TPL2 expression in intestinal myofibroblasts inhibits tumor growth by preventing HGF secretion.

  • Major finding: TPL2 expression in intestinal myofibroblasts inhibits tumor growth by preventing HGF secretion.

  • Mechanism: TPL2 loss activates c-MET to promote epithelial proliferation but does not affect inflammation.

  • Impact: TPL2-mediated repression of HGF production may broadly suppress epithelial tumorigenesis.

Cells within the tumor microenvironment, particularly protumorigenic inflammatory cells, have been shown to contribute directly to the pathogenesis of colitis-associated colorectal cancer (CAC) via stimulation of epithelial cell growth and survival. Other stromal cells that have been implicated in epithelial tumors may also play a role in CAC, including intestinal subepithelial myofibroblasts (IMF); however, the pathways in these cells that modulate CAC are not well studied. Using the azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of CAC, Koliaraki and colleagues examined the role of one potentially important protein, mitogen-activated protein kinase kinase kinase 8 (MAP3K8, also known as tumor progression locus 2 or TPL2), which regulates inflammatory and oncogenic pathways via ERK signaling. Global Tpl2 deficiency in this model enhanced tumor formation and disease progression, suggesting that TPL2 functions as a tumor suppressor in CAC. Tpl2 loss did not alter inflammatory cell infiltration but instead resulted in increased proliferation and reduced apoptosis of colonic epithelial cells, as well as upregulation of CAC markers and oncogenic genes. Interestingly, tissue-specific ablation of Tpl2 in IMFs but not myeloid cells or intestinal epithelial cells enhanced the formation of early high-grade dysplasia and increased tumor number and size, suggesting that TPL2 exerts its tumor-suppressive function by modulating IMF-dependent cross-talk with tumor epithelial cells. Consistent with this idea, Tpl2-deficient IMF cells exhibited elevated hepatocyte growth factor (HGF) secretion both in response to AOM/DSS and after treatment with TGF-β3, a known negative regulator of HGF. Furthermore, pharmacologic inhibition of the HGF receptor c-MET, which is expressed on epithelial cells, abrogated the formation of high-grade dysplasia in Tpl2-deficient mice. These findings identify IMF-expressed TPL2 as an important modulator of oncogenic HGF–c-MET signaling in CAC and suggest that TPL2 may mediate the tumor-suppressive effects of TGF-β3 in other solid tumors.

Koliaraki V, Roulis M, Kollias G. Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis. J Clin Invest 2012 Oct 14 [Epub ahead of print].