Evaluation of the effects of THC on migration, proliferation, and tumor growth in HPV-negative HNSCC.

Abstract

e18062 Background: Head and neck squamous cell carcinoma (HNSCC) is a significant global health concern, with over 60,000 new cases and approximately 14,000 deaths annually in the United States. Major risk factors include tobacco and alcohol use, as well as human papillomavirus (HPV) infection, which accounts for a growing subset of cases. Concurrently, the rising prevalence of cannabis use—reported in over 18% of U.S. adults—has raised concerns about its role in cancer pathogenesis. THC (Δ9-tetrahydrocannabinol), the primary psychoactive component of cannabis, interacts with CB1 and CB2 receptors, often overexpressed in cancers like HNSCC. While background studies have shown anti-tumor effects of THC, such as apoptosis and reduced metastasis in some preclinical models, its immunosuppressive properties and interactions with tumor biology remain concerning. Prior research highlights THC’s potential to promote tumor progression and metastasis in HPV-negative HNSCC through activation of oncogenic pathways, including p38 MAPK signaling. Epidemiological data further suggest a 25% increased risk of HNSCC among chronic cannabis users, underscoring the need for detailed investigation into its role in HPV-negative tumor progression. Methods: The pro-tumorigenic effects of THC at a recreational dosage (1 µg/mL) were assessed using HPV-negative head and neck squamous cell carcinoma (HNSCC) cell line JHU011. Cell proliferation was evaluated through Aqua Bluer assay, while the impact on cell migration and invasion was determined using wound healing and trans-well migration/invasion assays. THC-mediated activation of the ERK and p38 MAPK signaling pathways was analyzed through ELISA and Western blot. Additionally, the in vivo effects of THC on tumor growth were investigated using an immunocompetent lateralized oral cavity tumor model. In this model, 4MOSC1 cells were orthotopically injected into the buccal mucosa of C57BL/6 mice, serving as an HPV-negative HNSCC model. Results: Our findings indicate that treatment with 1μM THC promotes migration and invasion of HPV-negative HNSCC cell JHU011, without affecting cell proliferation. Additionally, THC treatment activated the p38 MAPK pathway as well as ERK MAPK pathway in these cells. In vivo studies involving daily administration of 1μM THC demonstrated no significant effect on tumor growth compared to controls in 4MOSC1 HPV-negative HNSCC model using immunocompetent animals. Conclusions: THC at recreationally relevant doses promotes cell migration and invasion in HPV-negative HNSCC via p38 and ERK MAPK activation without affecting proliferation or in vivo tumor growth. These findings underscore the complex role of THC in cancer biology and warrant further investigation into its implications for HNSCC progression.