The detrimental invasiveness of glioma cells controlled by gadolinium chelate-coated gold nanoparticles.

Glioblastoma are characterized by an invasive phenotype, which is thought to be responsible for recurrences and the short overall survival of patients. In the last decade, the promising potential of ultrasmall gadolinium chelate-coated gold nanoparticles (namely Au@DTDTPA(Gd)) was evidenced for image-guided radiotherapy in brain tumors. Considering the threat posed by invasiveness properties of glioma cells, we were interested in further investigating the biological effects of Au@DTDTPA(Gd) by examining their impact on GBM cell migration and invasion. In our work, exposure of U251 glioma cells to Au@DTDTPA(Gd) led to high accumulation of gold nanoparticles, that were mainly diffusely distributed in the cytoplasm of the tumor cells. Experiments pointed out a significant decrease in glioma cell invasiveness when exposed to nanoparticles. As the proteolysis activities were not directly affected by the intracytoplasmic accumulation of Au@DTDTPA(Gd), the anti-invasive effect cannot be attributed to matrix remodeling impairment. Rather, Au@DTDTPA(Gd) nanoparticles affected the intrinsic biomechanical properties of U251 glioma cells, such as cell stiffness, adhesion and generated traction forces, and significantly reduced the formation of protrusions, thus exerting an inhibitory effect on their migration capacities. Consistently, analysis of talin-1 expression and membrane expression of beta 1 integrin evoke the stabilization of focal adhesion plaques in the presence of nanoparticles. Taken together, our results highlight the interest in Au@DTDTPA(Gd) nanoparticles for the therapeutic management of astrocytic tumors, not only as a radio-enhancing agent but also by reducing the invasive potential of glioma cells.

LRP-1 Matricellular Receptor Involvement in Triple Negative Breast Cancer Tumor Angiogenesis.

BACKGROUND: LRP-1 is a multifunctional scavenger receptor belonging to the LDLR family. Due to its capacity to control pericellular levels of various growth factors and proteases, LRP-1 plays a crucial role in membrane proteome dynamics, which appears decisive for tumor progression. METHODS: LRP-1 involvement in a TNBC model was assessed using an RNA interference strategy in MDA-MB-231 cells. In vivo, tumorigenic and angiogenic effects of LRP-1-repressed cells were evaluated using an orthotopic xenograft model and two angiogenic assays (Matrigel® plugs, CAM). DCE-MRI, FMT, and IHC were used to complete a tumor longitudinal follow-up and obtain morphological and functional vascular information. In vitro, HUVECs' angiogenic potential was evaluated using a tumor secretome, subjected to a proteomic analysis to highlight LRP-1-dependant signaling pathways. RESULTS: LRP-1 repression in MDA-MB-231 tumors led to a 60% growth delay because of, inter alia, morphological and functional vascular differences, confirmed by angiogenic models. In vitro, the LRP-1-repressed cells secretome restrained HUVECs' angiogenic capabilities. A proteomics analysis revealed that LRP-1 supports tumor growth and angiogenesis by regulating TGF-ß signaling and plasminogen/plasmin system. CONCLUSIONS: LRP-1, by its wide spectrum of interactions, emerges as an important matricellular player in the control of cancer-signaling events such as angiogenesis, by supporting tumor vascular morphology and functionality.