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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 7 of 15

Notch and drug-resistance
Relapse and refractory MM are hallmarks of MM disease, but the mechanisms underlying the development
of drug resistance in MM are still under investigation. Disease relapse can be a consequence of the presence
of drug-resistant MM clones initially present and/or emerging in the course of treatment [67,68] . MM
refractory chemotherapy mechanisms are complex, and may involve a combination of genetic and
epigenetic alterations, dysregulation of pathways involved in drug transport and cell death programs, and
the presence of drug-resistant cancer stem cells or dormant cells [67,68] .

The focus of the research in drug-resistance has recently shifted towards the identification of protective
mechanisms initiated by the marrow microenvironment [67,68] . Growing evidence supports an active role of
Notch signals, particularly from stromal cells, in the acquisition of a drug-resistant phenotype in MM cells.
Jagged 1-mediated activation of Notch signaling in MM cells by stromal cells is sufficient to protect MM
[69]
cells from melphalan- and mitoxantrone-induced apoptosis . This protective effect appears to be mediated
by Notch receptor 1 and not by Notch receptor 2, as overexpression of Notch receptor 1 in MM cells
[69]
prevents melphalan- and mitoxantrone-induced MM cell death . Dll 1 signaling, through Notch receptor
[62]
2, has been shown to contribute to drug resistance to bortezomib, in both murine and human MM cells .
In vitro and in vivo studies demonstrated that both intrinsic and stroma-mediated drug resistance to
bortezomib, lenalidomide, and melphalan also require Jagged ligands in MM cells [70,71] . Notch signals may
also contribute to the development of resistance to mitoxantrone as inhibition of Notch signaling with GSI
[50]
overcame the drug resistance to mitoxantrone induced by stromal cells . Although in this case the ligand-
receptor requirements were not evaluated, this effect appeared to be mediated by the transcriptional activity
of the Notch target gene Hes1 . Notch signaling, in particular Notch receptor 1, is also required for
[49]
resistance to doxorubicin. In this case, Notch receptor 1 regulates the expression of integrin αvβ5 in MM
cells, which enhances MM cell adhesion to vitronectin . Silencing Notch receptor 1 or blocking integrin
[72]
αvβ5 with an antibody reduced MM cell adhesion to vitronectin and reverted in MM cells the protection
from doxorubicin pro-apoptotic effects conferred by adhesion to vitronectin . Importantly, blocking the
[72]
Notch pathway with GSIs has been shown to prevent stroma-induced drug resistance by increasing
sensitivity of MM cells to bortezomib, doxorubicin, and melphalan in cell cultures and animal models of
MM [50,62,69] . Together, these studies suggest that specific Notch ligand-receptor signals confer resistance to
different anti-MM drugs, an observation that could be exploited in the clinic to overcome drug resistance to
particular therapies. Thus, the addition of Notch inhibitors to chemotherapy might be an interesting
strategy to increase drug sensitivity in refractory MM patients. Nonetheless, animal and clinical studies are
needed to determine the potential of targeting Notch inhibition to prevent or delay disease relapse in MM.

Notch and angiogenesis
Angiogenesis, the process of new blood vessel formation from the existing vasculature, is necessary for the
growth of MM cells [73-75] . Microvessel density is remarkably higher in the marrow of MM patients compared
to those with MGUS or healthy subjects [73-75] . Neovessel density correlates with the disease stage and shrinks
during remission, increasing again during the relapse/refractory phase, and reaching maximum expansion
in PLC [73-75] . Elevated levels of marrow angiogenesis correlate with decreased MM patient survival .
[76]
Angiogenesis is regulated by a broad spectrum of locally produced factors, with Vegf (A-E) members being
main drivers of this process in MM . Vegf factors bind to Vegf receptors 1-3, activate endothelial cells, and
[75]
[77]
initiate angiogenesis . The bone marrow microenvironment in MM also facilitates angiogenesis because it
is extremely hypoxic, which stimulates the production and release of Vegf.
Recent evidence suggests that Notch signals between MM cells, marrow cells, and endothelial cells can
contribute to angiogenesis in MM. Endothelial cells from MM patients exhibit higher expression of Jagged 1
and 2, Notch receptors 1 and 2, and Notch target genes than endothelial cells from MGUS patients [78,79] . In