Cannabinoids, the active components of marijuana and their derivatives, inhibit tumor growth in animal models, but the mechanism of their anti-tumoral action in vivo is still unclear. Because the generation of a new vascular supply (angiogenesis) is causally involved in the progression of the majority of solid tumors, the aim of this study was to test whether cannabinoids inhibit tumor angiogenesis.
PRINCIPAL FINDINGS
1. Cannabinoid administration inhibits tumor angiogenesis
We induced malignant tumors in immune-deficient mice by subcutaneous flank inoculation of rat C6 glioma cells or human grade IV astrocytoma cells and injected them for 8 days with vehicle or the nonpsychoactive CB2 cannabinoid agonist JWH-133 at 50 μg/day. We found that tumors from cannabinoid-treated animals were smaller and paler than controls (Fig. 1⇓ A, B). Analysis of the vasculature by immunostaining of CD31, an endothelial cell marker, revealed no significant effect of JWH-133 on microvascular count (number of blood vessels per unit area) in the tumors (data not shown). However, cannabinoid administration turned the microvascular hyperplasia of control tumors (Fig. 1C, E⇓ ) to a pattern of blood vessels characterized predominantly by very small and narrow capillaries (Fig. 1D, F⇓ ). Moreover, whereas control tumors showed a fractionated immunostaining of smooth muscle α-actin (SMA) (Fig. 1G⇓ ), a smooth muscle cell and pericyte marker, in cannabinoid-treated tumors SMA-positive cells had a mature appearance and remained closely investing the endothelial wall (Fig. 1H⇓ ). We next examined whether these changes in tumor vascularization led to actual differences in vascular functionality as assessed by a vascular permeability assay. Tumor-bearing animals were anesthetized and Evans blue (1% in PBS, 100 μL/mouse) …
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