Systemic inflammation is associated with circulating cell death released keratin 18 fragments in colorectal cancer

Systemic inflammation is a stage-independent marker of poor prognosis in colorectal cancer (CRC), activated in a complex, multifactorial process. It has been proposed that one of the main factors driving systemic inflammation may be tumor necrosis. Keratin 18 (KRT18) fragments are released from dead cells and their serum levels are markers for apoptotic and necrotic cell death. In CRC, high KRT18 levels associate with advanced disease, but their relationship with tumor necrosis and systemic inflammation is unknown. In this study, serum total soluble KRT18 (tKRT18) and apoptosis-related, caspase-cleaved fragment (aKRT18) levels were measured preoperatively from 328 CRC patients, and their difference was calculated to assess necrosis related KRT18 (nKRT18) levels. The relationships of these markers with tumor necrosis, clinicopathologic features, systemic inflammation markers (C-reactive protein, albumin, and 13 cytokines), and survival were analyzed. High serum tKRT18, aKRT18, and nKRT18 levels showed association with a higher extent of tumor necrosis, distant metastasis, and increased levels of several markers of systemic inflammation, including CXCL8. High serum tKRT18 (multivariable HR 1.94, 95% CI 1.28-2.95, p = .002) and nKRT18 (multivariable HR 1.87, 95% CI 1.24-2.82, p = .003) levels were associated with poor overall survival independent of potential confounding factors. Our results show that tumor necrosis in CRC contributes to serum levels of KRT18 fragments, and both necrosis and KRT18 levels associate with systemic inflammation. Moreover, we show that serum tKRT18 and nKRT18 levels have independent prognostic value in CRC. Our observations confirm the link between cell death and systemic inflammation.