Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity?
Introduction
Cannabinoids, the active components of Cannabis sativa L. (marijuana) and their derivatives, exert a wide array of effects by activating specific receptors that are normally engaged by a family of endogenous ligands – the endocannabinoids (Howlett et al., 2002, Piomelli, 2003). Cannabis preparations have been used in medicine for centuries, and nowadays there is a renaissance in the study of their therapeutic effects (Di Marzo and Petrocellis, 2006, Mackie, 2006). Specifically, cannabinoids have been known to exert palliative effects in cancer patients since the early 1970s. The best established of these effects is the inhibition of chemotherapy-induced nausea and vomiting, and nowadays capsules of Δ9-tetrahydrocannabinol (THC), the major active component of cannabis, and its synthetic analogue nabilone are approved for that purpose (Guzmán, 2003, Hall et al., 2005). In addition, several clinical trials are testing other potential palliative properties of cannabinoids in oncology such as appetite stimulation and pain inhibition (Guzmán, 2003, Hall et al., 2005). Besides these palliative actions, cannabinoids have been proposed as potential antitumoral agents owing to their ability to inhibit the growth and angiogenesis of various types of tumor xenografts in animal models (Guzmán, 2003). Studies on malignant brain tumors (gliomas) and other models of cancer strongly support that cannabinoids decrease tumor progression by at least two mechanisms: the apoptotic death of tumor cells (Galve-Roperh et al., 2000, Casanova et al., 2003, Carracedo et al., 2006a, Carracedo et al., 2006b) and the inhibition of tumor angiogenesis (Blázquez et al., 2003, Blázquez et al., 2004, Blázquez et al., 2006, Casanova et al., 2003, Portella et al., 2003, Pisanti et al., 2007). It has also been reported that cannabinoids inhibit the migration and spreading of tumor cells (Portella et al., 2003, Blázquez et al., 2006, Grimaldi et al., 2006). However, the molecular targets of this cannabinoid effect remain elusive. Among the various factors involved in the acquisition of migrating and invasive capacities by cancer cells, the concerted action of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases – TIMPs) plays a pivotal role. MMPs have been long linked to cancer cell invasion owing to their crucial involvement in extracellular matrix breakdown. Accordingly, increased expression and activation of MMPs is found in almost all human cancers compared with normal tissue, and this increase has been associated with poor patient prognosis (Egeblad and Werb, 2002, Deryugina and Quigley, 2006, Overall and Kleifeld, 2006). Likewise, cannabinoid administration down-regulates MMP-2 expression in vascular endothelial and tumor cells (Blázquez et al., 2003, Pisanti et al., 2007). In addition to the MMPs, one of the most prominent MMP inhibitors, TIMP-1, is selectively up-regulated in numerous cancers, and this has been shown to be closely associated with negative prognosis, making TIMP-1 a promising candidate for new negative-prognosis marker (Hornebeck et al., 2005, Würtz et al., 2005, Yasui et al., 2005, Chirco et al., 2006). This finding may be explained, at least in part, by MMP-independent actions of TIMP-1 such as promotion of tumor cell proliferation and survival as well as of tumor angiogenesis (Hornebeck et al., 2005, Chirco et al., 2006). This background prompted us to explore the effect of cannabinoid administration on TIMP-1 expression by cancer cells. Here we report that cannabinoid administration inhibits TIMP-1 expression in cultured glioma cells, in mice bearing gliomas and in two patients with glioblastoma multiforme. In addition, our data support that this effect is mediated by the sphingolipid ceramide and the stress protein p8, two key signaling elements of cannabinoid antitumoral action (Guzmán, 2003, Blázquez et al., 2004, Carracedo et al., 2006a, Carracedo et al., 2006b).
Section snippets
Cannabinoids
THC and JWH-133 were kindly given by Alfredo Dupetit (The Health Concept, Richelbach, Germany) and J.W. Huffman (Department of Chemistry, Clemson University, SC), respectively. For in vitro incubations cannabinoids were directly applied at a final DMSO concentration of 0.1–0.2% (v/v). For in vivo administration to mice cannabinoids were prepared at 1% (v/v) DMSO in 100 μl PBS supplemented with 5 mg/ml bovine serum albumin. No significant influence of the vehicle was observed on any of the
THC inhibits TIMP-1 expression in mouse gliomas
To test whether cannabinoid administration affects TIMP-1 levels, we generated tumors by subcutaneous inoculation of glioma cells to mice. The specificity of cannabinoid action was ascertained by the parallel study of C6.9 and C6.4 glioma cells, which constitute well established models of cannabinoid-responsive and cannabinoid-resistant cells, respectively (Galve-Roperh et al., 2000, Gómez del Pulgar et al., 2002, Carracedo et al., 2006b). Tumors were treated with either vehicle or THC and
Discussion
Despite the widely described antitumoral actions of cannabinoids in various animal models of cancer (Guzmán, 2003), the molecular effectors of these actions have not been fully characterized as yet. Here we show that cannabinoid administration down-regulates TIMP-1 expression in mice bearing gliomas as well as in two patients with recurrent glioblastoma multiforme. Cannabinoid-induced inhibition of TIMP-1 expression was also evident in cultured glioma cells, indicating that the changes observed
Acknowledgements
We are indebted to Eva Resel for expert technical assistance and to the rest of the members of the lab for discussion and advice. This work was supported by grants from Ministerio de Educación y Ciencia (SAF2006-00918 to M.G.), Comunidad de Madrid (S-SAL/0261/2006 to M.G.) and Universidad Complutense de Madrid (PR1/07-14896 to C.B.).
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