Page 44 - Read Online

Tosato et al. J Cancer Metastasis Treat 2021;7:52 https://dx.doi.org/10.20517/2394-4722.2021.120 Page 7 of 14

[59]
bone marrow .

There is instead considerable evidence that the bone marrow microenvironment is altered when malignant
cells are present, and that malignant cells can drive change in the bone marrow microenvironments in
which they reside. These changes involve primarily the mesenchymal and endothelial cell components of
the niche.

Mesenchymal cells
Compared to age-matched healthy controls, mesenchymal stem cells (MSCs; defined as bone marrow cells
capable of differentiating into cartilage, bone, and fat) derived from MDS or AML bone marrows display a
reduced proliferative capacity, altered cell surface marker profile and disrupted secretory function,
particularly for osteopontin, Kit-ligand (Kitl/SCF), vascular endothelial growth factor-A (VEGF), placental-
d e r i v e d g r o w t h f a c t o r ( P l G F / P G F ) , a n g i o p o i e t i n s , i n f l a m m a t o r y c y t o k i n e s
(including IL-1β, IL-6, and TNFα), and chemokines (including CXCL12 and CCL3); these alterations in
MSCs, typically associated with senescence, have been implicated in increased malignant cell survival and
resistance to immune recognition and chemotherapy [57,60-67] . Clonal hematopoiesis associated with aging is
often associated with a pro-inflammatory bone marrow stroma, in part because the same mutations that
cause clonal expansion of hematopoietic cells also lead to increased expression of pro-inflammatory
[37]
genes .

In AML, bone marrow “stroma” is focally depleted, particularly in endosteal areas with high infiltration of
[68]
tumor cells, suggesting that AML cells remodel the stroma when present in sufficient number . Progressive
depletion of bone marrow stroma is associated with a progressive loss of healthy HSC and osteoblastic
cells . Consistent with these observations in vivo, MDS-derived MSCs display a reduced capacity to
[68]
+
support the survival of co-cultured normal CD34 HSC. This defect was linked to epigenetic and
transcriptional changes in MDS-derived MSCs . The addition of a hypomethylating agent to co-cultures of
[66]
+
+
normal CD34 cells and MDS-derived MSCs corrected the CD34 cell deficiency . MSC-derived exosomes
[66]
may mediate the communication of MDS-MSC with normal HSC . In turn, there is evidence that healthy
[69]
MSCs adopt phenotypic characteristics of MDS-derived MSCs when exposed to hematopoietic cells from
MDS patients, providing evidence that MDS hematopoietic cells display a pathogenic instructive
phenotype [65,67] .
An example of a pathogenic axis linking AML cells with bone marrow stromal cells involves the tyrosine
kinase Axl receptor. In this example, AML cells prompt secretion of Gas6 (growth arrest-specific 6) protein
+
from stromal cells. Gas6 promotes proliferation, survival and chemoresistance of Axl AML cells . Secreted
[70]
factors, exosomes and vesicular particles derived from malignant hematopoietic cells were found to be
mediators of MSCs remodeling in the malignant bone marrow. Extracellular vesicles derived from
malignant AML clones were reported to contribute to re-shaping the niche into a leukemia-permissive
microenvironment by inhibiting production of HSC-supportive factors [71,72] . AML-derived extracellular
vesicles were also found to transmit endoplasmic reticulum stress to the bone marrow stroma and to
[73]
promote MSC differentiation into osteo-lineage cells through bone morphogenic protein 2 . In addition,
tunneling nanotubules could facilitate direct transfer of mitochondria from bone marrow stromal cells to
the leukemic cells . An example of three-way crosstalk between malignant hematopoietic cells,
[74]
sympathetic nerves, and stromal cells links AML-induced disruption of sympathetic nerves and secondary
effects on bone marrow mesenchymal cells expressing beta2 adrenergic receptors (β adrenoreceptor) [64,75] .
2
Thus, it seems that the malignant cells in the bone marrow drive change in the mesenchymal cell
microenvironment, and the affected mesenchymal cells can, in turn, propagate change in the normal bone