Could signal transducer and activator of transcription 3 be a therapeutic target in obesity-related gastrointestinal malignancy?
K. E. O'Sullivan; J. V. Reynolds; C. O'Hanlon; J. N. O'Sullivan; J. Lysaght
Year of publication
J Gastrointest Cancer
INTRODUCTION: A large body of evidence has implicated the signal transducer and activator of transcription (STAT) family and particularly the ubiquitously expressed STAT3 protein in the pathogenesis of colorectal, hepatocellular, gastric and pancreatic carcinoma. DISCUSSION: Concomitantly, an increasing body of epidemiological evidence has linked obesity and its associated pro-inflammatory state with the development of gastrointestinal cancers. Visceral adipose tissue is no longer considered inert and is known to secrete a number of adipocytokines such as leptin, interleukin (IL)-6, IL-8, IL-1β and tumour necrosis factor-alpha (TNF-α) into the surrounding environment. Interestingly, these adipocytokines are strongly linked with the Janus kinase (JAK)/STAT pathway of signal transduction and there is experimental evidence linking IL-1β, IL-8 and TNF-α to JAK/STAT signaling in other tissues. The result is an up-regulation of a wide range of anti-apoptotic, pro-metastatic and pro-angiogenic genes and processes. This is particularly relevant for gastrointestinal malignancy as these factors have the potential to signal adjacent endothelial cells in a paracrine manner. CONCLUSION: This review examines the potential role of the STAT3 signaling pathway in the pathogenesis of obesity-related gastrointestinal malignancy and the potential therapeutic role of STAT3 blockade given its status as a signaling hub for a number of inflammatory adipocytokines.