The multifunctional role of Notch signaling in multiple myeloma

Abstract

Multiple myeloma (MM) is a hematologic cancer characterized by uncontrolled growth of malignant plasma cells in the bone marrow and currently is incurable. The bone marrow microenvironment plays a critical role in MM. MM cells reside in specialized niches where they interact with multiple marrow cell types, transforming the bone/bone marrow compartment into an ideal microenvironment for the migration, proliferation, and survival of MM cells. In addition, MM cells interact with bone cells to stimulate bone destruction and promote the development of bone lesions that rarely heal. In this review, we discuss how Notch signals facilitate the communication between adjacent MM cells and between MM cells and bone/bone marrow cells and shape the microenvironment to favor MM progression and bone disease. We also address the potential and therapeutic approaches used to target Notch signaling in MM.

Keywords: Notch; bone; multiple myeloma; osteoblasts; osteoclasts; osteocytes; tumor microenvironment; γ-secretase inhibitors.

Figure 1.

Activation of the canonical Notch signaling pathway. Notch mediates the transmission of near-range signals by physical contact between adjacent cells. The sending signal cell expresses Notch ligands that bind to Notch receptors in the receiving signal cell. Upon binding, the intracellular portion of the Notch receptor undergoes sequential proteolytic cleavage by Adam enzymes and the γ-secretase complex. The cleavage by the γ-secretase complex frees the Notch intracellular domain (NICD) from the transmembrane Notch domain and it translocates to the nucleus. In the nucleus, NICD promotes a transcriptional switch by binding to RbpjK and displacing of co-repressors and promoting the recruitment of MAML proteins and other transcriptional activators, activating the gene transcription of Notch target genes of the Hes and Hey families.

Figure 2.

The multifunctional role of Notch signaling in multiple myeloma (MM). MM cells exhibit increased expression of Notch components that help them to receive and transmit near-range signals from and to adjacent cells. Homotypic Notch communication between MM cells increases MM cell proliferation. Tumor growth is further supported by Notch signals received by stromal cells and osteocytes. In addition, MM cells enhanced angiogenesis via sending pro-angiogenic Notch signals to endothelial cells, stromal cells, and osteocytes. The increased angiogenesis in turn aids tumor growth by providing nutrients to the tumor. Both homotypic and heterotypic (from stromal cells) Notch signals confer drug-resistance to MM cells and promote MM cell survival. Moreover, Notch signals from and to bone cells contribute to the progression of the MM-induced osteolytic bone disease.