The Role of STAT1 for Crosstalk between Fibroblasts and Colon Cancer Cells

Pawan Kaler, Benjamin Y. Owusu, Leonard Augenlicht, Lidija Klampfer

Signaling between tumor cells and the associated stroma has an important impact on cancer initiation and progression. The tumor microenvironment has a paradoxical role in tumor progression and fibroblasts, a major component of the tumor stroma, have been shown to either inhibit or promote cancer development. In this study, we established that normal intestinal fibroblasts activate STAT1 signaling in colon cancer cells and, in contrast to cancer-associated fibroblasts, inhibit growth of tumor cells. Treatment of 18Co fibroblasts with the proinflammatory cytokine TNFα interfered with their ability to trigger STAT1 signaling in cancer cells. Accordingly, intestinal myofibroblasts isolated from patients with ulcerative colitis or Crohn's disease, which are activated and produce high levels of TNFα, failed to stimulate STAT1 signaling in tumor cells, demonstrating that activated myofibroblasts lose the ability to trigger growth-inhibitory STAT1 signaling in tumor cells. Finally, we confirmed that silencing of STAT1 in tumor cells alters the crosstalk between tumor cells and fibroblasts, suggesting STAT1 as a novel link between intestinal inflammation and colon cancer. We demonstrated that normal fibroblasts restrain the growth of carcinoma cells, at least in part, through the induction of STAT1 signaling in cancer cells and showed that changes in the microenvironment, as they occur in inflammatory bowel disease, alter the crosstalk between carcinoma cells and fibroblasts, perturb the homeostasis of intestinal tissue, and thereby contribute to tumor progression.