Immune Netw.  2017 Aug;17(4):214-227. 10.4110/in.2017.17.4.214.

Cytokine Signaling in Tumor Progression

• Lee M
• Rhee I

• KMID: 2388076
• DOI: http://doi.org/10.4110/in.2017.17.4.214

Abstract

Cytokines are molecules that play critical roles in the regulation of a wide range of normal functions leading to cellular proliferation, differentiation and survival, as well as in specialized cellular functions enabling host resistance to pathogens. Cytokines released in response to infection, inflammation or immunity can also inhibit cancer development and progression. The predominant intracellular signaling pathway triggered by cytokines is the JAK-signal transducer and activator of transcription (STAT) pathway. Knockout mice and clinical human studies have provided evidence that JAK-STAT proteins regulate the immune system, and maintain immune tolerance and tumor surveillance. Moreover, aberrant activation of the JAK-STAT pathways plays an undeniable pathogenic role in several types of human cancers. Thus, in combination, these observations indicate that the JAK-STAT proteins are promising targets for cancer therapy in humans. The data supporting this view are reviewed herein.

Keyword

Cytokine; JAK-STAT; Cancer; Kinase inhibitor

MeSH Terms

Animals
Cell Proliferation
Cytokines
Humans
Immune System
Immune Tolerance
Inflammation
Mice
Mice, Knockout
Transducers
Cytokines

Figure

• 

  Figure 1 Schematic representation of JAK-STAT structure. (A) The domain structure of JAKs and STATs. Four JAKs consist of the domains JH1 to JH7 based on their sequence similarity including 2 tyrosines after cytokine stimulation. JH1 is kinase domain and JH2 is the pseudo-kinase domain. The JH6 and JH7 domains introduce the binding of JAKs to main receptors. STATs consist of 7 specific domains, which are involved with various responses resulting in the regulation of protein modification by tyrosine and serine phosphorylation, methylation, sumoylation, and acetylation. (B) Classification of cytokine receptors which are type I and II according to their ligands and the association with JAKs to deliver their signals to the downstream. FERM, 4.1, ezrin, radixin, moesin; TAD, transactivation domain; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; EPOR, erythropoietin receptor; TPOR, thrombopoietin receptor; G-CSF, granulocyte-colony stimulating factor; IFN, interferon.

• 

  Figure 2 Schematic representation of the JAK-STAT pathway. The cytokine receptor induces activation of JAKs after cytokine stimulation following the phosphorylation of STATs. Furthermore, phosphorylated STATs undergo dimerization and translocate to the nucleus to activate target gene transcription. Genetic aberration in JAKs provoke serious diseases such as PV, ET, PMF as well as cancer. SOCS, suppressors of cytokine signaling; PI3K, phosphatidyl inositol 3 kinase; Akt, protein kinase B; FOXO, Forkhead box protein O; mTOR, mammalian target of rapamycin.

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