ABSTRACT
Metastasis to multiple organs is the primary cause of mortality
in breast cancer patients. The poor prognosis for
patients with metastatic breast cancer and toxic side
effects of currently available treatments necessitate the development
of effective tumor-selective therapies. Neural
stem cells (NSCs) possess inherent tumor tropic properties
that enable them to overcome many obstacles of drug
delivery that limit effective chemotherapy strategies for
breast cancer. We report that increased NSC tropism to
breast tumor cell lines is strongly correlated with the invasiveness
of cancer cells. Interleukin 6 (IL-6) was identified
as a major cytokine mediating NSC tropism to invasive
breast cancer cells. We show for the first time in a preclinical
mouse model of metastatic human breast cancer that
NSCs preferentially target tumor metastases in multiple
organs, including liver, lung, lymph nodes, and femur, versus
the primary intramammary fat pad tumor. For proofof-
concept of stem cell-mediated breast cancer therapy,
NSCs were genetically modified to secrete rabbit carboxylesterase
(rCE), an enzyme that activates the CPT-11 prodrug
to SN-38, a potent topoisomerase I inhibitor, to effect
tumor-localized chemotherapy. In vitro data demonstrate
that exposure of breast cancer cells to conditioned media
from rCE-secreting NSCs (NSC.rCE) increased their sensitivity
to CPT-11 by 200-fold. In vivo, treatment of tumor-
bearing mice with NSC.rCE cells in combination with
CPT-11 resulted in reduction of metastatic tumor burden
in lung and lymph nodes. These data suggest that NSCmediated
enzyme/prodrug therapy may be more effective
and less toxic than currently available chemotherapy strategies
for breast cancer metastases