Promoting the effect of microbubble-enhanced ultrasound on hyperthermia in rabbit liver.

PURPOSE: The heat-sink effect is one reason for the insufficient temperature increase in hyperthermia (HT) treatment for cancer. Microbubbles (MBs) nucleate inertial cavitation under therapeutic ultrasound (TUS) exposure, which form microbubble-enhanced ultrasound (MEUS), which results in blocking blood perfusion in the targeted liver tissues. This study aimed to determine if synergistic effects exist during HT in the liver when combined with MEUS. METHODS: Forty rabbits with surgically exposed livers were randomly divided into TUS + MB + HT, MB + HT, normal saline + HT, and MB + sham groups (n = 10 in each group). Liver perfusion was evaluated using contrast-enhanced ultrasound. The temperatures of the liver tissues were monitored using thermocouples. Pathological changes were determined by hematoxylin and eosin (H&E) staining. Serum hepatic transaminases were evaluated. RESULTS: MEUS pretreatment almost completely blocked the perfusion of targeted areas. The TUS + MB + HT and MB + HT groups showed significantly higher temperatures in treated areas than those in the other groups. However, the TUS + MB + HT group exhibited a more stable and regular increase in temperatures in the fitting curves compared with the MB + HT group. H&E staining revealed swelling hepatocytes, hemorrhage, and thrombosis in the portal area in the TUS + MB + HT group. CONCLUSION: MEUS reduced the blood perfusion in the targeted liver tissues, and, therefore, overcame the heat-sink effect during the HT procedure in rabbits. MEUS pretreatment might have the potential to enhance the therapeutic effect of HT.

Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1.

Cancer-secreted exosomes are critical mediators of cancer-host crosstalk. In the present study, we showed the delivery of miR-21-5p from colorectal cancer (CRC) cells to endothelial cells via exosomes increased the amount of miR-21-5p in recipient cells. MiR-21-5p suppressed Krev interaction trapped protein 1 (KRIT1) in recipient HUVECs and subsequently activated ß-catenin signaling pathway and increased their downstream targets VEGFa and Ccnd1, which consequently promoted angiogenesis and vascular permeability in CRC. A strong inverse correlation between miR-21-5p and KRIT1 expression levels was observed in CRC-adjacent vessels. Furthermore, miR-21-5p expression in circulating exosomes was markedly higher in CRC patients than in healthy donors. Thus, our data suggest that exosomal miR-21-5p is involved in angiogenesis and vascular permeability in CRC and may be used as a potential new therapeutic target.