Hyperthermia Inhibits Angiogenesis

Abstract

Since in vitro studies have demonstrated that capillary endothelial cells are thermosensitive, experiments were performed to determine the (in vivo) heat sensitivity of blood capillaries and their endothelial cells. Angiogenesis discs were implanted subcutaneously in mice, and vascular growth was stimulated by slow release of epidermal growth factor placed in the center of each disc. After 5 days of growth the discs were subjected to radiofrequency-induced hyperthermia. Heat exposures were 41, 42, 43, and 44 degrees C for 30 min. Control discs were sham treated. Seven days after heating the discs were extracted and paraffin embedded. Centripetal (radial) vessel growth was measured in magnified medial planar sections. An inverse relationship was demonstrated between vessel growth and exposure temperature. The extent of the fibroblastic growth was also inversely proportional to temperature. Thus, at least in this system, the microvasculature shows dose-dependent damage by hyperthermia, consistent with preceding in vitro observations. This inhibition of angiogenesis may result from endothelial cell killing, interference with cell replication, inhibition of cell migration, or a combination of these mechanisms.

Anti-angiogenic action of hyperthermia by suppressing gene expression and production of tumour-derived vascular endothelial growth factor in vivo and in vitro

“…Fajardo et al (1988) also reported that hyperthermia inhibits angiogenesis by interference with cell replication and/or inhibition of the migration of vascular endothelial cells. However, the effect of hyperthermia on the production of VEGF is not specified.…”

“…We recently reported that heat shock suppresses in vitro invasive activity of human fibrosarcoma HT-1080 cells by suppressing the production of membrane type 1-MMP (MT1-MMP) and the activation of proMMP-2/progelatinase A (Sato et al, 1999;Sawaji et al, 2000). On the other hand, Fajardo et al (1988) reported that hyperthermia inhibits angiogenesis in vivo. Therefore, it is likely that hyperthermia is efficacious for preventing tumour metastasis and invasion, but it remains unclear whether hyperthermia could influence the expression of VEGF in tumour cells.…”

In vivo models of angiogenesis

“…Introduced in 1988, the DAS implanted s.c. in mice provides a model of wound healing and of angiogenic responses to solid tumors and soluble substances [98].…”

“…A test agent or the suspension of tumor cells to be studied is placed at the center of the disc. The slow release of the test substance or of factors from the tumor cells is maintained by a film of ethylene-vinyl acetate co-polymer or by the use of agarose [98]. The abdomen and thorax of the mouse are convenient implantation sites.…”

Status of Clinical Hyperthermia

“…The discovery that heat-shock proteins are presented on cell surfaces after hyperthermia, where they may serve as specific receptors for natural killer-cells, is of particular interest (4). Hyperthermia also induces apoptosis (5-7) and inhibits angiogenesis (8), which may contribute to the observed antitumour effect.…”