Figure 3.

Palisading glial cells invade vascularized tissue as predicted by the model (A,B) and observed in histology (C,D). A: Computer simulation showing palisading cells escaping from the peri-necrotic region (dark gray) by undergoing a hypoxia-induced phenotypic change to upregulate motility and downregulate adhesion and proliferation. Cell-migration occurs via chemotaxis and haptotaxis in response to gradients of oxygen and ECM concentration, respectively (Methods). Brown: conducting vessels; yellow: non-conducting. B: Background shows distribution of oxygen concentration (“n” in legend). n=1 in vascularized tissue and is lower in the tumor (white/yellow: peri-necrotic region). C: 4x magnification of a high-grade glioblastoma interior. D: Corresponding fluorescent image showing vessels (green, red). As predicted by the simulations (A,B), palisading malignant glial cells (C) invade the vascularized tissue (D), amidst a tangle of thick and thin-walled large vessels and a few smaller vessels, from two areas of necrosis. Also note the distances between necrosis and vessels (C), corroborating our choice for diffusion penetration length L₂ (Supplement). Further phenotypic changes (e.g. down-regulation of motility and up-regulation of proliferation) may occur when migrating cells reach tissue regions richer in substrates, leading to the morphologies described in Fig. 4D,5A–D.