector (pBabe), and a chimeric form of E-cadherin that lacked the ability to bind beta-catenin (H-2Kd-EcadDeltaC25). Surface transplantation of 3-D cultures to nude mice demonstrated that only H-2Kd-Ecad cells showed a transition to a high-grade tumor characterized by aggressive and accelerated invasion in vivo. These findings provide direct evidence that abrogation of E-cadherin-mediated adhesion can mediate the transition from precancer to fully invasive carcinoma in human tissues.

ISBN: 0496785621Subjects--Topical Terms:

1017686
Biology, Cell.

Role of E-cadherin in the progression of squamous cell carcinoma.
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