Immunohistochemical expression of cannabinoid receptors in women’s cancers: what’s new?

The cannabinoid receptors belong to the G protein-coupled receptor superfamily and are integral part of the endocannabinoid system. Two main types of cannabinoid receptors are known: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). In the last few years, great attention has been paid to the immunohistochemical evaluation of CB1 and CB2 expression in various types of tumors, including women’s cancers, for the alleged anticancer properties of cannabinoids. Today, in the modern era of precision oncology, monoclonal antibodies for the immunohistochemical evaluation of CB1 and CB2 expression are available on the market; therefore, our recommendation is to submit preliminary the formalin-fixed, paraffin-embedded, bioptic or surgical specimen of neoplastic tissue, containing at least 100 tumor cells and coming from the selected patient with no history of cannabis abuse, to predictive immunohistochemistry, before undertaking any cannabinoid-based therapeutic attempt, in association with conventional anticancer treatments or when the most advanced care is failing. The receptor expression is determined through a ‘tumor proportion score’ (TPS), which represents the percentage of viable neoplastic cells showing partial or complete membrane staining. By exploiting a methodology analogous to that applied for PD-L1 (programmed death-ligand 1) testing on cancer tissues, the specimen can be considered to have a high CB1 and/or CB2 expression if TPS ≥ 50%; a value between 1–49% corresponds to a low expression, while below 1% certifies no significant expression and, thus, no eligibility to a cannabinoid-based pharmacological approach.

Cannabinoid receptors; Cannabinoid receptor 1 (CB1); Cannabinoid receptor 2 (CB2); Immunohistochemistry; Predictive immunohistochemistry; Tumor pro- portion score (TPS); Cancer

[1] Ottani A, Giuliani D. Hu 210: a potent tool for investigations of the cannabinoid system. CNS Drug Reviews. 2001; 7: 131–145.

[2] Kogan NM, Schlesinger M, Priel E, Rabinowitz R, Berenshtein E, Chevion M, et al. HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor. Molecular Cancer Therapeutics. 2007; 6: 173–183.

[3] Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discovery Today. 2017; 22: 105–110.

[4] Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Pediatric Anesthesia. 2008; 18: 915–921.

[5] Latek D, Kolinski M, Ghoshdastider U, Debinski A, Bombolewski R, Plazinska A, et al. Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β2AR. Journal of Molecular Modeling. 2011; 17: 2353–2366.

[6] Jäntti MH, Mandrika I, Kukkonen JP. Human orexin/hypocretin receptors form constitutive homo-and heteromeric complexes with each other and with human CB1 cannabinoid receptors. Biochemical and Biophysical Research Communications. 2014; 445: 486–490.

[7] Ibrahim BM, Abdel-Rahman AA. A pivotal role for enhanced brainstem orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats. Brain Research. 2015; 1622: 51–63.

[8] Flores A, Maldonado R, Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Frontiers in Neuroscience. 2013; 7: 256.

[9] Lavezzi AM, Ferrero S, Roncati L, Matturri L, Pusiol T. Impaired orexin receptor expression in the Kölliker-Fuse nucleus in sudden infant death syndrome: possible involvement of this nucleus in arousal pathophysiology. Neurological Research. 2016; 38: 706–716.

[10] Jordan CJ, Xi Z. Progress in brain cannabinoid CB2 receptor research: from genes to behavior. Neuroscience & Biobehavioral Reviews. 2019; 98: 208–220.

[11] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British Journal of Pharmacology. 2008; 153: 199–215.

[12] Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proceedings of the National Academy of Sciences. 1999; 96: 14136–14141.

[13] Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson N, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology. 2007; 152: 1092–1101.

[14] Ayakannu T, Taylor AH, Willets JM, Konje JC. The evolving role of the endocannabinoid system in gynaecological cancer. Human Reproduction Update. 2015; 21: 517–535.

[15] Yan L, Li J, Zhao T, Wang H, Lai G. Over-expression of cannabinoid receptor 2 induces the apoptosis of cervical carcinoma Caski cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2015; 31: 758–762. (In Chinese)

[16] Ayakannu T, Taylor AH, Konje JC. Cannabinoid receptor expression in estrogen-dependent and estrogen-independent endometrial cancer. Journal of Receptors and Signal Transduction. 2018; 38: 385–392.

[17] Guida M, Ligresti A, De Filippis D, D’Amico A, Petrosino S, Cipriano M, et al. The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma. Endocrinology. 2010; 151: 921–928.

[18] Messalli EM, Grauso F, Luise R, Angelini A, Rossiello R. Cannabinoid receptor type 1 immunoreactivity and disease severity in human epithelial ovarian tumors. American Journal of Obstetrics and Gynecology. 2014; 211: 234.e1–234.e6.

[19] Franks LN, Ford BM, Prather PL. Selective estrogen receptor modulators: cannabinoid receptor inverse agonists with differential CB1 and CB2 selectivity. Frontiers in Pharmacology. 2016; 7: 503.

[20] Prather PL, FrancisDevaraj F, Dates CR, Greer AK, Bratton SM, Ford BM, et al. CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen. Biochemical and Biophysical Research Communications. 2013; 441: 339–343.

[21] Ford BM, Franks LN, Radominska-Pandya A, Prather PL. Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development. PLoS One. 2016; 11: e0167240.

[22] Qamri Z, Preet A, Nasser MW, Bass CE, Leone G, Barsky SH, et al. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Molecular Cancer Therapeutics. 2009; 8: 3117–3129.

[23] Grimaldi C, Pisanti S, Laezza C, Malfitano AM, Santoro A, Vitale M, et al. Anandamide inhibits adhesion and migration of breast cancer cells. Experimental Cell Research. 2006; 312: 363–373.

[24] Elbaz M, Ahirwar D, Ravi J, Nasser MW, Ganju RK. Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-i/IGFIR pathways in breast cancer. Oncotarget. 2017; 8: 29668–29678.

[25] Pérez-Gómez E, Andradas C, Blasco-Benito S, Caffarel MM, García-Taboada E, Villa-Morales M, et al. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. Journal of the National Cancer Institute. 2015; 107: djv077.

[26] Blasco-Benito S, Moreno E, Seijo-Vila M, Tundidor I, Andradas C, Caffarel MM, et al. Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer. PNAS. 2019; 116: 3863–3872.

[27] Luca R. Diagnostic, prognostic and predictive immunohistochemistry in malignant melanoma of the skin. Klinicka Onkologie. 2018; 31: 152–155.

[28] Piscioli F, Pusiol T, Roncati L. Thin melanoma subtyping fits well with the American Joint Committee on Cancer staging system. Melanoma Research. 2016; 26: 636.

[29] Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD- L1-positive non-small-cell lung cancer. New England Journal of Medicine. 2016; 375: 1823–1833.

[30] Roncati L. Microsatellite instability predicts response to anti-PD1 immunotherapy in metastatic melanoma. Acta Dermatovenerologica Croatica. 2018; 26: 341–343.