Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

Abstract

Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach.

TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma

“…5 After intravascular or local delivery, hMSCs were shown to specifically integrate into gliomas when attracted by the release of cytokines and growth factors from the tumor cells. 22 Glioblastoma multiforme is the most aggressive form of glioma with a median survival time of only 14.6 months for patients after conventional therapy including resection, chemotherapy, and radiation.…”

“…In vivo studies showed that after peripheral injection MSCs can cross the blood-brain barrier and migrate to damaged areas in the brain, wherein they improve functional recovery in, for example, patients with ischemic stroke. 4 Another interesting aspect in hMSC biology is their tropism for brain tumor tissues, 5 which is similar to that of neural stem cells. 6 High-grade gliomas have the ability for deep infiltration of local structures leading to disease recurrence despite tumor resection, radiotherapy, and chemotherapy.…”

“…The hMSC tropism for gliomas made these cells a promising tool for their use as a gene vector system in the treatment of highly aggressive brain tumors. 5 Despite these multiple potentials of hMSCs, little is known about key regulators that control commitment of hMSCs to the neural lineage and the molecular mechanisms of hMSC recruitment to gliomas.…”

Cancer Stem Cells in Tumor Heterogeneity

“…It is well-established that mesenchymal stem cells are recruited from the bone marrow into tumors (Birnbaum et al, 2007) and in brain tumors, neural stem cells exhibit great tropism towards the tumors (Aboody et al, 2000). Indeed, such tropism has been widely suggested to potentially function as a way to specifically deliver anti-cancer therapeutics into tumor tissue (Bexell et al, 2010). Although the topic remains controversial, mesenchymal stem cells have been suggested to have a more direct role in tumorigenesis than previously anticipated.…”

Glioma cancer stem cells and their role in therapy

“…Mesenchymal stem cells have many attributes that support their use as a tumor specific therapeutic vehicle in clinical practice. It has been shown that MSCs share some characteristics with pericytes (Bexell et al, 2009;Bexell et al, 2010). This property might facilitate the migration of MSCs to highly vascularised glioblastomas.…”