MMP-2 siRNA Inhibits Radiation-Enhanced Invasiveness in Glioma Cells

Our previous work and that of others strongly suggests a relationship between the infiltrative phenotype of gliomas and the expression of MMP-2. Radiation therapy, which represents one of the mainstays of glioma treatment, is known to increase cell invasion by inducing MMP-2. Thus, inhibition of MMP-2 provides a potential means for improving the efficacy of radiotherapy for malignant glioma.We have tested the ability of a plasmid vector-mediated MMP-2 siRNA (p-MMP-2) to modulate ionizing radiation-induced invasive phenotype in the human glioma cell lines U251 and U87. Cells that were transfected with p-MMP-2 with and without radiation showed a marked reduction of MMP-2 compared to controls and pSV-transfected cells. A significant reduction of proliferation, migration, invasion and angiogenesis of cells transfected with p-MMP-2 and in combination with radiation was observed compared to controls. Western blot analysis revealed that radiation-enhanced levels of VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38 were inhibited with p-MMP-2-transfected cells. TUNEL staining showed that radiation did not induce apoptosis in U87 and U251 cells while a significant increase in TUNEL-positive cells was observed when irradiated cells were simultaneously transfected with p-MMP-2 as compared to controls. Intracranial tumor growth was predominantly inhibited in the animals treated with p-MMP-2 alone or in combination with radiation compared to controls.MMP-2 inhibition, mediated by p-MMP-2 and in combination with radiation, significantly reduced tumor cell migration, invasion, angiogenesis and tumor growth by modulating several important downstream signaling molecules and directing cells towards apoptosis. Taken together, our results demonstrate the efficacy of p-MMP-2 in inhibiting radiation-enhanced tumor invasion and progression and suggest that it may act as a potent adjuvant for radiotherapy in glioma patients

Zirconolite, zircon and monazite-(Ce) U-Th-Pb age constraints on the emplacement, deformation and alteration history of the Cummins Range Carbonatite Complex, Halls Creek Orogen, Kimberley region, Western Australia

In situ SHRIMP U-Pb dating of zirconolite in clinopyroxenite from the Cummins Range Carbonatite Complex, situated in the southern Halls Creek Orogen, Kimberley region, Western Australia, has provided a reliable 207Pb/206Pb age of emplacement of 1009 ± 16 Ma. Variably metamict and recrystallised zircons from co-magmatic carbonatites, including a megacryst ~1.5 cm long, gave a range of ages from ~1043–998 Ma, reflecting partial isotopic resetting during post-emplacement deformation and alteration. Monazite-(Ce) in a strongly foliated dolomite carbonatite produced U-Th-Pb dates ranging from ~900–590 Ma. Although the monazite-(Ce) data cannot give any definitive ages, they clearly reflect a long history of hydrothermal alteration/recrystallisation, over at least 300 million years. This is consistent with the apparent resetting of the Rb-Sr and K-Ar isotopic systems by a post-emplacement thermal event at ~900 Ma during the intracratonic Yampi Orogeny. The emplacement of the Cummins Range Carbonatite Complex probably resulted from the reactivation of a deep crustal structure within the Halls Creek Orogen during the amalgamation of Proterozoic Australia with Rodinia over the period ~1000–950 Ma. This may have allowed an alkaline carbonated silicate magma that was parental to the Cummins Range carbonatites, and generated by redox and/or decompression partial melting of the asthenospheric mantle, to ascend from the base of the continental lithosphere along the lithospheric discontinuity constituted by the southern edge of the Halls Creek Orogen. There is no evidence of a link between the emplacement of the Cummins Range Carbonatite Complex and mafic large igneous province magmatism indicative of mantle plume activity. Rather, patterns of Proterozoic alkaline magmatism in the Kimberley Craton may have been controlled by changing plate motions during the Nuna–Rodinia supercontinent cycles (~1200–800 Ma)