The Interleukin-11 signaling cascade: a promising target for cancer treatment — ASN Events
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  3. The Interleukin-11 signaling cascade: a promising target for cancer treatment

The Interleukin-11 signaling cascade: a promising target for cancer treatment (#319)

Matthias Ernst 1 , Michael Griffin 2 , Kirsten Edwards 3 , Tracy Putoczki 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia
  3. CSL Ltd., Melbourne, VIC, Australia

Interleukin (IL)-11 is a pleiotropic member of the IL-6 family of cytokines. Despite its discovery over 20 years ago, characterisation of the function of IL-11 has been over shadowed by its famous sibling IL-6. We have recently solved the first crystal structure of human IL-111, which signals through specific a-subunit receptors and transmembrane b-subunit GP130 receptors. The formation of the IL-11 signaling complex results in the recruitment of JAKs and subsequent activation of the pro-tumourigenic transcription factor, STAT3. Constitutive STAT3 activation is a hallmark of gastrointestinal cancers, and associated with poor prognosis. We have shown that elevated IL-11 expression is linked to high STAT3 activation in human gastrointestinal cancers2.

 

In order to compare the requirement of IL-6 and IL-11 signaling for gastrointestinal tumour progression we have coupled il6-/- mice, which lack both classic and trans-signaling, and il11ra-/- mice with a unique suite of gastric, inflammation-associated and sporadic colon cancer mouse models. Our results demonstrate that while both cytokines contribute to tumour progression, IL-11 has a dominant role in the development of gastrointestinal cancers2. We show that the production of IL-11 by cells within the tumour microenvironment promotes STAT3 activation in non-haematopoietic cells, which triggers the progression of tumours.

 

We have generated novel IL-11 signaling antagonists and demonstrate in numerous endogenous mouse and human xenograft models that therapeutic targeting of IL-11 signaling reduces inflammation in the tumour microenvironment and inhibits the progression, invasion and metastasis of tumour cells. Importantly, inhibition of IL-11 does not result in many of the side-affects commonly associated with inhibition of other components of the JAK/STAT pathway. Our results highlight an unappreciated hierarchy between IL-6 and IL-11, and suggest that understanding the cross-talk between cytokines and the tumour microenvironment will prove critical to the design and success of anti-cytokine reagents as future cancer therapies.

  1. Putoczki et al. (2014) Acta Cryst. D70, doi:10.1107/S1399004714012267
  2. Putoczki et al. (2013) Cancer Cell, 24(2):257