Zone‐specific remodeling of tumor blood vessels affects tumor growth

• Published in: Cancer Vol. 110; no. 10; pp. 2347 - 2362
• Main Authors: Tilki, Derya, Kilic, Nerbil, Sevinc, Sema, Zywietz, Friedrich, Stief, Christian G., Ergun, Suleyman
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.11.2007; Wiley-Liss
• Subjects: Biological and medical sciences; blood vessel stabilization; Blood Vessels - ultrastructure; Humans; Immunohistochemistry; Medical sciences; Microscopy, Electron; necrosis; Neoplasms - blood supply; Neoplasms - pathology; Neovascularization, Pathologic; tumor; Tumors; ultrastructure; vascular remodeling; Vascular remodeling; Cancerology; Stability; Tumor growth; Stabilization; Ultrastructure; Blood vessel; tumor; Circulatory system; Malignant tumor; blood vessel stabilization; Necrosis
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.23024

BACKGROUND. Chaotic organization, abnormal leakiness, and structural instability are characteristics of tumor vessels. However, morphologic events of vascular remodeling in relation to tumor growth are not sufficiently studied yet. METHODS. By using the rat rhabdomyosarcoma tumor model vascular morphogenesis was studied by light and electron microscopy and immunohistochemistry in relation to tumor regions such as tumor surrounding (TSZ), marginal (TMZ), intermediate (TIZ), and center (TCZ) zones. RESULTS. The analyses revealed that blood vessels of TSZ display a regular ultrastructure, whereas blood vessels of TMZ showed a chaotic organization and unstable structure with a diffuse or even lacking basal lamina, and missing or irregular assembled periendothelial cells. In contrast, blood vessels of TIZ and TCZ exhibited a more or less stabilized vessel structure with increased diameter. Correspondingly, normal assembly of α‐smooth‐muscle‐actin (α‐SMA)‐positive cells into the vessel wall was observed in blood vessels of TSZ, TIZ, and TCZ. Also, Ang1 immunostaining was strongest in large vessels of TIZ and TCZ, whereas Ang2 staining was prominent in small vessels of TIZ. Tie2 staining was detectable in small and large vessels of all tumor zones. Immunostaining for αvβ3‐integrin was strongest in small vessels of TMZ, whereas large vessels of TIZ and TCZ were almost negative. CONCLUSIONS. The results indicate a zone‐specific remodeling of tumor blood vessels by stabilization of vessels in TIZ and TCZ, whereas small vessels of these zones obviously undergo regression leading to tumor necrosis. Thus, a better understanding of vascular remodeling and stabilization in tumors would enable new strategies in tumor therapy and imaging. Cancer 2007. © 2007 American Cancer Society. Vascular stabilization leads to a remodeling of tumor vasculature accompanied by a reduction of vascular density because of partial regression of blood vessels and an extensive necrosis of tumor tissue. Thus, a better understanding of tumor vascular remodeling might optimize the assessment of the efficiency of tumor therapeutics via imaging and open additional strategies in tumor therapy.