mTORC1 Signaling Drives Inflammation-Associated Tumor Growth

Chronic inflammation enhances the growth and progression of gastrointestinal tumors in large part through activation of the STAT3 transcription factor, which is driven by signaling of the cytokines interleukin (IL)-6 and IL-11 through their receptor, IL-6 signal transducer (IL-6ST, also known as GP130), which stimulates Janus-activated kinases (JAK). Activation of mTOR complex 1 (mTORC1), a critical regulator of cell growth, has also been linked to protumorigenic inflammatory cytokine expression, but its role in gastrointestinal tumor progression is unclear. Thiem and colleagues found frequent coactivation of mTORC1 and STAT3 within tumor epithelial cells and adjacent stroma in both human intestinal-type gastric cancer (IGC) samples and a mouse model of gastric cancer driven by an activating mutation in gp130 that recapitulates human IGC. mTORC1 activation was induced by IL-11 ligand stimulation of GP130 and subsequent JAK-dependent activation of phosphoinositide 3-kinase (PI3K)/AKT signaling but occurred independently of GP130 tyrosine phosphorylation and STAT3 activity. Strikingly, treatment of gp130-mutant mice with RAD001 (everolimus), a clinically approved mTORC1-specific inhibitor, significantly reduced tumor burden; continuous prophylactic RAD001 administration was also sufficient to suppress tumor formation. In addition, RAD001 similarly diminished tumor growth in a mouse model of colitis-associated colon cancer, suggesting that GP130-stimulated mTORC1 activity is broadly required for the initiation and progression of inflammation-associated gastrointestinal tumors in mice. This antitumor effect was not associated with suppression of inflammation or impaired STAT3 activation but rather was mediated by decreased cyclin expression, reduced cancer cell proliferation, and ineffective tumor vascularization. These findings implicate mTORC1 signaling as a driver of inflammation-associated tumor growth and suggest that PI3K/mTORC1 inhibitors may provide therapeutic benefit to patients with these types of tumors.

Thiem S, Pierce TP, Palmieri M, Putoczki TL, Buchert M, Preaudet A, et al. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J Clin Invest 2013 Jan 16 [Epub ahead of print].

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