Poster Presentation 25th Lorne Cancer Conference 2013

Cytokines as key targets in cancer related inflammation  (#320)

Tracy Putoczki 1 , Rita Busuttil 2 , Alex Boussioutas 2 , Kirsten Edwards 3 , Brent McKenzie 3 , Matthias Ernst 1
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. CSL Ltd., Melbourne, VIC, Australia

Chronic inflammation, caused by environmental factors, persistent infections or autoimmune disorders, is associated with an increased risk of cancer development. Conversely, in many established cancers, oncogenic changes can trigger an inflammatory microenvironment that promotes the progression of tumours. These inflammatory responses have distinct roles in many stages of tumour development, including initiation, promotion, malignant transformation, invasion and subsequent metastasis. Moreover, inflammation can alter immune surveillance and the tumour response to therapies. Many studies have focused heavily on the role of the pro-inflammatory cytokine Interleukin (IL)-6 in the regulation of the dynamic cross talk between immune cells and stromal cells with neighbouring cancer cells. While these studies have provided vast insight into the molecular events that promote tumourigenesis, they have overlooked the role of other IL-6 family cytokines in this process. We have focused on IL-11, which similar to IL-6, is produced by fibroblasts, macrophages and lymphocytes and can interact with a membrane-bound form of its ligand-binding receptor. This receptor interaction triggers signaling through the formation of a hexameric complex, including a gp130 receptor homodimer, leading to the activation of the Jak/Stat3 signaling pathway. Stat3 has been recognized as one of the central mediators of the inflammatory process, and a key participant in the promotion of tumourigenesis. We provide striking evidence that IL-11, which is elevated in human cancers, is a more potent driver of Stat3 activation and tumour progression than its famous sibling, IL-6. We demonstrate that genetic or pharmacological inhibition of IL-11 signaling limits tumour-associated inflammation and delays the onset, progression, invasion and metastasis of tumourigenic cells. Our results suggest that understanding the cross-talk between cytokines and the tumour microenvironment will prove critical to the design and success of future cancer therapies.