Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases

Rose Milando; Adam Friedman

Disclosures

Am J Clin Dermatol. 2019;20(2):167-180. 

In This Article

Cannabinoids and Cutaneous Neoplasia

Much evidence has shown that uncontrolled inflammation in the skin not only leads to inflammatory conditions such as those listed above but is also a hallmark in UV-related and chemically induced skin cancers. Because cannabinoids play a role in modifying inflammation and epidermal cell differentiation and proliferation, they have been investigated for their role in regulating melanoma and non-melanoma skin cancer.[113,114]

Melanoma Skin Cancer

When melanocytes undergo carcinogenesis, they gain the ability to evade apoptosis, promote angiogenesis, and proliferate uncontrolled.[115] Because human melanomas and melanoma cell lines express both CB1r and CB2r, studies have been conducted to understand the interaction between the endocannabinoid system and melanoma formation.[116] For example, activation of CB1r and CB2r promotes apoptosis and inhibits cancer growth of human melanoma cells in mice. Additionally, autophagy, loss of viability, and apoptosis of melanoma cell lines A375, SK-MEL-28, and CHL-1 are induced by THC in vitro and in vivo.[116] Similarly, Glodde et al.[117] found that, in vivo, THC treatment reduced the growth of melanomas in a CB1r- and CB2r-dependent fashion. However, in this experiment, THC reduced melanoma growth only in vivo, and not in vitro, indicating that the tumor microenvironment might play a role in this pathway.[117] These studies indicate that the cannabinoid system has an anti-tumorigenic effect.

However, in other studies, activation of the endocannabinoid system was shown to promote melanoma cell growth. Genetic deletion of CB1r in human melanoma cell lines showed less viability and reduced migration as compared with controls, suggesting that activation of the endocannabinoid system via CB1r might promote melanoma tumorigenesis.[118]

One explanation for contradictory study results is the effect of the tumor microenvironment, which might not be adequately accounted for in in vitro studies.[117] Additionally, the amount of cannabinoid added to the system can influence the end effect. For example, Pucci et al.[119] described how, at low doses, AEA stimulates melanin production in a CB1r-dependent fashion; at high doses, AEA triggers apoptosis via a TRPV1-dependent pathway.[119]

Non-melanoma Skin Cancer

Because cannabinoids regulate aspects of keratinocyte homeostasis, it follows that they can also influence the development of squamous cell and basal cell carcinomas.[114] However, the exact nature of that influence is debated, as the results of many studies are contradictory. For example, Zheng et al.[120] noticed that mice devoid of CB1r and CB2r had significantly lower rates of UVB-induced inflammation and tumorigenesis than mice with functioning cannabinoid receptors. This indicates a pro-carcinogenic receptor-dependent pathway within the endocannabinoid system, whereas others, such as Casanova et al.[121] have shown the opposite, determining that CB1r/CB2r agonist WIN-55,212–2 and CB2r agonist JWH-133 were able to induce apoptosis and decrease angiogenesis in PDV.C57 epidermal tumors. Still others state that cannabinoids exert an effect on tumorigenesis that is independent of either CB1r or CB2r activation. One such study demonstrated that AEA induced apoptosis independent of CB1r and CB2r via inhibition of nuclear factor (NF)-κB.[122]

One possible explanation for these discrepancies lies in the different cannabinoid dosages used in these studies. Nanomolar concentrations of endocannabinoids (representative of endogenous levels) are associated with nonmelanoma skin cancer tumorigenesis in UVB-related and chemically induced models, whereas micromolar concentrations (representative of exogenous administration) decrease non-melanoma skin cancer.[114]

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