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ro-anandamide treatment of rat thyroid epitheliomas in vitro and in vivo, with
subsequent inhibition of p21 ras , leads to sensibly increased levels of p27, an
effect that may contribute to the anti-proliferative actions of (endo)cannabinoids
in this model [37].
Finally, as shown by using various biochemical and pharmacological
approaches, the stimulation of CB 2, or of both CB 1 and CB 2, receptors can also
lead to significant counteraction of tumor growth via various mechanisms [38,
39]. In fact, inhibition of cell mitosis was shown not to be the only mechanism
through which cannabinoids block solid tumor growth, particularly when CB 2
or other non-CB 1 receptors (see below) are involved. ∆ 9 -THC was found to
induce the programmed death (apoptosis) of glioma and prostate cancer cells
[40, 41]. The increased ceramide levels observed in glioma cells after cannabinoid
action would drive the prolonged activation of the Raf1/MEK/ERK signaling
cascade [42] and Akt inhibition [43], as well as induction of cyclooxygenase-2
(COX-2) expression [44]. While the relation between ERK activation
and cell fate is complex and depends on many factors [45], the involvement of
oxidative stress [46] and stress-activated protein kinases [47] cannot be ruled out
during (endo)cannabinoid-induced apoptosis (Fig. 2). At any rate, these effects
of CB 2 receptor stimulation result in glioma cell apoptosis in vitro, and in powerful
inhibition of glioma growth in vivo [38, 42], although some of the tumors
developed in vivo can be significantly less sensitive to ∆ 9 -THC than others [42].
Cannabinoid receptor stimulation leads to inhibition of tumor
angiogenesis and metastasis
Expression of various oncogenes, particulary ras, can lead to a marked induction
of a potent paracrine stimulator of angiogenesis, the vascular endothelial
growth factor (VEGF) [48] (Fig. 2). The enhanced expression of VEGF is
associated with a large number of human tumor types, including human thyroid
tumors and cancer cells. The observation that met-fluoro-anandamide is
able to block p21 ras activity [33], and that endocannabinoids can inhibit the
expression of several growth factors and/or their receptors (see above), suggested
that CB 1 receptor stimulation could also interfere with VEGF and
VEGF receptors. Indeed, in rat thyroid epitheliomas, met-fluoro-anandamide
was found to inhibit the growth of already established tumors, in part by reducing
the expression of VEGF and of the VEGF receptor Flt-1, which plays a
crucial role in mediating VEGF-induced neo-angiogenesis and endothelial cell
proliferation [37]. The expression of both VEGF and Flt-1 was suppressed not
only in the tumor in vivo but also in tumor cells in vitro, indicating that the
blockage of VEGF signaling may have a direct effect on tumor growth and
metastasis, not only by blocking neo-angiogenesis but also by disrupting
VEGF/VEGF receptor autocrine pathways [49].
It has been reported that CB 1 and CB 2 cannabinoid receptors are expressed
in normal epidermis and in mouse skin tumors, and in this case both receptors