Throughout the course of tumor evolution, a vast group of host cells, ranging from
fibroblasts to macrophages, sustain a supportive TME for disease progression, specifically
by interfering immunosurveillance against cancer cells 55]. Among these disease-favorable stromal cells, several subpopulations are virtually
bone marrow-derived cells (BMDCs) and frequently implicated in tumor expansion via
homing to the primary site as active components of the local TME. Being a typical
representative of BMDCs but still keeping differentiation potential, MSCs mainly derive
from the bone marrow but are indeed resident in virtually all organs and mature tissues,
receiving much interest in recent years particularly in cancer biology. In contrast
to TAMs, which compose a terminal lineage, MSCs remain primitive and can generate
adipocytes, pericytes, chondrocytes, neurons, osteocytes, and mainstay stromal cells,
including fibroblasts and endothelial cells, and can also transdifferentiate into
both ectodermal and endodermal cells, thereby displaying a high plasticity and contributing
to tissue regeneration 56]-59]. MSCs migrate towards the tumor site and become a major component of tumor-adjacent
stroma. Approximately 20% of CAFs originate from bone marrow and derive from MSCs,
as demonstrated by studies using mouse models of inflammation-induced tumors 60]. Tumors employ various strategies to recruit MSCs and chemokines are the most reported;
for instance, breast tumors secret monocyte chemotactic protein-1 to stimulate the
migration of MSCs, while prostate tumors release CXCL16 to attract MSCs via binding
to the CXCR receptor on these cells 43],61]. Once relocated to the tumor site, MSCs actively communicate with several cell types,
including cancer cells and nearby immune cells, thus being biologically involved in
the regulation of tumor development. Specifically, MSCs have intrinsic clinical value
and hold potential for therapeutic use in stem cell-based cancer therapy as a vehicle
to deliver gene products to targeted sites 62]-64].
MSCs are capable of modulating immune status; however, the immunoregulatory function
of MSCs is not intrinsic but depends on their cytokine milieu 65]. MSCs isolated from spontaneous lymphomas have a strikingly high expression of CCL2
compared with bone marrow-derived MSCs (BM-MSCs), and promote tumor growth by recruiting
type 2 like TAMs to tumor site, a phenomenon that can be mimicked by treating BM-MSCs
with tumor necrosis factor alpha (TNF-?) 66]. Combination treatment of MSCs with interferon gamma (IFN-?) and TNF-? would dramatically
increase the expression of several chemokines and inducible nitric oxide synthase
(iNOS), a key immune suppressive molecule 67]. Further, the immunosuppressive effect of MSCs induced by IFN-? and TNF-? can be
dramatically enhanced by IL-17, which enhances mRNA stability by modulating the protein
level of ARE/poly(U)-binding/degradation factor 1, a well-known factor that promotes
mRNA decay 68]. T cell migration is driven by chemokines into proximity with MSCs, where T cell
responsiveness is suppressed by nitric oxide (NO). The MSC-mediated immunosuppression
may interfere with the anti-tumor immunity and help the tumor escape immunological
surveillance. Interestingly, MSCs derived from p53-deficient mice express more iNOS
and exhibited greater immunosuppressive capacity in the presence of inflammatory cytokines.
When inoculated with B16F0 melanoma in mice, p53-deficient MSCs resulted in tumors
larger than those harboring wild type MSCs, and such a tumor promoting effect could
be abolished by administration of the iNOS inhibitor, S-methylisothiourea 69]. However, information collected from studies of the murine system may not be directly
extended to humans because human MSCs utilized indoleamine 2,3-dioxygenase (IDO) instead
of iNOS to suppress immune response 70]. Therefore, a recent study employed a humanized MSC system, which allows mouse iNOS
promoter-driven IDO expression to be activated by inflammatory cytokines similar to
the human IDO promoter 71]. Interestingly, humanized MSCs reduced the tumor-infiltrating CD8+ T cells and B cells when co-injected with tumor cells in mice, thus promoting tumor
growth, highlighting the important interaction between MSCs and other components of
the TME as well as the possibility of restoring tumor immunity in humans by therapeutic
targeting IDO activity. Tumor-resident MSCs seem to be pathologically educated to
favor tumor growth; inflammatory cytokines may act as a major driver for the change
of local microenvironments, but other factors are also likely to be implicated in
TME-exerted modifications. As supporting evidence, several studies demonstrated that
exosomes derived from BM-MSCs can induce progenitor cells to undergo mesenchymal-to-epithelial
transition (MET), indicating active message delivery between cancer cells and the
bone marrow TME 72],73].
Of note, growth factors and cytokines released by MSCs invoke proliferative signaling
of cancer cells and protect them against cell death, a function that can be exerted
passively. Chemotherapy to leukemia elicits resistance by rebuilding an microenvironmental
niche that allows cancer-propagating cells to evade apoptosis, and MSCs generate replatable
mesenspheres and express CD29, CD51, and chemokine receptor CCR1 47]. In ovarian cancer, MSC secretions promote phosphatidylinositol 3-kinase (PI3K)/Akt
signaling and the X-linked inhibitor of apoptosis protein phosphorylation, inducing
carboplatin-specific resistance through trogocytosis 74]. Interestingly, MSCs can also release two distinct polyunsaturated fatty acids, 12-oxo-5,8,10-heptadecatrienoic
acid and hexadeca-4,7,10,13-tetraenoic acid, which are in minute quantities but induce
resistance to a broad spectrum of chemotherapeutic agents, particularly platinum analogs
75].
The contribution of MSCs to tumor progression and resistance is well established,
while the MSC-mediated Tregs expansion and immunosuppression has recently attracted
increasing interest. In particular, human leukocyte antigen-G5 secreted by MSCs stimulates
FoxP3+ CD25Hi CD4+ Tregs proliferation and maintains the immunosuppressive activity by reducing T lymphocytes
and NK functions for an extended period upon co-culture in vitro76],77]. Tregs maintain immune tolerance and prevent inflammation by restraining the activity
of cytotoxic T cells and the proliferation of effector T cells, correlating with poor
prognosis in cancer patients. Depletion of Tregs inhibits the progression of breast
cancer, leukemia, myeloma, fibrosarcoma, colon adenocarcinoma, and lung cancer, while
primary tumor infiltration by Tregs promotes the metastatic potential 55].