Abstract
As an approach to improve treatment of breast cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs, HB1.F3 cells) consisting of neural stem cells (NSCs) expressing cytosine deaminase and the interferon-beta genes, HB1.F3.CD and HB1.F3.CD.IFN-β. In this model, MDA-MB-231/Luc breast cancer cells were implanted in the right hemisphere of the mouse brain, while pre-stained GESTECs with redfluorescence were implanted in the contralateral brain. Two days after stem cells injection, 5-fluorocytosine (5-FC) was administrated via intraperitoneal injection. Histological analysis of extracted brain confirmed the therapeutic efficacy of GESTECs in the presence of 5-FC based on reductions in density and aggressive tendency of breast cancer cells, as well as pyknosis, karyorrhexis, and karyolysis relative to a negative control. Additionally, expression of PCNA decreased in the stem cells treated group. Treatment of breast cancer cells with 5-fluorouracil (5-FU) increased the expression of pro-apoptotic and anti-proliferative factor, BAX and p21 protein through phosphorylation of p53 and p38. Moreover, analysis of stem cell migratory ability revealed that MDA-MB-231 cells endogenously secreted VEGF, and stem cells expressed their receptor (VEGFR2). To confirm the role of VEGF/VEGFR2 signaling in tumor tropism of stem cells, samples were treated with the VEGFR2 inhibitor, KRN633. The number of migrated stem cells decreased significantly in response to KRN633 due to Erk1/2 activation and PI3K/Akt inhibition. Taken together, these results indicate that treatment with GESTECs, particularly HB1.F3.CD.IFN-β co-expressing CD.IFN-β, may be a useful strategy for treating breast cancer metastasis to the brain in the presence of a prodrug.
Highlights
Metastasis is the movement of cancer cells from primary tumor sites to distant organs and tissues, including the brain, liver, and bones, via the blood and lymphatic vessels [1]
Metastatic breast cancer mice models and therapeutic effects of stem cells As shown in Figure 1A, we demonstrated the therapeutic effect of hNSCs with 5-FC in breast cancer metastasis to the brain
neural stem cells (NSCs) expression of cytosine deaminase (CD)+/−IFN-β significantly inhibited growth of the tumor burden, while the co-expressing stem cells treated group showed a stronger reduction of tumor burden than the group treated with CD expressing stem cells alone
Summary
Metastasis is the movement of cancer cells from primary tumor sites to distant organs and tissues, including the brain, liver, and bones, via the blood and lymphatic vessels [1]. Lung (40–50%), breast (15–25%), melanoma (5–20%), colon and kidney related primary cancer commonly spread to the brain [4]. Breast cancer metastases are the second most common type of brain metastases, followed by lung cancer, and these are generally found in younger and premenopausal women [8]. The prevalence of brain metastases has historically been estimated to be 10–16% with a 1-year survival rate of 20% [10]. While surgical treatment of the primary tumor may be successful, therapies for metastatic breast cancer carry the risk of neurological and cognitive deficits. Treatment of MDA-MB-231, aggressive breast cancer cells, with a monoclonal antibody specific for ROR1 inhibited cancer cell migration and invasion in vitro and tumor metastasis in vivo, indicating that ROR1 may suppress breast cancer progression and metastasis via regulating epithelial-mesenchymal transition (EMT) [12]
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