In
tumors,
caveolin-1, the structural
protein of caveolae, constitutes a key switch through its function as a
tumor suppressor and a promoter of
metastases. In endothelial cells (EC),
caveolin is also known to directly interact with the
endothelial nitric oxide synthase (eNOS) and thereby to modulate
nitric oxide (NO)-mediated processes including vasodilation and angiogenesis. In this study, we examined whether the modulation of the stoichiometry of the
caveolin/eNOS complex in EC lining
tumor blood vessels could affect the
tumor vasculature and consecutively
tumor growth. For this purpose, we used cationic
lipids, which are delivery systems effective at targeting
tumor vs. normal vascular networks. We first documented that in vitro
caveolin transfection led to the inhibition of both
VEGF-induced EC migration and tube formation on
Matrigel. The
DNA-lipocomplex was then administered through the tail vein of
tumor-bearing mice. The direct interaction between recombinant
caveolin and native eNOS was validated in coimmunoprecipitation experiments from
tumor extracts. A dramatic
tumor growth delay was observed in mice transfected with
caveolin- vs.
sham-transfected animals. Using
laser Doppler imaging and microprobes, we found that in the early time after lipofection (e.g., when macroscopic effects on the integrity of the
tumor vasculature were not detectable),
caveolin expression impaired NO-dependent
tumor blood flow. At later stages post-transfection, a decrease in
tumor microvessel density in the central core of
caveolin-transfected
tumors was also documented. In conclusion, our study reveals that by exploiting the exquisite regulatory interaction between eNOS and
caveolin and the propensity of cationic
lipids to target EC lining
tumor blood vessels,
caveolin plasmid delivery appears to be a safe and efficient way to block neoangiogenesis and vascular function in solid
tumors, independently of any direct effects on
tumor cells.