A role for stroma-derived annexin A1 as mediator in the control of genetic susceptibility to T-cell lymphoblastic malignancies through prostaglandin E2 secretion

摘要

Cancer susceptibility is essentially attributable to multiple low-penetrance genes. Using\udinterspecific consomic and congenic mice between the tumour-resistant SEG/Pas and\udthe tumour-sensitive C57BL/6J strains, a region on chromosome 19 involved in the\udgenetic resistance to γ-irradiation-induced T-cell lymphomas (Tlyr1) has been\udidentified. Through the development of non-overlapping sub-congenic strains, it has\udbeen further demonstrated that Anxa1 may be a candidate resistance gene on the basis of\udits differential expression in thymus stroma cells after γ-radiation exposure. In addition,\udthymus-stroma cells of thymic lymphomas exhibited a significant reduction in the\udexpression levels of Anxa1. Interestingly, the activity of Anxa1 relies on prostaglandin\udE2 (PGE2) induction that brings about apoptosis in thymocytes. In fact, in vitro\udtransfection experiments revealed that PGE2 production was enhanced when HEK 293\udcells were transfected with full-length cDNAs of Anxa1, with PGE2 production in the\udcells transfected with the allele of the resistant strain (Anxa1Tyr) being higher than that\udin cells transfected with the allele of the susceptible strain (Anxa1Phe). Furthermore, the\udpresence of this compound in the medium induced apoptosis of immature\udCD4+CD8+CD3low cells in a dose-dependent manner. These results improve our\udknowledge of the molecular mechanisms triggering T-cell lymphoblastic lymphoma\uddevelopment, while highlighting the relevance of the stroma in controlling genetic\udsusceptibility, and the use of PGE2 as a new therapeutic approach in T-cell\udhaematogical malignancies.