Characterising cancer-associated fibroblast heterogeneity in non-small cell lung cancer: a systematic review and meta-analysis

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with evidence suggesting they represent a heterogeneous population. This study summarises the prognostic role of all proteins characterised in CAFs with immunohistochemistry in non-small cell lung cancer thus far. The functions of these proteins in cellular processes crucial to CAFs are also analysed. Five databases were searched to extract survival outcomes from published studies and statistical techniques, including a novel method, used to capture missing values from the literature. A total of 26 proteins were identified, 21 of which were combined into 7 common cellular processes key to CAFs. Quality assessments for sensitivity analyses were carried out for each study using the REMARK criteria whilst publication bias was assessed using funnel plots. Random effects models consistently identified the expression of podoplanin (Overall Survival (OS)/Disease-specific Survival (DSS), univariate analysis HR 2.25, 95% CIs 1.80-2.82) and alpha -SMA (OS/DSS, univariate analysis HR 2.11, 95% CIs 1.18-3.77) in CAFs as highly prognostic regardless of outcome measure or analysis method. Moreover, proteins involved in maintaining and generating the CAF phenotype (alpha -SMA, TGF-beta and p-Smad2) proved highly significant after sensitivity analysis (HR 2.74, 95% CIs 1.74-4.33) supporting attempts at targeting this pathway for therapeutic benefit.

Automated summary

This study summarizes the prognostic role of various proteins in CAFs in non-small cell lung cancer, highlighting podoplanin and α-SMA as consistently highly predictive proteins. Targeting proteins involved in maintaining and generating the CAF phenotype may have therapeutic benefits.