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The results of these reports suggest that cannabinoid receptor stimulation by chemical carcinogens and UVB light promotes tumor development but that exogenously administered cannabinoid ligands induce tumor cell death.
Whereas the endogenous levels of endocannabinoids (nanomolar range) associated with carcinogen exposure increases tumor growth, the exogenous administration of cannabinoids (micromolar range) decreases tumor growth.
This suggestion is consistent with our previous studies demonstrating that low concentrations of anandamide (< 10 μM) increased NMSC cell proliferation while high concentrations (> 10 μM) caused cell death and apoptosis .
Collectively, the data suggest that ECS components are functional in keratinocytes and can be targeted to bring about tumor cell death.
Recent research suggests that the ECS plays a critical role in melanoma development and progression. Cannabinoid receptors CB1 and CB2 are expressed in human melanomas and numerous melanoma cell lines suggesting functional endocannabinoid signaling in this cancer type .
In this study, the cytotoxicity of ∆9-THC was further increased in melanoma cells co-treated with cannabidiol (CBD). Furthermore, the anti-tumor effects were replicated in a melanoma xenograft mouse model . Similarly, Glodde’s group reported that ∆9-THC decreased the growth of melanoma in vitro and in vivo and that this effect was not observed in mice lacking CB1 and CB2 receptors, pointing to a CB receptor-dependent mechanism . Interestingly, a different report demonstrated that ∆9-THC preferentially eliminated melanoma compared to non-tumorigenic melanocytes by inhibiting the activity of the pro-survival proteins, Akt and pRb . As such, phytocannabinoids may emerge as a selective and effective class of anti-melanoma agents.
In this investigation we report evidence that human keratinocytes have a functional “endocannabinoid system,” i.e. AEA and the biochemical machinery to bind, synthesize, transport, and hydrolyze it.
We also show that differentiating keratinocytes have decreased levels of endogenous AEA, due to increased degradation of this lipid through AMT and FAAH. In addition, we demonstrate that exogenous AEA inhibits keratinocyte differentiation in vitro, through a CB1-dependent mechanism that involves inactivation of protein kinase C, activating protein-1, and transglutaminase.
Our findings give a biochemical foundation for the effects of AEA on epidermal cells, especially in relation to pain sensation (12), response to UV irradiation (16), cell proliferation (17), and tumor growth (18). In this context, the finding, that human keratinocytes partake in the peripheral endocannabinoid system and that AEA can inhibit epidermal differentiation, opens new perspectives in the understanding of skin development and in the treatment of human skin diseases where cell hyperproliferation takes place.
In conclusion, we report evidence that human keratinocytes have a functional “endocannabinoid system,” which may sustain the peripheral actions of AEA at the skin level.
On the footsteps of Karsak et al., we further investigated the immunological role of the eCB-signaling using human epidermal keratinocytes. We found that protein (but, interestingly, not mRNA) expression and activity of the aforementioned eCB-degrading enzyme FAAH was positively regulated by Toll-like receptor (TLR) 2 activation (Oláh et al., 2016a). This quite fascinating result clearly demonstrated how deeply the ECS is involved in the regulation of one of the most fundamental immune processes, i.e. the TLR-activation-induced pro-inflammatory signaling.
Indeed, administration of selective FAAH-inhibitors (and thereby restoration of the homeostatic, anti-inflammatory eCB signaling leading to the activation of CB1 and CB2 receptors) was able to almost completely abrogate the TLR2-mediated pro-inflammatory response (Oláh et al., 2016a).
Based on these data, FAAH appears to be an important “decision maker” in the initiation and maintenance of cutaneous inflammation; thus, increase/restoration of the homeostatic cutaneous eCB tone by topically applied FAAH-inhibitors possesses great potential in alleviating skin inflammation (Fig. 1A).
Excitingly, modulating the activity of the ECS has turned out to hold tremendous therapeutic potential for a multitude of diseases and pathological conditions affecting humans [13,15,16], ranging from inflammatory , neurodegenerative [18–20], gastrointestinal [21,22], liver [23,24], cardiovascular disorders [25,26] and obesity [27,28], to ischemia/reperfusion injury , cancer  and pain .
The pilosebaceous unit of the human skin, comprising the intimately localized hair follicle (HF) and the sebaceous gland (SG), can be regarded as the ‘brain’ of the skin because it controls a wide-array of the biological functions of this organ (from stem-cell supply through immunomodulation to cytokine production)
Casanova et al.  have demonstrated that various human skin tumors (e.g. basal cell carcinoma, squamous cell carcinoma) express both CB1 and CB2.
Local administration of synthetic CB1 and CB2 agonists induced growth inhibition of malignant skin tumors generated by intradermal inoculation of tumorigenic PDV.C57 mouse keratinocytes into nude mice.
The ECS has numerous important immune modulatory effects (e.g. suppression of production of various cytokines, chemokines, arachidonic acid-derived pro-inflammatory metabolites and nitric oxide) during inflammation .
Moreover, the skin inflammation was suppressed by locally administered THC .