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

Abstract

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.

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Fig. 1: Expressions of CNR1 and CNR2 in colorectal cancer.
Fig. 2: Effect of Δ9-THC on colorectal tumor growth in xenograft mouse models.
Fig. 3: Effect of Δ9-THC on colorectal tumor metastasis in a tail vein-injected mouse model.
Fig. 4: Effect of Δ9-THC on angiogenesis in colorectal cancer in vitro and in vivo.
Fig. 5: Roles of STAT1 in Δ9-THC-induced angiogenesis in colorectal cancer.
Fig. 6: Knockout of STAT1 by CRISPR/Cas9 system disrupts the interaction between colorectal cancer cells and vascular endothelial cells.
Fig. 7: Interaction between cancer cells and vascular endothelial cells through STAT1-dependent angiogenesis and tumor growth in colorectal cancer.

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Acknowledgements

We thank Taiwan Human Disease Induced Pluripotent Stem Cell Service Consortium (Taiwan-iPSC consortium) for helping with iPSC generation. We are grateful for Dr. Ching-Chow Chen (National Taiwan University) for providing human CRC cells for this project. The authors would like to express their gratitude to the National Taiwan University College of Medicine for facility support.

Funding

This work was financially supported by the Ministry of Science and Technology (MOST) in Taiwan, under Grant MOST108-2636-B-002-007, MOST109-2636-B-002-007, and MOST110-2636-B-002-016. The authors would like to express their gratitude to the National Taiwan University College of Medicine for facility support.

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C.-K.L., P.-H.C., S.-K.N. and W.-Y.L.: collection and/or assembly of data, data analysis and interpretation; C.-K.L. and T.-T.W.: manuscript writing; T.-T.W.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

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Correspondence to Tzu-Tang Wei.

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Luo, CK., Chou, PH., Ng, SK. et al. Cannabinoids orchestrate cross-talk between cancer cells and endothelial cells in colorectal cancer. Cancer Gene Ther (2021). https://doi.org/10.1038/s41417-021-00346-0

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