Figure 6. Heterogeneity of the Bev effect on tumor cell proliferation despite successful blockade of blood vessel formation.

(A–B) Progression of the tumor under continuous Bev treatment. Mean projection images over a depth of 200 µm showing the evolution of tumor cell densities under Bev (10 mg/kg) treatment in 2 mice whose tumor burdens on D0 were similar (same mean fluorescence intensities within 6%, not shown). Treatment was initiated after the first visualization on D0. Tumor cells were more invasive and spread in B compared to A (see insets). Insets are the zoom of the region of interest outlined with dashed line. After 3 weeks the tumor cell density was more than 2 times larger in B than in A. (C–D) Independence of tumor progression from local blood vessel density. Max intensity projection of the tumor cell densities (green outline) at D14 in a 30 µm section of the tumors presented in A and B, side by side with the corresponding projection images of the vascular network (red outline). Tumor margins are highlighted with dotted yellow lines. Highest tumor cell densities are preferentially located in the central area (between vertical lines in C) with no bias toward the most vascularized sub-regions 1 or 3 compared to 2; High tumor cell densities are found in less vascularized subregions of the tumor (simple arrow versus double arrows in D). Scale bars, 400 µm.