Stem cells as a therapeutic delivery vehicle

Research on alternative therapeutic means of targeting malignant gliomas is of great importance since current treatments such as chemotherapy, radiation and surgical resection have proven ineffective in guaranteeing patients long-term survival. Overall, malignant gliomas are highly aggressive tumors with a median survival time of 12 to 18 months. They are composed of rapidly dividing cells, have the ability to invade normal brain tissue, and are known to increase the number of blood vessels responsible for aiding in tumor growth. In essence, the growth of gliomas depends on the balance between biological regulators that control the tumor growth and angiogenesis, the process of forming blood vessels.

A major obstacle in the treatment of brain tumors is obtaining therapeutic levels of potent drugs at the site of the tumor. Previous studies from our laboratory have demonstrated that human stem cells have the ability to track down human glioma cells, especially those that have migrated into the normal brain. Therefore, a potential solution is the use of stem cells as therapeutic delivery vehicles.

During his research time in Boston , Dr. Lorenzo Bello a neurosurgeon from Milan , Italy identified a protein fragment called PEX that is naturally found in various tumors and is responsible for inhibiting tumor angiogenesis, tumor invasion and tumor cell proliferation. His studies clearly demonstrated that the administration of PEX resulted in a 99% inhibition of the growth of human malignant glioma cell lines grown in nude mice. These studies were published in Cancer Research .

Dr. Seung Ki-Kim, a neurosurgeon from Korea, evaluated the antitumor activity of PEX-producing human neural stem cells against malignant glioma. Histological analysis showed that PEX transduced neural stem cells migrates to the tumor boundary and caused a 90% reduction of tumor volume. This reduction in tumor volume was associated with a significant decrease in angiogenesis. These results support the use of neural stem cells as delivery vehicle for targeting therapeutic genes against human glioma. Bypassing ethical issues concerned with using neural stem cells we have decided to study adult-derived bone marrow stem cells in treating gliomas. Another possible avenue under investigation is the use of stem cells derived from normally discarded umbilical chord blood. All these avenues of research studying the effectiveness of using implanted stem cells strive to increase the therapeutic levels of experimental drugs or anti-tumor proteins at the site of tumor. These studies were published in Clinical Cancer Research .

The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. Dr. Nils Ole Schmidt, a neurosurgeon from Germany analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. We demonstrated that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors. These studies were published in Neoplasia .

Related Publications

Bello L, Valeria Lucini V, Carrabba G, Giussani C, Machluf M, Mauro Pluderi M, Nikas D, Jianping Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Peter McL Black PM. Simultaneous inhibition of glioma angiogenesis, cell proliferation and invasion by a natural occurring fragment of human metalloproteinase-2. Cancer Research 2001; 61:8730-8736.

Kim SK, Cargioli TG, Machluf M, Yang W, Sun Y, Al-Hashem R, Kim SU, Black PM, Carroll RS. PEX producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clinical Cancer Research, 2005; 11(16):5965-70 .

Schmidt NO, Przyleci W, Yang W, Ziu M, Teng Y, Kim SU, Black PM, Aboody KS, Carroll RS. Brain tumor tropism of transplanted human neural stem cells in induced by vascular endothelial growth factor. Neoplasia, 2005: 623-629.