The Interplay between Cancer Biology and the Endocannabinoid System-Significance for Cancer Risk, Prognosis and Response to Treatment

Simple Summary This review analyses the complex involvement of the various components of the endocannabinoid system (ECS) in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, central nervous system (CNS) tumours, and melanoma). The same ECS component can exert both protective and pathogenic effects in different tumour subtypes, which are often pathologically driven by different biological factors. Although an attractive target in cancer, the use of components in anti-cancer treatment is still interlinked with many legal and ethical issues that need to be considered. The legislation which outlines the permissive boundaries of their therapeutic use in oncology is still unable to follow the current scientific burden of evidence, but the number of ongoing clinical trials might tip the scale forward in the near future. The various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and the signalling network behind it, are implicated in several tumour-related states, both as favourable and unfavourable factors. This review analyses the ECS's complex involvement in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, CNS tumours, and melanoma). Changes in the expression and activation of CBRs, as well as their ability to form distinct functional heteromers affect the cell's tumourigenic potential and their signalling properties, leading to pharmacologically different outcomes. Thus, the same ECS component can exert both protective and pathogenic effects in different tumour subtypes, which are often pathologically driven by different biological factors. The use of endogenous and exogenous cannabinoids as anti-cancer agents, and the range of effects they might induce (cell death, regulation of angiogenesis, and invasion or anticancer immunity), depend in great deal on the tumour type and the specific ECS component that they target. Although an attractive target, the use of ECS components in anti-cancer treatment is still interlinked with many legal and ethical issues that need to be considered.