In vivo proteomic imaging analysis of caveolae reveals pumping system to penetrate solid tumors

• Published in: Nature medicine Vol. 20; no. 9; pp. 1062 - 1068
• Main Authors: Oh, Phil, Testa, Jacqueline E, Borgstrom, Per, Witkiewicz, Halina, Li, Yan, Schnitzer, Jan E
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2014; Nature Publishing Group
• Subjects: 101/28; 101/58; 13/106; 14/1; 14/35; 14/63; 59; 631/1647/2067; 631/61/2297; 631/67/2321; 64/110; 64/60; 64/86; 692/308/2778; 82/51; 82/80; Analysis; Animals; Biomedicine; Blood; Cancer Research; Caveolae - metabolism; Fluorescence; Humans; Image Processing, Computer-Assisted - methods; Infectious Diseases; Medical imaging; Metabolic Diseases; Microscopy; Molecular Medicine; Neoplasms - metabolism; Neurosciences; Proteomics; Rodents; technical-report; Technology application; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3623

Proteomic-imaging analysis of caveolae shows active transvascular pumping of antibodies across the endothelial cell barrier and into solid tumors against a concentration gradient. Technologies are needed to map and image biological barriers in vivo that limit solid tumor delivery and, ultimately, the effectiveness of imaging and therapeutic agents. Here we integrate proteomic and imaging analyses of caveolae at the blood-tumor interface to discover an active transendothelial portal to infiltrate tumors. A post-translationally modified form of annexin A1 (AnnA1) is selectively concentrated in human and rodent tumor caveolae. To follow trafficking, we generated a specific AnnA1 antibody that targets caveolae in the tumor endothelium. Intravital microscopy of caveolae-immunotargeted fluorophores even at low intravenous doses showed rapid and robust pumping across the endothelium to enter mammary, prostate and lung tumors. Within 1 h, the fluorescence signal concentrated throughout tumors to exceed the peak levels in blood. This transvascular pumping required the expression of caveolin 1 and annexin A1. Tumor uptake with other antibodies were >100-fold less. This proteomic imaging strategy reveals a unique target, antibody and caveolae pumping system for solid tumor penetration.