FIGURE 1.
Top: the microvasculature of solid tumors demonstrates a number of structural abnormalities when compared with that of healthy tissues. As shown in A, endothelial cells demonstrate aberrations in shape and are often separated by wide and irregular interendothelial junctions. In addition, there are fewer pericytes, which are often loosely attached to endothelial cells and lie within a basement membrane that is either abnormally thin or thick. The widened endothelial junctions, coupled with the more tenuous vascular investment by pericytes, promote vascular hyperpermeability and facilitate the intravasation of tumor cells into the circulation, such that they can disseminate to form distant metastases. The accompanying functional derangements in tumor microvessels create a hostile microenvironment that fuels tumor growth, metastasis, and resistance to therapies. B: preclinical and clinical data support the notion that anti-angiogenic therapies can “normalize” the tumor vasculature, restoring the structural and functional aberrations of vessels towards a more normal state. Bottom: abnormalities in perivascular cell (PVC) morphology in solid tumors. A: PVCs (stained for α SMA) in normal pancreatic vessels provide a circumferential and tight investment of arterioles and venules in the normal pancreas, with a more dense arrangement around the arteriole. B: double staining for PVCs and endothelial cells (ECs, stained for CD31) in a smaller arteriole and venule in the pancreas shows a regular arrangement of PVCs around the arteriole, with more irregularly arranged and shaped PVCs around the venule. C: PVCs (stained for desmin) on a normal pancreatic capillary are arranged longitudinally along the vessel axis. D and E: PVCs in the MCa-IV mammary carcinoma show morphological abnormalities (stained for αSMA in D and desmin in E) including an irregular arrangement and cytoplasmic projections in multiple directions. F: PVCs in the Lewis Lung Carcinoma (LLC) show loose associations with ECs. G and H: PVCs in the MCa-IV carcinoma and LLC showing occasional PVC-PVC contact and overlap. [Scale bar in H applies to all panels. Bar lengths: 35 µm (A, F–H); 30 µm (B); 15 µm (C); 80 µm (D and E).] [Top panel from Jain RK. N Engl J Med 360: 2669–2671, 2009, with permission, copyright MMS; bottom panel from Morikawa et al. (206), with permission.]