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Sabol et al. J Cancer Metastasis Treat 2021;7:20 https://dx.doi.org/10.20517/2394-4722.2021.35 Page 11 of 15

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.

inhibition of this pathway in other tissues have precluded the approval of GSI for the clinical care of MM
patients. Although there are clinical trials evaluating the effects of targeting individual Notch components in
other cancers, improved and safer strategies to target this pathway for the treatment of MM are still needed.
Novel approaches to effectively and safely target Notch are currently under development to exploit this
pathway in the clinic. In addition, more studies are required to determine if the combination of Notch
inhibitors with other anti-MM therapeutics can delay/prevent disease relapse, repair damaged bone, and
improve patient outcomes.

DECLARATIONS
Acknowledgments
We acknowledge Drs. Manish Adhikari and Amy Y. Sato (University of Arkansas for Medical Sciences) for
critical review and editing of the manuscript.

Authors’ contributions
Made substantial contributions to conception and design of this review: Delgado-Calle J
Original draft preparation: Sabol HM, Delgado-Calle J
Writing, review, and editing of manuscript: Sabol HM, Delgado-Calle J
Performed literature research: Sabol HM, Delgado-Calle J

Availability of data and materials
Not applicable.