Genetic alterations and epigenetic alterations of cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) are one major type of component identified in the tumor microenvironment. Studies have focused on the genetic and epigenetic status of CAFs, since they are critical in tumor progression and differ phenotypically and functionally from normal fibroblasts. The present review summarizes the recent achievements in understanding the gene profiles of CAFs and pays special attention to their possible epigenetic alterations. A total of 7 possible genetic alterations and epigenetic changes in CAFs are discussed, including gene differential expression, karyotype analysis, gene copy number variation, loss of heterozygosis, allelic imbalance, microsatellite instability, post-transcriptional control and DNA methylation. These genetic and epigenetic characteristics are hypothesized to provide a deep understanding of CAFs and a perspective on their clinical significance.

Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity

“…The CTL-suppressive MAF phenotype remained stable even after separation from the cancer microenvironment. This observation supports the notion put forward recently by many leading authors of the field, that at least some changes promoting the transition of DF to CAF may rely on highly stable epigenetic modifications [55][56][57][58]. That is, some parameters of the MAF phenotype may arise following a single priming event, resulting in long-term consequences, rather than being maintained by cancer cells via persistently secreted cytokines or similar mechanisms [1,59].…”

Targeting the tumour stroma to improve cancer therapy

“…In addition to their reactive nature, and similarly to cancer cells, stromal cells can undergo genetic changes 187 . Mutations in the tumour suppressor genes TP53 and PTEN have been found in the stromal compartment of human cancers (separated from epithelial cells using laser microdissection) 188,189 .…”

“…Epigenetic mechanisms can also lead to phenotypic changes in CAFs; the differential gene expression observed in CAFs relative to non-activated fibroblasts 196–199 is largely the result of changes in DNA methylation and other epigenetic alterations 187,200–204 . A specific example has been shown in the conversion of non-activated lung fibroblasts into CAFs via p300-histone acetyltransferase-mediated acetylation of STAT3, which causes an invasive phenotype in CAFs after exposure to the cytokine leukaemia inhibitory factor (LIF), derived from either tumour cells or other stromal cells 204,205 .…”

MEIS1 knockdown may promote differentiation of esophageal squamous carcinoma cell line KYSE‐30

“…Malignancy is a complex heterogeneous illness introduced through accumulation of different damaging genetic and epigenetic alterations in tumor cells. Notably, disruption of various signaling networks and multiple molecular mechanisms involved in tumor onset and development can lead to extensive deregulation of gene expression profiles in human cancers (Beerenwinkel, Schwarz, Gerstung, & Markowetz, 2014;Chatterjee et al, 2018;Du & Che, 2017). Among identified genetic changes in the cancer etiology, abnormal expression of different gene categories such as tumor suppressors, oncogenes, DNA repair genes, stem cell-related surface markers and cancer stem cells (CSCs) specific transcriptional factors (TFs), can be noted as leading cause of tumorigenesis (Sadikovic, Al-Romaih, Squire, & Zielenska, 2008;Zhao, Li, & Zhang, 2017).…”