Partial loss of colonic primary cilia promotes inflammation and carcinogenesis

Abstract

Primary cilia (PC) are important signaling hubs in cells and their deregulation has been associated with various diseases including cancer. Here we explored the role of PC in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts. Colons of mice exposed to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced colitis had decreased numbers of PC. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Colons from DSS-treated mice with PC-deficiency on fibroblasts displayed an elevated production of the pro-inflammatory cytokine IL-6 and colonic epithelial cells had diminished levels of HES-1, a key transcription factor of Notch signaling. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/871772v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1f8eccdorg.highwire.dtl.DTLVardef@1829b3borg.highwire.dtl.DTLVardef@19d632aorg.highwire.dtl.DTLVardef@1d9833b_HPS_FORMAT_FIGEXP M_FIG C_FIG