Abstract
BackgroundTumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression.MethodsIn order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine.ResultsUnder the TNFα overexpression, significant upregulation of two genes was observed: proinflammatory cytokine IL6 gene in melanoma cells A375 and gene for pro-apoptotic ligand TRAIL in colorectal carcinoma cells HT29, both mediated by TNFα/TNFR1 signaling. Malignant melanoma line A375 displayed also increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology (shortened and condensed mitochondria) both in melanoma and colorectal carcinoma cells. Overexpression of TNFα was not linked with significant affection of the subpopulation of cancer stem-like cells in vitro. However, we could demonstrate a decrease in aldehyde dehydrogenase (ALDH) activity up to 50%, which is associated with to the stemness phenotype.ConclusionsOur in vitro study of direct TNFα influence demonstrates two distinct outcomes in tumor cells of different origin, in non-epithelial malignant melanoma cells of neural crest origin, and in colorectal carcinoma cells derived from the epithelium.
Highlights
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and protumorigenic activity, affecting tumor cell biology, the balance between cell survival and death
We aimed to show the interconnection of apoptosis, changes in mitochondrial status, autophagy and senescence accompanied by changes of mRNA expression profile
In engineered melanoma cells (A375hTNFa, M4BeuhT NFa) and colorectal carcinoma cells (HT29hTNFa, HCT 116hTNFa), stable retroviral transduction elevated the mRNA expression of Tumor necrosis factor α (TNFα) transgene up to 130.000x
Summary
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and protumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression. Tumor necrosis factor α (TNFα), a key inflammatory cytokine, can drive both tumor elimination and promotion in cancer patients, depending on the dose and cancer type [1,2,3]. Engineered MSC overexpressing TNFα, coinjected with malignant melanoma cells, reduced growth of subcutaneous xenografts. Such engineered TNFα-MSC kept the TNFα production for more than 3 months and lost their significant tumor supportive potential [9]. They had no inhibitory potential on induced experimental melanoma lung metastases after systemic administration [10]
Sign-in/Register to view highlights & summary 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.
