Abstract
Recent studies have shown an anti-tumour activity of cannabinoid receptors CB1 and CB2 in gliomas. This effect was mediated by neurotrophins in breast and prostate carcinoma, while in gliomas this relationship has not yet been considered. The aim of this study was to investigate the expression of cannabinoid receptors CB1 and CB2, neurotrophin NGF and NT-3 and their receptors TrkA and TrkC in glioma and endothelial cells. The analysis was performed in 14 gliomas and 2 non-tumour brain specimens by immunohistochemistry and real-time quantitative-polymerase chain reaction (RTQ-PCR). Gliomas showed a weak immunoreactivity for CB1 and CB2 in tumour and in endothelial cells, and for NGF/TrkA mainly in tumour cells, while a moderate/diffuse immunoreactivity was found for NT-3/TrkC. CB2 was expressed on 3 out of 6 low-grade gliomas and in all high-grade gliomas. Non-tumour brain tissues were weakly positive in astrocytes and endothelium for CB1, CB2, NT-3 and TrkC and negative for NGF and TrkA. By RTQ-PCR, gliomas showed low mRNA levels of NGF/TrkA and moderate levels of CB1, NT-3 and TrkC. CB2 mRNA expression was low or absent. A potential role of cannabinoids, particularly of CB2 agonists devoid of psychotropic side effects, in glioma therapy could have a basis in glioblastomas, because they were all positive, though weakly, to CB2. The presence of neurotrophins and their receptors, mainly NT-3 and TrkC, suggests a possible role of these pathways in glioma growth/invasion, but further investigations are required to verify this hypothesis and a potential relationship between cannabinoids and neurotrophins.
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References
Velasco L, Ruiz L, Sánchez MG, Díaz-Laviada I (2001) Δ(9)-Tetrahydrocannabinol increases nerve growth factor production by prostate PC-3 cells. Involvement of CB1 cannabinoid receptor and Raf-1. Eur J Biochem 268:531–535
Melck D, De Petrocellis L, Orlando P et al (2000) Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141:118–126
De Petrocellis L, Melck D, Palmisano A et al (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A 95:8375–8380
Portella G, Laezza C, Laccetti P et al (2003) Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J 17:1771–1773
Casanova ML, Blazquez C, Martinez-Palacio J et al (2003) Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111:43–50
Velasco G, Galve-Roperh I, Sanchez C et al (2004) Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47:315–323
Galve-Roperh I, Sanchez C, Cortes ML et al (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319
Blazquez C, Gonzalez-Feria L, Alvarez L et al (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623
Gerard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 279:129–134
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65
Nunez E, Benito C, Pazos MR et al (2004) Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53:208–213
Held-Feindt J, Dorner L, Sahan G et al (2006) Cannabinoid receptors in human astroglial tumors. J Neurochem 98:886–893
Sanchez C, de Ceballos ML, del Pulgar TG et al (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61:5784–5789
McAllister SD, Chan C, Taft RJ et al (2005) Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. J Neurooncol 74:31–40
Hart S, Fischer OM, Ullrich A (2004) Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha-converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res 6:1943–1950
Gómez del Pulgar T, Velasco G, Sánchez C et al (2002) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188
Gómez del Pulgar T, de Ceballos ML, Guzmán M, Velasco G (2002) Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 277:36527–36533
Singer HS, Hansen B, Martinie D, Karp CL (1999) Mitogenesis in glioblastoma multiforme cell lines: a role for NGF and its TrkA receptors. J Neurooncol 45:1–8
Kokunai T, Iguchi H, Tamaki N (1999) Differentiation and growth inhibition of glioma cells induced by transfer of trk A proto-oncogene. J Neurooncol 42:23–34
Watanabe T, Katayama Y, Kimura S, Yoshino A (1999) Control of proliferation and survival of C6 glioma cells with modification of the nerve growth factor autocrine system. J Neurooncol 41:121–128
Pflug BR, Colangelo AM, Tornatore C, Mocchetti I (2001) TrkA induces differentiation but not apoptosis in C6-2B glioma cells. Neurosci Res 64:636–645
Kimura S, Yoshino A, Katayama Y et al (2002) Growth control of C6 glioma in vivo by nerve growth factor. J Neurooncol 59:199–205
Wang Y, Hagel C, Hamel W et al (1998) Trk A, B, and C are commonly expressed in human astrocytes and astrocytic gliomas but not by human oligodendrocytes and oligodendroglioma. Acta Neuropathol (Berl) 96:357–364
Wadhwa S, Nag TC, Jindal A et al (2003) Expression of the neurotrophin receptors Trk A and Trk B in adult human astrocytoma and glioblastoma. J Biosci 28:181–188
Chiaretti A, Aloe L, Antonelli A et al (2004) Neurotrophic factor expression in childhood low-grade astrocytomas and ependymomas. Childs Nerv Syst 20:412–419
Kim JY, Sutton ME, Lu DJ et al (1999) Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 59:711–719
Blazquez C, Casanova ML, Planas A et al (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17:529–531
Tamagno I, Shiffer D (2006) Nestin expression in reactive astrocytes of human pathology. J Neurooncol 80:227–233
Ray A, Ho M, Ma J et al (2004) A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10:7613–7620
Kim JY, Sutton ME, Lu DJ et al (1999) Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 59:711–719
Denkins Y, Reiland J, Roy M et al (2004) Brain metastases in melanoma: roles of neurotrophins. Neuro-oncology 6:154–165
Emanueli C, Schratzberger P, Kirchmair R, Madeddu P (2003) Paracrine control of vascularization and neurogenesis by neurotrophins. Br J Pharmacol 140:614–619
Takeo C, Nakamura S, Tanaka T et al (2003) Rat cerebral endothelial cells express trk C and are regulated by neurotrophin-3. Biochem Biophys Res Commun 305:400–406
Guzman M, Duarte MJ, Blasquez C et al (2006) A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95:197–203
Walsh D, Nelson KA, Mahmoud FA (2003) Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer 11:137–143
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Calatozzolo, C., Salmaggi, A., Pollo, B. et al. Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurol Sci 28, 304–310 (2007). https://doi.org/10.1007/s10072-007-0843-8
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DOI: https://doi.org/10.1007/s10072-007-0843-8