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

Medical marijuana has been approved by the FDA for treating chemotherapy-induced nausea and vomiting. However, less is known about its direct effects on tumor cells and the tumor microenvironment. In this study, RNA-sequencing datasets in the NCBI GEO repository were first analyzed; upregulation of cannabinoid receptors was observed in both primary and metastatic colorectal cancer (CRC) tumor tissues. An increase of cannabinoid receptors was also found in patients with CRC, azoxymethane/dextran sulfate sodium-induced CRC and CRC metastatic mouse models. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC)-induced tumor progression in both primary and metastatic mouse models and also increased angiogenesis. A human growth factor antibody array indicated that Δ⁹-THC promoted the secretion of angiogenic growth factors in CRC, leading to the induction of tube formation and migration in human-induced pluripotent stem cell-derived vascular endothelial cells. The nuclear translocation of STAT1 played important roles in Δ⁹-THC-induced angiogenesis and tumor progression. Pharmacological treatment with STAT1 antagonist or abrogation of STAT1 with CRISPR/Cas9-based strategy rescued those effects of Δ⁹-THC in CRC. This study demonstrates that marijuana might increase the risk of CRC progression and that inhibition of STAT1 is a potential strategy for attenuating these side effects.