Introduction: Glioblastoma is malignant, aggressive, and resistant to treatment. We demonstrate the ability of human adipose-derived mesenchymal stem cells (hAMSCs) to home to and suppress brain tumor initiating cells (BTIC) implicated in glioblastoma progression. Bone morphogenetic protein 4 (BMP4) has anti-tumor effects; however a method to effectively deliver BMP4 to tumor sites yet needs to be investigated. In this study, we investigated the use of hAMSCs as a vehicle to deliver BMP4 to BTICs, by using bioengineered BMP4-secreting hAMSCs (BMP4-hAMSC), for the treatment of glioblastoma.
Methods: hAMSCs were transduced to express BMP4; effects on BTIC proliferation, differentiation, and migration were assessed with state-of-the-art proprietary nanotechnology developed by us. We investigated the effect of BTICs on hAMSC proliferation, differentiation, and malignant transformation into tumor associated fibroblasts (TAFs) via western blot, immunofluorescence, and real-time RT-PCR. NOD/SCID mice were intracranially injected with BTICs derived from our own patient samples obtained from the operating room. Furthermore, mice underwent systemic injections of BMP4-hAMSCs to assess the safety of stem cell therapy, and their effect on GBM proliferation and migration. Impact on survival was determined post-BMP4-hMSC treatment.
Results: BMP4-hAMSCs decreased migration (p<0.001), proliferation (p<0.001), and induced differentiation (p<0.001) of BTIC in vitro. In addition, hAMSCs remained multipotent upon exposure to BTIC-secreted factors, indicating retained stem-cell characteristics and integrity. In addition, BMP4-hAMSCs did not undergo oncogenic transformation upon exposure to BTICs in vitro and in vivo. Moreover, systemically delivered BMP4-hAMSCs significantly improved median survival in mice, whereby they significantly outlived controls (p=0.002).
Conclusions: BMP4-hAMSCs are non-oncogenic and significantly decrease tumor burden and improve survival in mice. Our findings provide the groundwork for future clinical trials investigating the therapeutic potential of bioengineered stem cells for the treatment of glioblastoma.
Patient Care: This study will improve patient care by investigating novel treatment strategies for malignant brain tumors.
Learning Objectives: By the conclusion of this session, participants should be able to describe how bioengineered mesenchymal stem cells may be used for the treatment of the malignant brain tumor glioblastoma.