
Cancer‐associated fibroblasts show heterogeneous gene expression and induce vascular endothelial growth factor A ( VEGFA ) in response to environmental stimuli
Author(s) -
Inoue Kenichi,
Kishimoto Satoko,
Akimoto Kazumi,
Sakuma Masashi,
Toyoda Shigeru,
Inoue Teruo,
Yoshida Kenichiro,
Shimoda Mitsugi,
Suzuki Shuji
Publication year - 2019
Publication title -
annals of gastroenterological surgery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.308
H-Index - 15
ISSN - 2475-0328
DOI - 10.1002/ags3.12249
Subject(s) - paracrine signalling , biology , angiogenesis , vascular endothelial growth factor a , vascular endothelial growth factor , tumor microenvironment , cancer research , mmp1 , extracellular matrix , gene expression , cancer , pathology , gene , microbiology and biotechnology , genetics , medicine , receptor , vegf receptors
Aim Cancer‐associated fibroblasts (CAF) play a crucial role in angiogenesis in the complex tumor microenvironment. However, fibroblasts show extensive heterogeneity and their dynamic functions against stressors remain largely unknown. Methods We collected patient‐derived CAF and carried out perturbation‐based monitoring of the dynamic functions. Clinically relevant experimental stimuli were defined as follows: hypoxia, cisplatin, fluorouracil, coculture with cancer spheroids (interaction through paracrine signals). We selected 18 marker genes that encode components for fibroblast activation, intracellular communication, and extracellular matrix remodeling. Quantitative reverse transcription polymerase chain reaction was carried out for data collection and statistical analyses were carried out using SPSS software. Results Kruskal‐Wallis multivariate analysis of variance showed that variations in expression of 11 marker genes were explained, in part, by a difference in tissue of origin. Friedman and two‐sided Wilcoxon signed rank tests detected significant perturbations in expression of marker genes. Paracrine signal from cancer spheroids induced vascular endothelial growth factor A ( VEGFA ) in CAF but not in fetal lung fibroblasts. Conclusion We have established perturbation‐based monitoring of patients’ CAF. Further data collection and individual patient follow up is ongoing to identify critical determinants of disease outcome.