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Page 8 of 12 Solimando et al. J Cancer Metastasis Treat 2022;8:9 https://dx.doi.org/10.20517/2394-4722.2021.166

Thus, a biomarker profiling for fibrosis onset can also represent an attractive therapeutic target [64,66] .
Moreover, the need for timely and niche-oriented treatment can represent a breakthrough. Multiple targets
directly treat the underlying disease, such as IL-6 inhibition [67,68] . Nonetheless, aging-induced inflammation
is a physiological process involving an inflammatory microenvironment and corrupted angiogenesis [69,70] .
Regarding optimal treatment timing, hemoglobin seems to be a sensitive marker since erythropoiesis is a
sensitive process that is mainly impacted by inflammation. Nevertheless, hemoglobin, transferrin, and
ferritin concentrations should be reviewed and hopefully be made age-specific [71-73] . Cytokine blockade, anti-
inflammatory therapy, anti-senescence therapies, and specific targets for the hematopoiesis-
microenvironment crosstalk are promising approaches . Notably, exercise affects the microenvironment
[74]
[75]
and hematopoiesis and reduces cardiovascular risk . Those results are supported by pre-clinical data
pointing towards a direct role of exercise in decreasing leptin levels. These homeostatic changes halted the
vicious cycle between cell quiescence and decreased hematopoietic output of inflammatory leukocytes’
hematopoietic output through altered chromatin accessibility of cell cycle genes. Indeed, exercise has been
related to increased HSC quiescence, intact niche, and decreased inflammatory cells .
[75]
Context-dependent increase in HSC fitness: cell-intrinsic germline defect
Inherited bone marrow failure, such as somatic mosaicism, represents a paradigmatic example to
understand that the random mutation can involve a group of cells harboring intrinsic germline defects.
Some mutations can be detrimental and others neutral, but HSC fitness can also be increased, leading to
[76]
somatic reversion with partial restoration of normal hematopoiesis . The exact mechanism, in this case,
can be represented by a direct correction, such as in Dyskeratosis congenital, in which a mutation in the
telomerase complex is relatively frequent and somatic mosaicism may lead to the correction of the
mutation, restoration of gene function, and restoration of hematopoiesis . Indirect correction can also be
[77]
realized by partial function restoration, such as in Fanconi anemia. Furthermore, as learned from severe
congenital neutropenia, CSF3R mutation can lead to an augmented granulopoiesis . A fourth example is
[78]
Shwachman-Diamond syndrome, when TP53 mutation or loss of EIF6 is implicated in bone marrow failure
and can lead to partial restoration of hematopoiesis. Unfortunately, some of these mutations also predispose
to MDS and AML. Finally, this unravels how these features of the bone marrow neighborhood are linked to
molecular mechanisms of corrupted vessel formation, cell adhesion, and aggressive phenotype . Crucial
[34]
mechanisms promoting bone marrow niche corruption due to alteration in the vascular and endosteal also
mediate immunosuppression during malignant development and progression [8,79] . As is now well known,
hematopoiesis grows and evolves through constant crosstalk with the surrounding milieu, and emerging
evidence indicates that several gatekeepers and immune-corrupted environments frequently occur
simultaneously in response to this crosstalk between the hematopoietic or committed cells and the vascular
niche as immune-patrolling checkpoint [4,80] . Accordingly, cell-adhesion modulators and strategies
combining vascular-directed therapy and immunotherapy seem to hold promise to tip the balance of the
bone marrow niche and improve patient outcomes [81-85] .

CONCLUSIONS
The survival and commitment of stem cells in the bone marrow are ensured by the hematopoietic niches’
microenvironment, namely the osteoblastic and the perivascular. The control mechanisms of hematopoiesis
are finely regulated at this level and are based on both direct and indirect intercellular communications,
ensuring proper and constant support to stemness. Somatic mosaicism can affect genes crucial in cell
function, such as self-renewal, which may lead to increased HSC clonal expansion observed in aging.
Chronic inflammation, related to several neoplastic and non-neoplastic diseases, causes genetic and
epigenetic changes in the stromal cells and the release of inflammatory cytokines in the microenvironment
of stem niches. The switch toward an inflammatory microenvironment causes direct consequences on the
regenerative capacity and maturation of the same hematopoietic stem cells affecting the hematopoiesis. As