Macrophage-specific ablation of Vegfa in PyMT implant tumors blocks blood vessel permeability and tumor cell intravasation at the TMEM. A and C, immunofluorescence.

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Macrophage-specific ablation of Vegfa in PyMT implant tumors blocks blood vessel permeability and tumor cell intravasation at the TMEM. A and C, immunofluorescence of tumor sections stained for the presence of vascular junction proteins at TMEM macrophages. Macrophage-specific ablation of Vegfa in PyMT implant tumors blocks blood vessel permeability and tumor cell intravasation at the TMEM. A and C, immunofluorescence of tumor sections stained for the presence of vascular junction proteins at TMEM macrophages. Tumor sections are stained for VE-cadherin (red), CD31 (green), and VEGFA (gray). Sequential sections are stained for CD31 (green), TIE2 (red), and CD68 (gray). A, control tumors (Vegfaflox) or (C) after ablation of Vegfa (Vegfaflox;Csf1r-Cre). CD68+ macrophage in the TMEM outlined in white box, and adjacent endothelium in the TMEM in pink box. Yellow indicates merged signal of CD31 and TIE2 (left) or CD31 and VE-Cadherin (right). Decreased VE-Cadherin at the TMEM (F, right) seen as decreased VE-Cadherin, resulting in green (CD31) at vascular junction. Scale bar, 15 μm. B and D, quantification of the relative intensity of VEGFA or vascular junction proteins (ratio of VE-cadherin to CD31 in blood vessels) in A and C at TMEM or away from the TMEM in (B) control tumors (Vegfaflox) or (D) after ablation of Vegfa in Vegfaflox;Csf1r-Cre tumors along 25 μm lengths of blood vessel (n = 3). , relative fluorescence intensity of VE-Cadherin/CD31; , relative VEGFA intensity. Red dashed line, presence of a CD68+ macrophage. E, quantification of average pixel intensity of VE-Cadherin/CD31immunofluorescence staining in 25-μm lengths of blood vessel at TMEM or away from the TMEM in the presence of VEGFAhi macrophages (Vegfaflox, n = 3) or after macrophage-specific ablation of Vegfa (Vegfaflox;Csf1r-Cre, n = 3) from data in B and D. Asterisks indicate post-ANOVA comparisons with significant difference. F, human breast cancer tumor sections stained for the presence of vascular junction proteins at TMEM macrophages. Tumor sections are stained for TMEM; MENA (red), CD68 (brown), and CD31 (blue), (RBC in aqua) by IHC. Sequential sections are stained for VE-cadherin (green), TIE2 (gray), and VEGFA (red) by immunofluorescence. TMEM outlined in black box in IHC and white box in immunofluorescence. Scale bar, 15 μm. G, quantification of normalized average pixel intensity of VE-Cadherin staining in vasculature at TIE2hi/VEGFAhi macrophages of the TMEM or away from the TMEM (n = 23 at the TMEM, n = 24 away from the TMEM in 5 individual patient samples; ***, P = 0.0001). H, diagram summarizing TMEM macrophage-mediated induction of blood vessel permeability promotes tumor cell intravasation. TMEM assembly with close association between the nonmigratory TMEM tumor cell (TC; green, T1) and TIE2hi/VEGFAhi macrophage (blue, M1) on blood vessels. VEGFA destabilizes vascular junctions, resulting in vascular permeability and tumor cell (T2) intravasation. Allison S. Harney et al. Cancer Discovery 2015;5:932-943 ©2015 by American Association for Cancer Research