Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition

Mol Cell Endocrinol. 2017 Aug 15;451:1-14. doi: 10.1016/j.mce.2017.05.033. Epub 2017 May 30.

Abstract

The effects of Jak Stat signaling and the persistent activation of Stat3 and Stat5 on tumor cell survival, proliferation and invasion have made the Jak Stat pathway a favorite target for drug development and cancer therapy. This notion was strengthened when additional biological functions of Stat signaling in cancer and their roles in the regulation of cytokine dependent inflammation and immunity in the tumor microenvironment were discovered. Stats act not only as transcriptional inducers, but affect gene expression via epigenetic modifications, induce epithelial mesenchymal transition, generate a pro-tumorigenic microenvironment, promote cancer stem cell self-renewal and differentiation, and help to establish the pre-metastatic niche formation. The effects of Jak Stat inhibition on the suppression of pro-inflammatory responses appears most promising and could become a strategy in the prevention of tumor progression. The direct and mediated mechanisms of Jak Stat signaling in and on tumors cells, the interactions with other signaling pathways and transcription factors and the targeting of the functionally crucial secondary modifications of Stat molecules suggest novel approaches to the future development of Jak Stat based cancer therapeutics.

Keywords: Immune therapy; Jak stat signaling in cancer; Signaling pathway interactions; Targeted therapeutics; Tumor microenvironment.

Publication types

  • Editorial
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunotherapy / methods*
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / genetics*
  • Janus Kinases / immunology
  • Molecular Targeted Therapy
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / pathology
  • STAT Transcription Factors / antagonists & inhibitors
  • STAT Transcription Factors / genetics*
  • STAT Transcription Factors / immunology
  • Signal Transduction
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents
  • STAT Transcription Factors
  • Janus Kinases