Intestinal GUCY2C prevents TGF-β secretion coordinating desmoplasia and hyperproliferation in colorectal cancer.

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-β secretion, activating fibroblasts through TGF-β type I receptors and Smad3 phosphorylation. In turn, activating TGF-β signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-β antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-β and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis

Phenyl Groups versus <i>tert</i>-Butyl Groups as Solubilizing Substituents for Some [5]Phenacenes and [7]Phenacenes

In recent years, we have used the photocyclizations of diarylethylenes to synthesize a number of [<i>n</i>]­phenacenes in the hope that they might be useful as the bridging groups for electron transfer processes in donor–bridge–acceptor molecules. Because [<i>n</i>]­phenacenes with <i>n</i> > 5 are very insoluble, their synthesis and characterization has required the attachment of solubilizing substituents such as <i>tert</i>-butyl. The studies of Pascal and co-workers of some large polynuclear aromatic compounds having multiple phenyl substituents prompted us to explore the use of phenyls as alternative solubilizing groups for [<i>n</i>]­phenacenes. Although phenyl groups turned out to provide significantly less solubilization than <i>tert</i>-butyl groups in these compounds, we found some interesting structural comparisons of the phenyl-substituted and <i>tert</i>-butyl-substituted [<i>n</i>]­phenacenes

Phenyl Groups versus <i>tert</i>-Butyl Groups as Solubilizing Substituents for Some [5]Phenacenes and [7]Phenacenes

In recent years, we have used the photocyclizations of diarylethylenes to synthesize a number of [<i>n</i>]­phenacenes in the hope that they might be useful as the bridging groups for electron transfer processes in donor–bridge–acceptor molecules. Because [<i>n</i>]­phenacenes with <i>n</i> > 5 are very insoluble, their synthesis and characterization has required the attachment of solubilizing substituents such as <i>tert</i>-butyl. The studies of Pascal and co-workers of some large polynuclear aromatic compounds having multiple phenyl substituents prompted us to explore the use of phenyls as alternative solubilizing groups for [<i>n</i>]­phenacenes. Although phenyl groups turned out to provide significantly less solubilization than <i>tert</i>-butyl groups in these compounds, we found some interesting structural comparisons of the phenyl-substituted and <i>tert</i>-butyl-substituted [<i>n</i>]­phenacenes