TY - JOUR
T1 - Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche
AU - Colombo, Michela
AU - Galletti, Serena
AU - Bulfamante, Gaetano
AU - Falleni, Monica
AU - Tosi, Delfina
AU - Todoerti, Katia
AU - Lazzari, Elisa
AU - Crews, Leslie A.
AU - Jamieson, Catriona H M
AU - Ravaioli, Sara
AU - Baccianti, Francesco
AU - Garavelli, Silvia
AU - Platonova, Natalia
AU - Neri, Antonino
AU - Chiaramonte, Raffaella
PY - 2016
Y1 - 2016
N2 - Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.
AB - Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.
KW - Bone marrow niche
KW - Interleukin-6
KW - Jagged
KW - Multiple myeloma
KW - Notch signaling
KW - Pathology Section
UR - http://www.scopus.com/inward/record.url?scp=84984873609&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984873609&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10820
DO - 10.18632/oncotarget.10820
M3 - Article
AN - SCOPUS:84984873609
VL - 7
SP - 56013
EP - 56029
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 35
ER -