Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

Ran Zhang; Feng Liu

doi:10.1186/s12967-022-03656-5

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

J Transl Med. 2022 Oct 4;20(1):453. doi: 10.1186/s12967-022-03656-5.

Authors

Ran Zhang¹, Feng Liu²

Affiliations

¹ Laboratory of Radio-Immunology, Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China.
² Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, 250012, Shandong, People's Republic of China. liufeng2019@sdu.edu.cn.

Abstract

Background: Cancer-associated fibroblasts (CAFs) play multiple roles in regulating tumor metastasis and treatment response. Current clinical indicators are insufficient to accurately assess disease risk and radiotherapy response, emphasizing the urgent need for additional molecular prognostic markers.

Methods: In order to investigate CAF-related genes associated with radiotherapy and construct prognostic CAF-related gene signatures for prostate cancer, we firstly established a radio-resistant prostate CAF cell subline (referred to as CAFR) from Mus-CAF (referred to as CAF) through fractionated irradiation using X-rays. Transcriptome sequencing for CAF and CAFR was conducted, and 2626 CAF-related differentially expressed genes (DEGs) associated with radiotherapy were identified. Human homologous genes of mouse CAF-related DEGs were then obtained.

Results: Functional enrichment analysis revealed that these CAF-related DEGs were significantly enriched ECM- and immune-related functions and pathways. Based on GSE116918 dataset, 186 CAF-related DEGs were correlated with biochemical recurrence-free survival (BCRFS) of prostate cancer patients, 16 of which were selected to construct a BCRFS-related CAF signature, such as ACPP, THBS2, and KCTD14; 142 CAF-related DEGs were correlated with metastasis-free survival (MFS), 16 of which were used to construct a MFS-related CAF signature, such as HOPX, TMEM132A, and ZNF467. Both Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets confirmed that the two CAF signatures accurately predicted BCRFS and MFS of prostate cancer patients. The risk scores were higher in patients with higher gleason grades and higher clinical T stages. Moreover, the BCRFS-related CAF signature was an independent prognostic factor and a nomogram consisting of BCRFS-related CAF signature and various clinical factors accurately predicted 2-, 3-, and 5-year survival time of prostate cancer patients. Furthermore, the risk score was positively correlated with multiple immune checkpoints.

Conclusions: Our established CAF signatures could accurately predict BCRFS and MFS in prostate cancer patients undergoing radiotherapy.

Keywords: Biochemical recurrence-free survival; Cancer-associated fibroblasts; Gene signature; Metastasis-free survival; Prostate cancer; Radiotherapy prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers / metabolism
Cancer-Associated Fibroblasts* / metabolism
Cancer-Associated Fibroblasts* / pathology
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Prognosis
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / radiotherapy

Substances

Biomarkers