A role for stroma-derived annexin A1 as mediator in the control of genetic susceptibility to T-cell lymphoblastic malignancies through prostaglandin E2 secretion.
Cancer susceptibility is essentially attributable to multiple low-penetrance genes. Using interspecific consomic and congenic mice between the tumor-resistant SEG/Pas and the tumor-sensitive C57BL/6J strains, a region on chromosome 19 involved in the genetic resistance to gamma-irradiation-induced T-cell lymphomas (Tlyr1) has been identified. Through the development of nonoverlapping subcongenic strains, it has been further shown that Anxa1 may be a candidate resistance gene on the basis of its differential expression in thymus stroma cells after gamma-radiation exposure. In addition, thymus stroma cells of thymic lymphomas exhibited a significant reduction in the expression levels of Anxa1. Interestingly, the activity of Anxa1 relies on prostaglandin E(2) (PGE(2)) induction that brings about apoptosis in thymocytes. In fact, in vitro transfection experiments revealed that PGE(2) production was enhanced when HEK 293 cells were transfected with full-length cDNAs of Anxa1, with PGE(2) production in the cells transfected with the allele of the resistant strain (Anxa1(Tyr)) being higher than that in cells transfected with the allele of the susceptible strain (Anxa1(Phe)). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4(+)CD8(+)CD3(low) cells in a dose-dependent manner. These results improve our knowledge of the molecular mechanisms triggering T-cell lymphoblastic lymphoma development while highlighting the relevance of the stroma in controlling genetic susceptibility and the use of PGE(2) as a new therapeutic approach in T-cell hematologic malignancies.
Santos
Javier
J
Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain.
González-Sánchez
Laura
L
Matabuena-Deyzaguirre
María
M
Villa-Morales
María
M
Cozar
Patricia
P
López-Nieva
Pilar
P
Fernández-Navarro
Pablo
P
Fresno
Manuel
M
Díaz-Muñoz
Manuel D
MD
Guenet
Jean-Louis
JL
Montagutelli
Xavier
X
Fernández-Piqueras
José
J
D000818:Animals; D017305:Annexin A1 / Q000235:genetics*; D002874:Chromosome Mapping; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D005720:Gamma Rays; D020022:Genetic Predisposition to Disease; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013953:Thymus Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection
D017305:Annexin A1; D015232:Dinoprostone