A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection

Abstract

Objective-We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells, and assessed the prognostic capability of their expression in cirrhosis.Design-We defined a hepatic stellate cell gene signature by comparing stellate, immune, and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective-prospective cohort of hepatitis Crelated early-stage cirrhosis (prognostic index derivation set), and validated in an independent retrospective cohort of post-resection HCC patients (n=82, prognostic index validation set). We then examined association between hepatic stellate cell signature expression and decompensation, hepatocellular carcinoma (HCC) incidence, and progression of Child-Pugh class as additional outcomes in the prognostic index derivation set, and HCC recurrence as an additional outcome in the validation set. We tested whether hepatic stellate cell signature expression is predictive of Results-The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors, and correlates with the extent of fibrosis in human, mouse, and rat datasets. The hepatic stellate cell signature contains several cell surface genes previously established as stellate cell-specific, as well as PCDH7, a novel protocadherin stellate cell surface marker. Importantly, association of clinical prognostic variables with overall survival (c-index: 0.66, 95% CI: 0.59-0.74) was improved by adding the hepatic stellate cell signature (cindex: 0.70, 95%CI: 0.62-0.78); we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival Conclusion-This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting, and isolation. Hepatic stellate cell signature expression may identify HCV cirrhosis or post resection HCC patients with poor prognosis.

Nonalcoholic Steatohepatitis Is Associated With Increased Mortality in Obese Patients Undergoing Bariatric Surgery

“…Module no.6 was enriched with TNF-α signalling via NF-κB pathway (p<0.001), indicating presence of inflammatory pathway activation in NASH-affected liver (Supplementary Table 15). Module no.5 was enriched with collagen-encoding genes, TGF-β target genes such as TGFB1I1 , epithelial-mesenchymal transition pathway (p=0.002), as well as 2 previously published hepatic stellate cell signatures 25, 26 , evidencing activated fibrogenesis (p<0.05).…”

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

“…Moreover, with relatively short follow-up periods, it cannot be completely excluded that liver stiffness was increased due to preexisting HCC. In contrast, a 122-gene HSC signature was not associated with the development of HCC in a cohort of patients with chronic hepatitis C and Child-Pugh A stage cirrhosis (50). Several studies have established that the presence of liver fibrosis, as determined by fibrosis staging or the presence of either α-SMA-positive myofibroblasts or activated HSC signatures, is associated with increased recurrence after curative HCC resection (50–53).…”

“…In contrast, a 122-gene HSC signature was not associated with the development of HCC in a cohort of patients with chronic hepatitis C and Child-Pugh A stage cirrhosis (50). Several studies have established that the presence of liver fibrosis, as determined by fibrosis staging or the presence of either α-SMA-positive myofibroblasts or activated HSC signatures, is associated with increased recurrence after curative HCC resection (50–53). As recurrences in many of these studies were early and therefore unlikely to represent de novo HCC formation, we discuss these studies in the TME section below.…”

“…There is increasing evidence from clinical studies that the presence of liver fibrosis, α-SMA-positive myofibroblasts, or activated HSC signatures is associated with a poor prognosis after curative HCC resection, suggesting a key role of the fibrotic TME in promoting HCC progression: In patients with curative HCC resection, a high degree of peritumoral myofibroblast infiltration was associated with a 2.6-fold hazard ratio for overall survival and a 3.3-fold hazard ratio for recurrence-free survival (52). Multiple studies have shown poor survival as well as increased metastasis and recurrence following resection in HCC patients with positive HSC gene signatures or high expression of α-SMA (50, 53, 80, 81). Similar findings were made in animal models, where coinjection of activated HSC and HCC cells into mice enhanced subcutaneous or orthotopic tumor growth (53, 80–85).…”

Hepatic stellate cells as key target in liver fibrosis

“…In addition, by using genome-wide transcriptome profiling, HSC-specific 122-gene and 194-gene signatures, associated with poorer patient prognoses, have been identified [15, 16]. …”