Olfactory Ensheathing Cells Facilitate Successful Gene Therapy for Glioma in Animal Models
Key findings
- In mice implanted with glioblastoma, olfactory ensheathing cells (OECs) migrated from the nasal cavity toward the primary tumor site and also followed tumor-initiating cells as they infiltrated adjacent brain tissue
- In culture, OECs delivered a therapeutic transgene to tumor cells that converted an inactive prodrug to 5-fluorouracil, leading to bystander tumor cell killing
- OECs on their own inhibited tumor cell proliferation in culture, suggesting that they have an intrinsic anticancer effect
- The culture results were reproduced in living mice with glioblastoma, where the transgene significantly reduced tumor volume and significantly prolonged survival
- It may be possible to extend OEC-based gene therapy to other transgenes, other types of cancer and other routes of administration
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Scientists have recently seen promising results after treating various neurological conditions through autologous transplantation of olfactory ensheathing cells (OECs). Normally, these cells help regenerate olfactory receptor neurons by accompanying axons as they grow from the nasal cavity into the olfactory bulb. In the central nervous system, they create a favorable environment for axon restoration by promoting structural remodeling and support, phagocytosing cellular debris and bacteria, modulating neuroinflammation and promoting neuroprotection.
Bakhos A. Tannous, PhD, director of the Experimental Therapeutics and Molecular Imaging Laboratory, and colleagues recognized that these properties might also make OECs suitable for relatively noninvasive treatment of cancer. They reasoned that since OECs naturally migrate to the central nervous system, these cells might be capable of acting as a "trojan horse" that would bypass the blood-brain barrier and deliver therapies to the brain.
In the Journal of the National Cancer Institute, Dr. Tannous and his team report success in using OECs to deliver a therapeutic transgene to the brains of mice with glioma, which reduced tumor volume and improved survival after just one intranasal application.
OECs Migrate to Brain Tumors Via the Nasal Pathway
The researchers first evaluated whether OECs traveling their natural route from the olfactory bulb to the central nervous system can target brain tumors. They implanted human glioblastoma stem-like cells (GSCs) into the brains of mice, then later intranasally administered OECs that expressed green fluorescent protein.
When observing the brains, the researchers saw that OECs had migrated from the nasal cavity not only toward the primary tumor site, but also along invasive tumor borders far from the initial site of transplantation.
OECs Deliver Therapeutics to Glioblastoma and Stem-like Cells in Culture
To assess the potential use of OEC for glioma gene therapy, the research team purified OECs from mouse olfactory bulb and engineered them to express a transgene called CU. At a tumor, this transgene converts the inactive prodrug, 5-fluorocytosine (5-FC), into the 5-fluorouracil (5-FU), a long-used chemotherapy drug. The active metabolites of 5-FU are incorporated into DNA and RNA, with the result that 5-FU is transferred to neighboring nontransduced cells via gap junctions and other mechanisms, leading to bystander killing of tumor cells.
The researchers engineered OECs (that did not express CU) and OECs that did express CU (OCUs) to express a fluorescent protein that would report for cell viability. They engineered human GSCs and glioblastoma cells to express a different reporter. They cultured each cell type separately and also co-cultured OECs or OCUs with tumor cells in the presence or absence of 5-FC or 5-FU (the latter as a positive control).
In the monocultures, the team found that all cells were sensitive to 5-FU, but only the OCUs were killed by 5-FC. In the co-cultures of OECs with tumor cells, 5-FC did not cause any cell deaths. However, in the co-cultures of OCUs with tumor cells, 5-FC significantly reduced the number of viable tumor cells and OCUs by about 80%.
The researchers observed a 40% decrease in tumor cell proliferation in cocultures with OECs or OCUs, even without 5-FC, compared with the untreated monoculture control. This suggests that OECs could have intrinsic antitumor activity.
OECs Deliver Glioma Gene Therapy In Vivo
The researchers then injected human GSCs expressing fluorescent proteins into the brains of mice. One week later, the animals received a single dose of OCUs or saline intranasally, and one week after that, all mice were treated with 5-FC for seven days.
On both bioluminescence imaging and histologic analysis, mice treated with OCUs plus 5-FC showed significantly less tumor growth and invasion than those treated with 5-FC alone. Even more important, mice treated with both OCUs and 5-FC survived significantly longer than the control group.
Advantages of OECs
OECs can be obtained from the olfactory epithelium in a simple procedure for autologous transplantation. This is already being done in clinical trials for the treatment of spinal cord injury. Furthermore, no toxicity or tumorigenesis has been reported so far with OEC transplantation.
The researchers used the CU transgene simply as a proof of concept. They predict that OEC-based gene delivery could be extended to other transgenes, as well as to other types of cancer and other routes of administration.
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