Abstract
Accumulating evidence implies that cell fusion is one of the driving forces of cancer invasion and metastasis. However, considerably less is still known about the triggering factors and underlying mechanisms associated with cancer-host cell fusion, particularly in inflammatory tumor microenvironment. In this study, we confirmed that inflammatory factor TNF-α could enhance fusion between squamous cell carcinoma cells 9 (SCC-9) and human umbilical vein endothelial cells (HUVEC). Further study revealed that TNF-α could promote up-regulation of syncytin-1 in SCC-9 and its receptor neutral amino acid transporter type 2 (ASCT-2) in HUVEC. Syncytin-1 acted as an important downstream effector in TNF-α-enhanced cancer-endothelial cell fusion. TNF-α treatment also led to the activation of Wnt/β-catenin signal pathway in SCC-9. The activation of Wnt/β-catenin signal pathway was closely associated with the up-regulation of syncytin-1 in SCC-9 and increased fusion between SCC-9 and HUVEC while blocking of Wnt/β-catenin signal pathway resulted in the corresponding down-regulation of syncytin-1 accompanied by sharp decrease of cancer-endothelial cell fusion. Taking together, our results suggest that Wnt/β-catenin signal pathway activation-dependent up-regulation of syncytin-1 contributes to the pro-inflammatory factor TNF-α-enhanced fusion between oral squamous cell carcinoma cells and endothelial cells.
Highlights
It is well recognized that cell fusion plays a crucial role in a variety of physiological events, such as fertilization, placentation, skeletal muscle formation, and tissue regeneration[1]
As inflammation microenvironment is strongly linked with tumor progression, we investigated whether pro-inflammatory factor TNF-αcould promote squamous cell carcinoma cells 9 (SCC-9) ×human umbilical vein endothelial cells (HUVEC) fusion
We further investigated the mechanisms underlying the enhanced oral cancer/endothelial cell fusion in inflammation microenvironment, focusing on the role of inflammatory factor TNF-αand subsequent Wnt/β-catenin activation-mediated fusogenic syncytin-1 up-regulation during cell fusion
Summary
It is well recognized that cell fusion plays a crucial role in a variety of physiological events, such as fertilization, placentation, skeletal muscle formation, and tissue regeneration[1]. We show that the pro-inflammatory factor TNF-αcan activate Wnt/β-catenin signal pathway and thereby enhance the fusion between oral squamous cell carcinoma cells and endothelial cells via up-regulation of fusogenic protein syncytin-1. These results provide new insight into the interaction between oral cancer cells and endothelial cells, demonstrate a signal transduction pathway that links inflammation, Wnt/β-catenin signal pathway and cell fusion in tumor microenvironment, and predict a novel potential role of chronic inflammation in tumor progression
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