Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4

Abstract

Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1-deficient (Casp1 −/− ) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.colon cancer | inflammation-induced colorectal cancer | NLR family, pyrin domain containing 3

Old, new and emerging functions of caspases

“…Further evidence for its role as a tumor suppressor comes from a mouse model of colitis-associated colorectal cancer. 135 Caspase-1-deficient mice showed enhanced tumor formation, characterized by early stage increase in epithelial cell proliferation in the colon and reduced apoptosis during advanced disease stage. 135 Recent studies have shown that originally generated caspase-1-deficient mice also harbor a mutation in the caspase-11 locus, which mediates LPS-induced lethality in these mice.…”

Epithelial NAIPs protect against colonic tumorigenesis

“…In one study, this was dependent on NLRC4 and was epithelial intrinsic rather than inflammation mediated (Hu et al, 2010), whereas, in another study, increased tumorigenesis involved NLRP3 and was inflammation and hematopoietic cell-dependent (Allen et al, 2010). Such discrepancies are suggested to arise from differences in microbiota between facilities or use of WT mice from external sources (Ubeda et al, 2012), but could also arise from opposing functions of inflammasome components in different tissues, which has been demonstrated in a skin tumorigenesis model (Drexler et al, 2012).…”

“…Several Nod-like receptors (NLRs) have previously been implicated in colon inflammation and tumorigenesis, mostly in protective roles (Allen et al, 2010;Hu et al, 2010;Chen et al, 2011;Elinav et al, 2011;Zaki et al, 2011;Carvalho et al, 2012). In some cases, this has been attributed to reduced inflammasomemediated release of IL-18, which is protective for the colonic epithelium (Allen et al, 2010;Dupaul-Chicoine et al, 2010).…”

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

“…Hu et al demonstrated [82] the protective effect of NLRC4 in azoxymethane-dextran sodium sulfate -induced colitis-associated colorectal cancer. This effect was independent of inflammation, which was the same in NLRC4-deficient and wild-type mice.…”

“…This effect was independent of inflammation, which was the same in NLRC4-deficient and wild-type mice. The protective role came from NLRC4 originating from non-hematopoietic cell compartment [82]. They proposed that epithelial NLRC4 signaling regulates apoptosis thorough p53 activation [83].…”