PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment

Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy.We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors.These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization

Unintentional drifts during quiet stance and voluntary body sway

We explored unintentional drifts in voluntary whole-body sway tasks following the removal of visual feedback. The main hypothesis was that the unintentional drifts were produced by drifts of referent coordinates for salient performance variables. Young healthy subjects stood quietly on a force platform and also performed voluntary body sway at 0.5 Hz both in the anterio-posterior and medio-lateral directions. Visual feedback on the center of pressure (COP) coordinate was provided and then turned off. During quiet stance trials, the subjects matched the initial COP coordinate with a target shifted by 3 cm anterior, posterior, left, or right from the coordinate during natural standing and activated the right tibialis anterior to 30% of its maximal voluntary contraction. During cyclical voluntary sway task, the nominal sway amplitude was always 4 cm while the midpoint was at one of the four mentioned locations. Removing visual feedback caused COP drifts during quiet stance trials that were consistent across trials performed by a subject but could be in opposite directions across subjects; there was a consistent drop in the activation level of tibialis anterior. During voluntary body sway, removing visual feedback caused a consistent increase in the voluntary sway amplitude and a drift of the midpoint that was consistent within but not across subjects. Motor equivalent and non-motor equivalent inter-cycle motion components were quantified within the space of muscle groups (muscle modes) under visual feedback and at the end of the period without visual feedback. Throughout the trial, there were large motor equivalent motion components, and they increased over the period without visual feedback. The results corroborate the idea that referent coordinate drifts at different levels of the control hierarchy can lead to unintentional drifts in performance. It suggests that directions of COP drifts are defined by two main factors, drift of the body referent coordinate toward the actual coordinate (that can lead to fall) and an opposite drift to ensure body motion to a safer location. Analysis of motor equivalence suggests that postural stability is not compromised during unintentional drifts in performance in contrast to earlier studies of multi-finger tasks. This may be due to the vital importance of postural stability for everyday actions.acceptedVersionThis is a post-peer-review, pre-copyedit version of an article published in [Experimental Brain Research]. The final authenticated version is available online at: https://doi.org/10.1007/s00221-017-4972-