Migration of mesenchymal stem cells towards glioblastoma cells depends on hepatocyte-growth factor and is enhanced by aminolaevulinic acid-mediated photodynamic treatment.

Hepatocyte-growth factor (HGF) is expressed by glioblastomas and contributes to their growth, migration and invasion. HGF also mediates migration of mesenchymal stem cells (MSC) to sites of apoptotic cell death. Moreover, MSC show tropism for glioblastomas, which is exploited in gene therapy to deliver the therapeutics to the tumor cells. Here, we have studied whether HGF contributes to the recruitment of MSC by glioblastoma cells and whether aminolaevulinic acid-mediated photodynamic therapy (ALA/PDT), a novel therapeutic approach that induces apoptosis in glioblastoma cells, affects HGF release and this migratory response. MSC expressed the HGF receptor MET and migrated towards U87 and U251 glioblastoma spheroids. Migration increased significantly when spheroids were subjected to ALA/PDT, which was associated with induction of apoptosis and up-regulation of HGF. Neutralizing HGF resulted in significant inhibition of MSC migration towards untreated as well as ALA/PDT-treated spheroids. Thus, glioblastoma cells express HGF, which contributes to the attraction of MSC. ALA/PDT induces apoptosis and augments HGF release causing enhanced MSC migration towards the tumor cells. ALA/PDT may therefore be exploited to improve targeting of MSC delivered gene therapy, but it may also constitute a risk in terms of beneficial effects for the tumor.

Modulation of migratory activity and invasiveness of human glioma spheroids following 5-aminolevulinic acid-based photodynamic treatment. Laboratory investigation.

OBJECT: Five-aminolevulinic acid-mediated photodynamic therapy (ALA/PDT) can improve the clinical outcome in patients suffering from glioblastoma. Besides direct phototoxicity, additional mechanisms may contribute. Therefore, the authors studied the influence of ALA/PDT on glioblastoma's migratory and invasive behavior in a human glioma cell spheroid model. METHODS: Glioma spheroids were grown from human U373 and A172 cell lines. After ALA/PDT of spheroids, the authors assessed the migration of tumor cells and their capacity to invade a collagen matrix, as well as changes in their viability, morphology, and expression of matrix metalloproteinases (MMPs). RESULTS: The authors found that ALA/PDT caused long-lasting, nearly complete suppression of glioma cell migration and matrix invasion compared with nontherapeutic controls, including either irradiation or incubation with ALA only. Although ALA/PDT induced tumor cell apoptosis, suppression of migration/invasion was not simply due to phototoxicity because 50% of tumor cells remained vital throughout the observation period. Moreover, the morphology of ALA/PDT-treated cells changed significantly toward a polygonal, epithelial-like appearance, which was associated with alterations in the actin cytoskeleton. Furthermore, downregulation of MMP-7 and -8 was observed after treatment whereas other MMPs remained unchanged. CONCLUSIONS: In addition to directly eliminating glioma cells through apoptosis, ALA/PDT alters their invasiveness, possibly due to the effects on the cytoskeletal organization and MMP expression.

Hepatocyte growth factor-mediated attraction of mesenchymal stem cells for apoptotic neuronal and cardiomyocytic cells.

Human bone marrow-derived mesenchymal stem cells (MSC) home to injured tissues and have regenerative capacity. In this study, we have investigated in vitro the influence of apoptotic and necrotic cell death, thus distinct types of tissue damage, on MSC migration. Concordant with an increased overall motility, MSC migrated towards apoptotic, but not vital or necrotic neuronal and cardiac cells. Hepatocyte growth factor (HGF) was expressed by the apoptotic cells only. MSC, in contrast, revealed expression of the HGF-receptor, c-Met. Blocking HGF bioactivity resulted in significant reduction of MSC migration. Moreover, recombinant HGF attracted MSC in a dose-dependent manner. Thus, apoptosis initiates chemoattraction of MSC via the HGF/c-Met axis, thereby linking tissue damage to the recruitment of cells with regenerative potential.