Inflammatory Regulation by TNF-α-Activated Adipose-Derived Stem Cells in the Human Bladder Cancer Microenvironment

Int J Mol Sci. 2021 Apr 13;22(8):3987. doi: 10.3390/ijms22083987.


Mesenchymal stem cells (MSCs), such as adipose-derived stem cells (ADSCs), have the most impressive ability to reduce inflammation through paracrine growth factors and cytokines that participate in inflammation. Tumor necrosis factor (TNF)-α bioactivity is a prerequisite in several inflammatory and autoimmune disease models. This study investigated the effects of TNF-α stimulate on ADSCs in the tumor microenvironment. The RNAseq analysis and cytokines assay demonstrated that TNF-α stimulated ADSCs proliferation and pro-inflammatory genes that correlated to leukocytes differentiation were upregulated. We found that upregulation of TLR2 or PTGS2 toward to IRF7 gene-associated with immunomodulatory and antitumor pathway under TNF-α treatment. In TNF-α-treated ADSCs cultured with the bladder cancer (BC) cell medium, the results showed that apoptosis ratio and OCT-4 and TLR2 genes which maintained the self-renewal ability of stem cells were decreased. Furthermore, the cell survival regulation genes including TRAF1, NF-kB, and IRF7 were upregulated in TNF-α-treated ADSCs. Additionally, these genes have not been upregulated in BC cell medium. A parallel study showed that tumor progressing genes were downregulated in TNF-α-treated ADSCs. Hence, the study suggests that TNF-α enhances the immunomodulatory potential of ADSCs during tumorigenesis and provides insight into highly efficacious MSC-based therapeutic options for BC.

Keywords: adipose-derived stem cells; bladder cancer; immunomodulatory; inflammatory microenvironment; tumor necrosis factor-α; tumorigenicity.

MeSH terms

  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Immunomodulation / drug effects
  • Immunosuppression Therapy
  • Inflammation / pathology*
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / pathology*
  • NF-kappa B / metabolism
  • Signal Transduction / drug effects
  • Tumor Microenvironment* / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / immunology
  • Urinary Bladder Neoplasms / pathology*


  • Cytokines
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • NF-kappa B
  • Tumor Necrosis Factor-alpha