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Human neural stem cell tropism to metastatic breast cancer
Donghong Zhao1, Joseph Najbauer, Alexander J Annala
1Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010-3000, USA. dozhao@coh.org
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 proof-of-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 NSC-mediated enzyme/prodrug therapy may be more effective and less toxic than currently available chemotherapy strategies for breast cancer metastases.
Insights
Neural stem cells (NSCs) target breast cancer metastases, offering a novel delivery system. Genetically modified NSCs activate chemotherapy, showing reduced tumor burden and potential for less toxic breast cancer treatment.
Area of Science:
- Oncology
- Stem Cell Biology
- Drug Delivery
Background:
- Metastasis is the leading cause of death in breast cancer patients.
- Current treatments for metastatic breast cancer have toxic side effects and limited efficacy.
- Neural stem cells (NSCs) exhibit tumor-homing properties, suggesting potential for targeted cancer therapy.
Purpose of the Study:
- To investigate the potential of neural stem cells (NSCs) for targeted delivery of therapeutics to metastatic breast cancer.
- To identify mechanisms of NSC tropism to breast cancer cells.
- To evaluate the efficacy of a novel stem cell-mediated enzyme/prodrug therapy for metastatic breast cancer.
Main Methods:
- Assessed NSC tropism to breast cancer cell lines and correlated it with invasiveness.
- Identified Interleukin 6 (IL-6) as a key cytokine mediating NSC tropism.
- Developed genetically modified NSCs (NSC.rCE) to secrete rabbit carboxylesterase (rCE) for activating CPT-11 prodrug.
- Evaluated the efficacy of NSC.rCE and CPT-11 combination therapy in a preclinical mouse model of metastatic breast cancer.
Main Results:
- NSC tropism to breast cancer cells correlated with invasiveness, with IL-6 identified as a key mediator.
- NSCs preferentially targeted multiple metastatic sites (liver, lung, lymph nodes, femur) in vivo.
- In vitro, NSC.rCE enhanced breast cancer cell sensitivity to CPT-11 by 200-fold.
- In vivo, combined NSC.rCE and CPT-11 treatment reduced metastatic tumor burden in the lungs and lymph nodes.
Conclusions:
- NSCs demonstrate significant tropism for metastatic breast cancer sites.
- Stem cell-mediated enzyme/prodrug therapy using NSCs is a promising strategy for treating breast cancer metastases.
- This approach may offer a more effective and less toxic alternative to conventional chemotherapy for metastatic breast cancer.
