The Role of STAT3 in an Oncogenic Stemness Signaling Pathway

STAT3 is a transcription factor that may drive tumor development when overactivated1

In normal cells, STAT3 is activated in a highly regulated and transient process, and its signaling is involved in physiological functions including development, differentiation, immunity, and metabolism.2 However, when STAT3 signaling is overactivated, it can drive the development and progression of tumors.1 STAT3 is constitutively active in cancer stem cells (CSCs) and may be critical for maintaining their stemness, the ability to self-renew and differentiate.3,4

STAT3 signaling maintains stemness in CSCs and may promote tumorigenesis, metastasis, and recurrence3,5

STAT3 is constitutively active in CSCs3,5

Overactivation of STAT3 in CSCs may lead to increased expression of genes that3,6:

  • Maintain stemness (eg, c-Myc, β-catenin, andothers)
  • Support proliferation and survival
  • Promote metastasis
  • Promote tumor immune evasion

Overactivation of STAT3 in CSCs may generate an inflammatory positive feedback loop7

  • STAT3 promotes production of proinflammatory cytokines, notably IL-6
  • IL-6 in turn stimulates STAT3 activation
  • This inflammatory feedback loop can promote tumor progression

Overactivated STAT3 signaling may drive stemness in CSCs5

Via these mechanisms, overactivated STAT3 signaling may lead to CSCs gaining and maintaining the ability to5:

  • Generate and regrow tumors
  • Metastasize
  • Resist conventional cancer therapies

STAT3 may be a potential target for research8

Current preclinical research suggests that targeting STAT3 may inhibit stemness of CSCs, which in turn may inhibit their tumorigenicity, metastatic potential, and resistance to conventional cancer therapies. STAT3 inhibition has not been found to affect the growth or survival of normal cells.

References

  1. Wang SW, Sun YM. The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncol. 2014;44(4):1032-1040.
  2. Siveen KS, Sikka S, Surana R, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136-154.
  3. Cafferkey C, Chau I. Novel STAT 3 inhibitors for treating gastric cancer. Expert Opin Investig Drugs. 2016;25(9):1023-1031.
  4. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111.
  5. Hajimoradi M, Mohammad Hassan Z, Ebrahimi M, et al. STAT3 is overactivated in gastric cancer stem-like cells. Cell J. 2016;17(4):617-628.
  6. Kamran MZ, Patil P, Gude RP. Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013;2013:421821.
  7. Yuan J, Zhang F, Niu R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 2015;5:17663.
  8. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844.