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it has been observed that cannabinoid receptor cb1 antagonists reduce cancer cell proliferation. moreover, anandamide has been found to suppress cell proliferation of human glioblastoma. cannabinoids have been reported to modulate the expression of genes associated with cancer cell proliferation, migration, and invasion. for example, exposure to a cb1 receptor antagonist has been found to increase the expression of human epidermal growth factor receptor 2 (her2) in her2-overexpressing breast cancer cells, which could explain some of the anti-tumor effects of cb1 antagonists reported in the literature reference 1295 . cannabinoids have been found to reduce the growth of cancer cells and to induce apoptosis in cancer cells references 1296 and 1297 . the cannabinoid receptor cb1 has been suggested to be involved in various types of cancer, including testicular, gastric, cervical, colon, and breast cancer. cb1 receptor blockade has been reported to reduce tumor growth in an animal model of human breast cancer reference 1283 . the expression of cb1 receptors on tumor-associated macrophages has been found to correlate with tumor-induced angiogenesis and with the expression of inflammatory and pro-angiogenic factors such as vegf, il-1, il-6 and il-8. targeting cannabinoid receptors on tumor-associated macrophages has been shown to decrease tumor growth, angiogenesis, and the expression of pro-inflammatory cytokines. in contrast, anandamide has been found to induce angiogenesis of human skin microvascular endothelial cells and to increase the expression of cell adhesion molecules, which in turn may increase the metastatic capacity of tumor cells. these findings indicate that the cannabinoid system exerts a dual effect on the regulation of tumor development and growth: it can either promote or inhibit tumor growth depending on the stage of tumor development references 1274 and 1280 . cannabinoids have been found to inhibit the growth of human tumor xenografts, including prostate cancer, gastric cancer, glioma, and breast cancer. experimental data indicate that cancer cells display a high sensitivity towards the effects of cannabinoids, which include reduced proliferation and induction of apoptosis. it should be noted that studies that have examined the action of cannabinoids on human tumor growth have been performed with different cannabinoids, various cannabinoid receptor ligands, and administration routes. as a consequence, the findings should be interpreted with caution and the observed effects of cannabinoids might be explained by differential effects of different cannabinoid receptor ligands. in addition, the mechanisms of anti-tumor actions of cannabinoids have not yet been elucidated; for example, it has not been established whether cannabinoids activate (i.e., have agonistic activity) or inhibit (i., have antagonistic activity) the same downstream mediators that are important for the actions of the endogenous cannabinoid system reference 1295 .
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