Biomedical Engineering Reference
In-Depth Information
49
for cells to migrate.
Accordingly, the presence of TAMs correlates
with poor prognosis in lymphoma.
50
Although metastasis was not
used as an endpoint in this study, CCR2 silencing did reduce TAM
accumulation, tumor volume, and tumor vascularization after
lymphoma cell implantation.
Intravenous administration of siRNA targeting CCR2 at a dose of
0.5 mg/kg resulted in anti-tumor activity, reducing tumor volume
and TAM levels by ~50% after five days. However, more than 90% of
cancer-related deaths are caused by metastasis, not primary tumors.
The small size of the lesions, their propensity to spread to multiple
organs, and their biological complexity have traditionally hampered
anti-metastatic therapies.
51
Importantly, recent biological studies
have identified targets that inhibit disease progression.
52
These
genes of interest are often identified via
migration assays
before cancer cells lacking these genes are surgically implanted
and tested for metastatic potential.
in vitro
53, 54
For example, expression
of epiregulin, Cox-2, and MMPs increased vascular permeability,
facilitating the migration of breast cancer cell to the lungs.
54
Small
molecules are typically tested in these models; however, RNAi may
be a better technology for such studies, as silencing persists for days
following exposure to the drug. To demonstrate that therapeutic
RNAi could reduce metastasis, we used lipidoid-complexed siRNA
to silence Claudin-3 (CLDN3) in a metastatic ovarian cancer model.
CLDN3 protein forms junctions between adjacent epithelial cells,
yet its overexpression in ovarian tumors has been correlated to
increased motility and MMP production.
55
Relative to control
treatments, tumor growth was retarded by intratumoral injection of
98N
42
Similarly,
intraperitoneal injections of CLDN3 siRNA at a dose ~7 mg/kg
reduced tumor metastasis and increased survival of mice relative to
controls.
-5-formulated CLDN3 siRNA at a dose of ~1 mg/kg.
12
7.9
Future Directions and Conclusions
In little more than 10 years, RNAi has fundamentally changed the
way biologists study the genome and its implications in disease and
medicine. Excitingly, the role of RNA continues to broaden. Specific
gene silencing via siRNA has been augmented by miRNA-mediated
regulation of gene networks and, more recently, regulation by
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