Cannabinoids orchestrate cross-talk between cancer cells and endothelial cells in colorectal cancer

Marijuana has recently become legalized both for recreational and medicinal use and its prevalence is on the rise. This study expands the understanding of marijuana use and colorectal cancer carcinogenesis.

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Marijuana has recently become legalized both for recreational and medicinal use, and its prevalence is on the rise 1. Medical marijuana has been approved by the FDA for treating chemotherapy-induced nausea and vomiting 2,3. Although the effects of cannabinoids have been investigated in multiple cancer types, there are controversial results regarding its effect on tumor growth. Several publications reported the anti-cancer effects of Δ9-tetrahydrocannabinol (Δ9-THC), the active ingredient in cannabis plants and medical marijuana 4,5. Those studies often used extremely high-dosing range of cannabinoids, which exceed the binding constants between cannabinoids and cannabinoid receptors. On the contrary, many publications reported that Δ9-THC with physiological doses enhanced tumor growth and metastasis 6-9. Recent systematic review and meta-analysis study showed an increase in certain cancers with marijuana use 10, however, the association between cannabinoids and tumor growth remains unclear. 

In this study, we demonstrated the oncogenic role of cannabinoid receptors in colorectal cancer (CRC) by disclosing increased expressions of CB1 and CB2 receptors in patients with colorectal adenocarcinoma at National Taiwan University Hospital and in mouse models. Δ9-THC with a physiological dose promoted CRC tumor growth and angiogenesis in mouse models. Using human induced pluripotent stem cell (iPSC) and in vivo angiogenesis models, we discovered that Δ9-THC increased the secretion of five growth factors from CRC cells through the nuclear translocation of STAT1 transcription factor. Pharmacological treatment with STAT1 antagonist or abrogation of STAT1 with CRISPR/Cas9-based strategy rescued the adverse effects of Δ9-THC in CRC.  

We are reporting for the first time that Δ9-THC promotes CRC tumor growth and angiogenesis via a STAT1-dependent manner. We hypothesize that clinical co-treatment with STAT1 antagonist and Δ9-THC would allow for beneficial effects of Δ9-THC such as appetite stimulant and sedation while protecting from adverse effects on tumor cells and tumor microenvironment in patients with CRC. 

Photos include: Cong-Kai Luo, Pei-Hsuan Chou, Shang-Kok Ng, Wen-Yen Lin, Zuo-Yi Hong, Hsin-Hui Wang, Chun-Hao Wang, You-Xuan Li, Pin-Jung Liu, Dai-Jung Chung and Tzu-Tang Wei, all from The TTW Lab – Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine (NTUCM), Taipei, Taiwan 

For further information, the original article is available at

https://www.nature.com/articles/s41417-021-00346-0

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Tzu-Tang Wei

Assistant Professor , National Taiwan University