Carcinogenesis Advance Access published online on December 24, 2005
Carcinogenesis, doi:10.1093/carcin/bgi331
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1 Laboratorio de Genética Molecular Humana, Departamento de Biología, Universidad Autónoma de Madrid, 28049-Madrid, España
* To whom correspondence should be addressed. Aberrant expression of some tumour suppressor genes and oncogenes by thymocytes had been involved in the development of primary thymic lymphomas induced by
Received October 25, 2005
Revised November 22, 2005
Accepted December 20, 2005
CARCINOGENESIS
Epigenetic silencing of E- and N-cadherins in the stroma of mouse thymic lymphomas
M. Matabuena de Yzaguirre 1,
J. Santos Hernández 1,
P. Fernández Navarro 1,
P. López Nieva 1,
M. Herranz 2,
M. F. Fraga 2,
M. Esteller 2 *,
A. Juarranz 3,
and
J. Fernández-Piqueras 1
2 Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
3 Unidad de Biología Celular, Departamento de Biología, Universidad Autónoma de Madrid, 28049-Madrid, España
M. Esteller, E-mail: mesteller{at}cnio.es
Abstract 
-irradiation, but genetic alterations affecting critical genes expressed by stromal cells have not been yet explored. This paper analyzes a series of such tumours induced in C57BL/6J and in F1 hybrids of BALB/c and C57BL/6J mouse strains. As expected, hystopathological analyses revealed profound disorganizations within the thymus with a poor demarcation of the cortical and medullar areas. Immunological and quantitative on line RT-PCR analyses confirm that E-cadherin (Cdh1) is essentially expressed by stromal cells of the thymus, while evidencing that the expression of this gene is significantly reduced in all tumours. In addition, and contrary to what one would expect, N-cadherin (Cdh2) that is exclusively expressed by stromal cells is likewise down-regulated in most of the thymic lymphomas. Although hypermethylation of the promoter region appears to be involved in the inactivation of Cdh2 in all tumours, additional epigenetic mechanisms mediated by repressors such as Snai1 may also play a role in Cdh1 silencing. These results represent the first reported case for tumor-associated gene alterations occurring not in the tumor cells per se, but in the stromal cells of primary thymic lymphomas. Additionally, since the expression of both genes is significantly up-regulated after a single-high dose of -radiation, but remained unchanged in treated thymic-lymphoma-free-mice, epigenetic down-regulation of E- and N-cadherin appears to occur concomitantly with the progression towards the most advanced stages of -radiation-induced thymic lymphomas.-radiation; Stroma-epithelial-cells; E- and N-cadherins; Epigenetic regulation.
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