Human Amniotic Fluid-Derived Mesenchymal Stem Cells As Therapeutic Vehicles: A Novel Approach For the Treatment of Bladder Cancer

Abstract

Recent studies support cell-based therapies for cancer treatment. An advantageous cell type for such therapeutic schemes are the mesenchymal stem cells (MSCs) that can be easily propagated in culture, genetically modified to express therapeutic proteins, and exhibit an innate tropism to solid tumors in vivo. Recently, we successfully isolated and expanded MSCs from second-trimester amniotic fluid (AF-MSCs). The main characteristic of AF-MSCs is their efficient and rapid expansion in vitro. Herein, we investigated the AF-MSCs tropism and capability to transport interferon beta (IFNβ) to the region of neoplasia in a bladder tumor model. To this end, we used the T24M bladder cancer cell line, previously generated from our studies, and developed a disease progression model in immunosuppressed mice, that can recapitulate the molecular events of bladder carcinogenesis. Our results documented that AF-MSCs exhibited high motility, when migrated either to T24M cells or to T24M-conditioned medium, and we further identified and studied the secreted factors which may trigger these enhanced migratory properties. Further, lentivirus-transduced AF-MSCs, expressing green fluorescent protein (GFP) or IFNβ, were intravenously administered to T24M tumor-bearing animals at multiple doses to examine their therapeutic effect. GFP- and IFNβ-AF-MSCs successfully migrated and colonized at the tumor site. Notably, significant inhibition of tumor growth as well as prolonged survival of mice were observed in the presence of IFNβ-AF-MSCs. Collectively, these results document the great potential of AF-MSCs as anti-cancer vehicles, implemented by the targeting of the tumor site and further facilitated by their high proliferation rate and expansion efficiency in culture.

Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells

“…75 Another recent study also reports that AF-MSCs engineered to express interferon-b can be adopted as therapeutic vehicles for the treatment of bladder cancer by the targeting of the tumor site and further by their high proliferation rate and expansion efficiency in culture. 76 Consequentially, these results indicate that amniotic-derived stem cells can serve as a vehicle in cell-based gene-directed enzyme prodrug system to selectively target malignant cancers. As the studies of engineered stem cells strategies using amnion-derived stem cells are in an early stage, more extensive trials are need to intensify their anticancer potential as therapeutic gene delivery vehicles.…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part IV: Image- Guided, Remote-Controlled Opening of the Blood–Brain Barrier for Systemic Brain Tumor Therapy

“…Investigators have demonstrated the in vivo migratory capacity of stem cells toward primary GBM tumors as well as invasive tumor cells that intermingle with normal brain tissue (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Various stem cells such as embryonic stem cells, mesenchymal stem cells, neural stem cells, induced pluripotent stem cells (iPSCs), and neural stem cells derived from iPSCs have been shown to migrate to intracranially established GBMs when implanted loco-regionally within the brain, and their ability to secrete anti-GBM therapies after genetic modification has been investigated (29).…”

“…A major advantage of this process over using focused ultrasound and microbubbles for BBB opening is the fact that this process relies on the combination of physical energy deposition and a biologic response (stem cell tumor tropism). Thus, although a much larger volume would need to be heated by HIFU to nonlethal temperatures (42-43°C), the BBB opening will be much more focused and enhanced only where the heated engineered stem cells are located, which has been demonstrated to be adjacent to primary and invasive GBM cells ( Figure 1D, E) (2)(3)(4)(16)(17)(18)(19)(20). Although there is an added component of therapeutic stem cells, this technique can potentially be performed in a noninvasive manner, as the engineered stem cells can be placed directly into a GBM resection cavity during standard-of-care surgery using an encapsulation technique.…”

Stem cell technology and engineering for cancer treatment

“…Stem cells are also utilized to delivery immunestimulatory cytokines including IL-12 (Duan et al, 2009;Eliopoulos et al, 2008;Gao et al, 2010), IL-21 (Hu et al, 2011), IL-24 , TNF-α (Shahrokhi et al, 2013), and IFN-γ (Bitsika et al, 2012). TRAIL (tumor necrosis factor related apoptosis induced ligand) (Shahrokhi et al, 2013) , nanoparticles (Gao et al, 2013) and anti-angiogenic factors (Ghaedi et al, 2011).…”