Abstract
Objective: Resveratrol, a safe and multitargeted natural agent, has been linked with inhibition of survival and invasion of tumor cells. Tumor Necrosis Factor-β (TNF-β) (Lymphotoxin α) is known as an inflammatory cytokine, however, the underlying mechanisms for its pro-carcinogenic effects and whether resveratrol can suppress these effects in the tumor microenvironment are poorly understood. Methods: We investigated whether resveratrol modulates the effects of 5-Fluorouracil (5-FU) and TNF-β on the malignant potential of human colorectal cancer (CRC) cells (HCT116) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R) in 3D-alginate tumor microenvironment. Results: CRC cells cultured in alginate were able to migrate from alginate and the numbers of migrated cells were significantly increased in the presence of TNF-β, similar to TNF-α, and dramatically decreased by resveratrol. We found that TNF-β promoted chemoresistance in CRC cells to 5-FU compared to control cultures and resveratrol chemosensitizes TNF-β-induced increased capacity for survival and invasion of HCT116 and HCT116R cells to 5-FU. Furthermore, TNF-β induced a more pronounced cancer stem cell-like (CSC) phenotype (CD133, CD44, ALDH1) and resveratrol suppressed formation of CSC cells in two different CRC cells and this was accompanied with a significant increase in apoptosis (caspase-3). It is noteworthy that resveratrol strongly suppressed TNF-β-induced activation of tumor-promoting factors (NF-κB, MMP-9, CXCR4) and epithelial-to-mesenchymal-transition-factors (increased vimentin and slug, decreased E-cadherin) in CRC cells. Conclusion: Our results clearly demonstrate for the first time that resveratrol modulates the TNF-β signaling pathway, induces apoptosis, suppresses NF-κB activation, epithelial-to-mesenchymal-transition (EMT), CSCs formation and chemosensitizes CRC cells to 5-FU in a tumor microenvironment.
Highlights
The worldwide incidence of colorectal cancer (CRC) has risen to approximately 1.2 million new cases and 0.6 million deaths annually [1]
The aim of this study was to examine the potential role of Tumor Necrosis Factor-β (TNF-β) to induce an inflammatory microenvironment to promote CRC cell malignancy alone or during treatment with 5-FU in human CRC cells (HCT116 and HCT116R) in a 3D-alginate tumor microenvironment
We investigated the modulatory effects of resveratrol on Tumor Necrosis Factor (TNF)-β-mediated inflammatory signaling in the treatment of CRC either alone or in combination with 5-FU
Summary
The worldwide incidence of colorectal cancer (CRC) has risen to approximately 1.2 million new cases and 0.6 million deaths annually [1]. A key feature to support and modulate colon cancer progression is the result of complex interaction of tumor cells with their microenvironment [3,4,5]. It is recognized that chronic inflammation alters the tumor microenvironment supporting development and progression of cancer [6,7]. Activation of the pro-inflammatory NF-κB-signaling pathway represents a central event in the tumor-development progress and enhances tumor progression [8]. Several pro-inflammatory mediators that have been shown to alter the tumor microenvironment, including members of the
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
