Biomedical Engineering Reference
In-Depth Information
receptor, stromal cell-derived factor-1 (SDF-1), are thought to be the most
important pair of cytokines in attracting MSCs to migrate to the tumor, as
CXCR4/SDF-1a interaction plays an important role in inflammation, tumor
tropism of stem cells, and the pathology of gliomas.
65
Therefore, the
microenvironment of the tumor site plays an important role in the migration
of MSCs.
66
Also, a better understanding of the signaling transduction
pathways associated with the tropism of these MSCs to gliomas will help to
elucidate the role of MSCs in tumor growth and may permit more efficient
targeted delivery of MSCs to the desired sites for therapeutic purposes.
67
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12.3.3 MSCs as Tumor Target Vehicles for Gene Delivery
The evidence that the tumor microenvironment favors the homing of
exogenous MSCs has supported the rationale for developing engineered
MSCs as a tool to track tumor sites and deliver anticancer agents within these
areas. Several reports have proven the efficiency of MSCs as cell carriers for
in vivo delivery of various clinically relevant anticancer agents following
engraftment within tumor sites (Table 12.2). The observation that unmodified
MSCs could have an anti-tumorigenic activity further supports the use of
MSCs in cancer immunotherapy.
68
Besides, MSCs have proven to be effective
in
delivering
oncolytic
adenovirus
for
the
treatment
of
cancer
with
low
systemic toxicity,
69,70
suggesting MSCs are promising cell vehicles for cancer
therapy.
Several research groups have reported promising results following the
injection of genetically engineered MSCs into animal models bearing different
tumors.
9,43,71,72
For example, Nakamura et al.
10
used gene-modified MSCs as
a new tool for gene therapy of malignant brain neoplasms. Gene modification
of MSCs by infection with an adenoviral vector encoding human IL-2 clearly
enhanced the antitumor effect and further prolonged the survival of tumor-
bearing rats, indicating that gene therapy employing MSCs as a targeting
vehicle is promising as a new therapeutic approach for brain tumors. Studeny
et al.
9
injected MSCs transduced with an adenoviral expression vector carrying
the human IFN-b gene into mice with MDA231 or A375SM pulmonary
metastases, resulting in suppression of the pulmonary metastases and
prolonged survival. This suggests MSCs may be an effective platform for the
targeted delivery of therapeutic proteins to cancer sites. Loebinger et al.
73
also
demonstrated that MSCs could accumulate in tumor tissues (Figure 12.4)
and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-
expressing MSCs were able to inhibit tumor growths, suggesting that the
TRAIL-expressing MSCs have a wide potential therapeutic application, which
includes the treatment of both primary tumors and their metastases. Also,
MSCs were transduced by the rAAV-IFN-b or green fluorescent protein ex
vivo and used as cellular vehicles to target lung metastasis of TRAMP-C2
prostate cancer cells in a therapy model. The results indicated a significant
reduction of tumor volume in lungs following IFN-b expressing MSC therapy.
