Archives
The main drawback of NSC based
The main drawback of NSC-based anti-tumor therapies is that, despite the effective tumor tropism exhibited by NSCs, only small portions of transplanted cells can migrate towards the tumor. Several recent publications have revealed that 70–80% tumor volume reduction can be achieved in various orthotopic GBM xenograft models (Aboody et al., 2006; Lee et al., 2009) even when only 20–30% of implanted NSCs are able to effectively migrate from their implantation site to the tumor area (Ahmed et al., 2011a; Lee et al., 2009; Zhao et al., 2008; Jeon et al., 2008; Kim et al., 2010). Enhancing such homing capacity will likely be one of the critical goals for the fulfillment of the preclinical promise of NSC-based anti-cancer therapeutic strategies. The mechanisms that guide selective tumor-tropic NSC migration are yet to be completely understood. Recent data from our lab and others have suggested that chemokines and pro-angiogenic factors produced by the tumor microenvironment may serve as chemoattractants (Ahmed et al., 2011a; Imitola et al., 2004). It has been shown that NSCs preferentially distribute within hypoxic areas in intracranial glioma xenografts. In addition, hypoxia inducible factor 1 alpha (HIF-1α) knockdown in glioma cells prevented the hypoxia-induced recruitment of NSCs (Zhao et al., 2008). This impaired migration was due to decreased vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), and urokinase-type plasminogen activator (uPA) expression in tumor cells (Zhao et al., 2008). It was also demonstrated that intratumoral upregulation of VEGF induced a long-range attraction of transplanted human NSCs from distant sites in the adult levels of (Schmidt et al., 2005). In addition to VEGF, activation of MMPs has also been pointed as a mechanism of hypoxia-mediated NSC tropism to malignant areas (Zhao et al., 2008; Xu et al., 2007; Lamszus et al., 2000). Taken together, these data indicated that tumor-derive hypoxia-inducible chemo-attractant factors play a critical role in promoting tumor-tropic migration of NSCs. However, the downstream signaling pathways involved in this targeted migration remain to be elucidated. Therefore, the goal of this study is to understand why only certain implanted NSCs possess migratory capacity. We also aim to establish a mechanism that can be leveraged as a possible target to enhance NSC migration and payload delivery capacity to the diffuse tumor burdens through selective overexpression of such molecule. Here we examined both the migratory and non-migratory fraction of NSC populations with functional assays, both in vitro and in vivo. Based on an array based analysis data presented here suggest MMP14 as a novel functional downstream target of VEGFA and VEGFR2 signaling, driving NSC migration and homing to targeted tumor areas.
Materials and methods
Results
Discussion
The role of NSCs as therapeutic carriers against malignant brain tumors has been widely studied and well established (Aboody et al., 2000; Ahmed et al., 2013; Auffinger et al., 2013; Thaci et al., 2012; Ahmed et al., 2011b). Due to their safety profile, inherent tumor-tropism, and immunosuppressive properties, HB1.F3.CD NSCs are considered one of the optimal carriers for anti-cancer therapeutics and have recently entered a phase I clinical trial for patients with recurrent malignant gliomas (NCT01172964). However, the major obstacle for the clinical application of NSC-based anti-cancer therapies is only a small fraction of carrier cells that possess tumor-tropic migratory capacities in preclinical animal models (Ahmed et al., 2011a; Lee et al., 2009; Zhao et al., 2008; Jeon et al., 2008; Kim et al., 2010). Here, our main goal is to understand why some NSCs can effectively migrate and deliver their therapeutic payload to targeted tumor areas while others are not. To better comprehend this process, we examined both migratory and non-migratory NSC populations in vitro and in vivo. We closely assessed their mechanism and route of migration, and through gene expression analysis we identified two essential genes were driving this process: VEGF-A and MMP14.