Biomedical Engineering Reference
In-Depth Information
underling the migration of MSCs to tumors sites have not been well
characterized. Until now, two possible mechanisms have been proposed
(Figure 12.3). (1) Secretion of chemokines/cytokines from tumor tissues
increases the migration of MSCs. The tumor tropism of MSCs might be
mediated by several receptor-ligand combinations.
56
Cytokines, such as
vascular endothelial cell growth factors, transforming growth factors
(TGFs), fibroblast growth factors (FGFs), platelet-derived growth factors,
monocyte chemo-attractants, protein-1, and IL-8 released from the neoplasm
or inflammatory tissue are possible factors that mediate the activation of MSC
migration.
10,57
It is already known that these factors released from cancer cells
promote the migration of endothelial cell and stromal cell progenitors from the
bone marrow towards the cancer bed
58,59
or tissues surrounding the tumor,
therefore enhancing the formation of tumor-stroma.
60
Similar mechanisms
would be anticipated for tumor-stromal formation in glioma, and the
migration of implanted MSCs. Additionally, adhesion molecules, such as b1-
and b2-integrins and L-selectin, may also play a significant role in the
mobilization and homing of MSCs to gliomas.
61,62
MSCs injected intratumo-
rally are mostly distributed at the border zone between tumor and normal
parenchyma. They develop a capsule-like structure, and also infiltrate into the
tumor bed relatively uniformly.
10
Tissue repair is a balance between damage
and repair. When the balance is broken, the injured vessel requires the
recruitment of more progenitor cells which contribute to lesion formation.
MSCs exhibit multipotent differentiation potential, and have been shown
to give rise to different mesodermal cell lineages, including osteoblasts,
chondroblasts, and adipocytes under proper experimental conditions both in
vitro and in vivo.
63
Therefore, MSCs could migrate towards the tumor site and
participate in the formation of tumor stroma, which provides a new strategy
for tumor therapy. Using MSCs as a tumor-targeted vehicle for the delivery of
tumor therapeutic genes may decrease the side effects of these genes. For
example, Studeny et al.
43
demonstrated that bone marrow-derived MSCs
transducted with an adenoviral vector carrying the human IFN-b gene can
produce biological agents locally at tumor sites. They also showed that MSCs
with enhanced expression of IFN-b inhibited the growth of malignant cells in
vivo. Importantly, this effect required the integration of MSCs into the tumors,
and therefore could not be achieved by systemically delivered IFN-b or by
IFN-b produced by MSCs at a site distant from the tumors. These results
indicated that MSCs may serve as a platform for delivering biological agents
into tumors. The successful engraftment of MSC in tissues would most likely
be triggered by tissue damage or tumor growth, which makes MSCs excellent
candidates for the cell-based delivery of therapeutics to tumor sites.
47
(2) The
interaction of the cytokines or chemokines with their corresponding receptors
would induce the migration of MSCs towards the tumor microenvironment.
These receptors, such as CXCR4, CX
3
CRl, CXCR6, CCRI, CCR7, etc., were
expressed on MSCs, and could interact with their respective ligands, namely
CXCLl2, CX3CLl, CXCLl6, CCL3, or CCLl9.
64
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Currently, CXCR4 and its
