The Notch pathway in tumor cell migration

This work aims to elucidate the relationship between two pathways which play a role both in stem cells and when deregulated in cancer: the pathway of Notch1 (Annu.Rev.Immunol. 23: 945) and the CC Chemokine Receptor 9 (CCR9) signaling. CCR9 is expressed in thymic multipotent precursors (TMP) which have the potentiality to give rise to T, B and dendritic cells (J.Exp.Med. 202: 21). The CCR9 agonist CCL25 is expressed by thymic stromal cells and mediates TMP localization in the thymic sub-capsular zone. CCL25 expression in the gut is also responsible for mature CCR9+ lymphocytes localization at this site and explains relapse location of CCR9+ leukemic cells in the gut (Blood 103: 2806); furthermore CCR9 affects prostate cancer cell migration and invasion (Clinical Cancer Res. 10: 8743). Through the siRNA technique and the use of DAPT, as inhibitor of Notch1 activation, we demonstrated that CCR9 expression in T-ALL cell lines is sustained by Notch1 signaling, and that Notch1 plays a role in CCR9-mediated biological effects such as CCL25-induced chemotaxis and anti-apoptotic effect. This evidence suggests that the integrated activities of these pathways during oncogenesis may allow leukemic stem cells to escape apoptosis and migration at specific sites.