Cancer-associated fibroblasts, clinicopathological characteristics and prognosis of liver cancer: A systematic review and meta-analysis based on real-world research

Abstract

BACKGROUND

Cancer-associated fibroblasts (CAFs), crucial components of the tumor microenvironment in primary and metastatic tumors, can impact the activity of cancer cells and contribute to their progression. Given their extensive interactions with cancer cells and other stromal cells, we aimed to evaluate the prognostic value of CAFs in patients with liver cancer (LC).

AIM

To investigate the association between CAF expression and clinicopathological characteristics as well as overall survival (OS) in patients with LC, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA).

METHODS

We performed a meta-analysis of cohort studies with available data on the effects of CAF expression on both clinicopathological characteristics and OS via hazard ratios (HRs) and risk ratios with 95% confidence intervals (CIs). Studies were subgrouped on the basis of CAF markers and cancer type, and the subgroup effects of CAF expression on both HCC and iCCA were analyzed through meta-regression. The Newcastle-Ottawa Scale was used to evaluate the included studies to guarantee their quality and minimize the possibility of bias.

RESULTS

Nine trials were selected and included a total of 1518 patients. According to our primary meta-analysis, the expression of CAFs in LC patients was significantly associated with a decrease in OS (LC: HR: 1.62; 95%CI: 1.34-1.97; P < 0.001; HCC: HR: 1.67; 95%CI: 1.34-2.07; P < 0.001; iCCA: HR: 1.47; 95%CI: 0.97-2.23; P = 0.07); nevertheless, it was not significantly associated with almost all clinicopathologic characteristics, including tumor size, venous infiltration, alpha-fetoprotein level, and differentiation grade. According to the subgroup analysis of smooth muscle actin (SMA) markers in both HCC patients and iCCA patients, high CAF expression in HCC (HR: 2.29; 95%CI: 1.01-5.22; P = 0.048) and iCCA (HR: 2.04; 95%CI: 1.09-3.81; P = 0.025) patients was a significant indicator of poor OS. Moreover, the clinicopathological characteristics were also verified by the SMA marker, which had a nearly significant effect on the venous infiltration of iCCA (risk ratio: 2.70; 95%CI: 0.97-7.49; P = 0.057).

CONCLUSION

High CAF expression, evaluated by both mixed markers and SMAs, is significantly associated with poor OS in patients with LC, including both HCC patients and iCCA patients. However, further research is necessary since how CAF expression and clinicopathologic features are related is yet unknown.

Keywords: Cancer-associated fibroblasts; Liver neoplasms; Prognosis; Liver cancer; Meta-analysis

Core Tip: This meta-analysis reveals that high expression of cancer-associated fibroblasts (CAFs), particularly marked by α-smooth muscle actin, is significantly associated with poor overall survival in liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. CAFs serve as a robust prognostic biomarker, with stronger predictive value in hepatocellular carcinoma. While their impact on clinicopathological features remains inconclusive, these findings highlight CAFs as potential therapeutic targets. Further research is needed to clarify their role in tumor progression and optimize clinical applications.