Notch deregulation occurs in several solid and hematopoietic tumors. Recently, Notch receptor oncogenic role has been shown to be critical in multiple myeloma (MM) which frequently displays over-expression of the Notch ligand, Jagged2. MM is a malignant disorder in which the tumor microenvironment plays a critical role: in this contest, Ig-secreting plasma cells accumulate in the bone marrow where they interacts with stroma and BM cells.
The cross-talk between MM cells and BM milieu activates signaling such as chemokines and their receptors (CRs) pathways that mediate growth, survival and migration of MM cells, cell-adhesion-mediated drug resistance (CAM-DR) and finally bone lesions trough hyper-stimulation of osteoclasts (OCLs) activity.
In our study we took advantage of a panel of MM and bone marrow stromal (BMSC) cell lines and investigated the effects of the Notch signaling withdrawal on MM cell and several chemokine systems. Inhibition of Notch activity, obtained by treatment with gamma-secretase inhibitor (GSI) or Jagged 1 and 2 knock-down indicated that Notch down-regulation hampers MM cell growth, arresting cell cycle progression and inducing increase of apoptosis.
Moreover the effects of Notch inhibition on the expression of a number of CRs and correspondent ligands which display a relevant role in MM were investigated: mRNA and protein expression of CXCR4 and SDF-1 were under Notch control. Functional consequences of Notch inhibition were analyzed: GSI XII inhibits SDF1-dependent chemotaxis and proliferation of MM cells.
Afterwards, the role of Notch in the MM cells relationship with the BM microenvironment was investigated trough co-culture assays. Our results show that Notch is able to control the cross-talk between MM and BMSCs trough the modulation of SDF-1 and other soluble factors produced by stroma, initiating in this way, a surviving loop.
Thus, Notch pathway is able to modulate the MM cell proliferation, apoptosis and migration by directly deregulating the CXCR4/SDF-1 axis activity and the cross-talk between MM cells and BMSCs
