Human Neural Stem Cells Can Target and Deliver Therapeutic Genes to Breast Cancer Brain Metastases

Abstract

The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.

Human neural stem cells transduced with IFN-β and cytosine deaminase genes intensify bystander effect in experimental glioma

“…19,20 In this study, we chose the human F3 NSC cell line, as it is a well-characterized and a well-established human NSC line. 3,[5][6][7]11 No signs of local or systemic toxicity were observed in case of animals injected with F3 cells alone. Importantly, these cells can be modified to stably express a therapeutic transgene.…”

“…In NSC-based gene therapy strategies targeting brain tumors, NSCs were mostly used to transport the CD/5-FC prodrug system to the tumor cells. [3][4][5][6][7][8] Recently, Dickson et al 21 showed that in mice, F3 human NSCs transiently expressing human IFN-b displayed tropism for sites of disseminated neuroblastoma, resulting in significant tumor growth. The sustained expression of IFN-b at disseminated sites of microscopic disease represents a novel therapeutic approach.…”

“…In particular, NSCs that are retrovirally transduced with suicide genes such as the cytosine deaminase (CD) gene show a remarkable 'bystander killer effect' on 5-fluorocytosine (5-FC)-treated glioma cells. 3,[5][6][7][8] Interferon-b (IFN-b) is known for its ability to interfere with viral replication and also for its antiproliferative effects on a variety of cancer cells. However, the efficacy of IFN-b is limited because of its extremely short half-life after intravenous administration as well as the systemic toxicity when this protein is administered at doses required to achieve the desired antitumor effect.…”

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

“…8,11,12 We have previously demonstrated that F3 human NSCs expressing the cytosine deaminase prodrug gene are endowed with selective migratory capacity and therapeutic effects against brain metastases from breast cancer. 11 Similarly, we reported that F3 NSCs transduced with the cytosine deaminase gene exhibit tropism and bystander killing effects for leptomeningeal medulloblastomas. 8 The results of the present study are in line with previous descriptions of NSC-based gene therapy in brain tumors and metastatic tumors.…”

“…[7][8][9] In addition, NSCs can target brain metastasis in leptomeningeal medulloblastoma, breast cancer, melanoma and disseminated neuroblastoma. 8,[10][11][12] Therefore, we adopted NSCs as a targeting delivery system for subdural medulloblastomas, which serves as a disseminated tumor model. Gene-directed enzyme prodrug therapy has been one of the therapeutic strategies in stem cell-based gene therapy.…”