Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome

Artur Mezheyeuski,Lina Wik Leiss,Jiri Hatina,Ulrika Segersten,Carina Strell,Per-Uno Malmström,Arne Östman

doi:10.1038/s41598-019-55013-0

Artur Mezheyeuski, Lina Wik Leiss + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-55013-0

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Abstract

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC). While recent studies point towards the existence of different fibroblast subsets, no comprehensive analyses linking different fibroblast markers to UBC patient survival have been performed so far. Through immunohistochemical analysis of five selected fibroblast markers, namely alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet derived growth factor receptor-alpha and -beta (PDGFRa,-b), this study investigates their association with survival and histopathological characteristics in a cohort of 344 UBC patients, involving both, muscle-invasive and non-muscle-invasive cases. The data indicates that combinations of stromal markers are more suited to identify prognostic patient subgroups than single marker analysis. Refined stroma-marker-based patient stratification was achieved through cluster analysis and identified a FAP-dominant patient cluster as independent marker for shorter 5-year-survival (HR(95% CI)2.25(1.08–4.67), p = 0.030). Analyses of interactions between fibroblast and CD8a-status identified a potential minority of cases with CD90-defined stroma and high CD8a infiltration showing a good prognosis of more than 80% 5-year-survival. Presented analyses point towards the existence of different stroma-cell subgroups with distinct tumor-modulatory properties and motivate further studies aiming to better understand the molecular tumor–stroma crosstalk in UBC.

Highlights

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC)
Recent research efforts on UBC aimed mostly to decipher molecular drivers of an invasive tumor phenotype through description of genetic varieties, and with the introduction of checkpoint inhibitory immunotherapy, awareness has risen for tumor infiltrating leukocytes[12,13]
Five tissue microarray (TMA) sets were subjected to IHC for alpha smooth muscle actin (ASMA), CD90, fibroblast activation protein (FAP) with CD8a, PDGFRa and PDGFRb

Summary

Introduction

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC). While the majority of these studies describe pro-tumoral effects of fibroblasts derived growth-factors, like the induction of epithelial to mesenchymal transition and invasion[5,10,15,16], one study demonstrated that sonic hedgehog (Shh) activated fibroblasts exhibit rather tumor restraining functions during the transition of in situ to invasive UBC17 These findings, taken together with studies on fibroblast - tumor cell interactions in other solid tumors, point towards the existence of different fibroblast subsets with different functional roles at various stages of tumor progression and invasion (reviewed in[18,19,20,21,22,23]). CD90 defined fibroblasts were adversely associated with clinical outcome[44,45] but were discussed as immune-regulatory fibroblasts[46,47,48]

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