Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment

Our plain-English summary of Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment, by X.M. Xue, Y.Y. Liu, X.M. Chen, et al (Frontiers in Pharmacology, 2022).

The study

• Authors: X.M. Xue, Y.Y. Liu, X.M. Chen, B.Y. Tao, P. Liu, H.W. Zhou, C. Zhang, L. Wang, Y.K. Jiang, Z.W. Ding, W.D. Shen, J. Zhang, S.M. Yang, F.Y. Wang
• Journal: Frontiers in Pharmacology
• Published: 2022;13:1064032
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Ecto-5'-nucleotidase (NT5E) encodes the cluster of differentiation 73 (CD73), whose overexpression contributes to the formation of immunosuppressive tumor microenvironment and is related to exacerbated prognosis, increased risk of metastasis and resistance to immunotherapy of various tumors. However, the prognostic significance of NT5E in pan-cancer is obscure so far. Methods: We explored the expression level of NT5E in cancers and adjacent tissues and revealed the relationship between the NT5E expression level and clinical outcomes in pan-cancer by utilizing the UCSC Xena database. Then, correlation analyses were performed to evaluate the relationship between NT5E expression and immune infiltration level via EPIC, MCP-counter and CIBERSORT methods, and the enrichment analysis were employed to identify NT5E-interacting molecules and functional pathways. Furthermore, we conducted single-cell analysis to explore the potential role of NT5E on single-cell level based on the CancerSEA database. Meanwhile, gene set enrichment analysis (GSEA) in single-cell level was also conducted in TISCH database and single-cell signature explorer was utilized to evaluate the epithelial-mesenchymal transition (EMT) level in each cell type. Results: The expression level of NT5E was aberrant in almost all cancer types, and was correlated with worse prognosis in several cancers. Notably, NT5E overexpression was related to worse overall survival (OS) in pancreatic adenocarcinoma (PAAD), head and neck squamous cell carcinoma (HNSC), mesothelioma (MESO), stomach adenocarcinoma (STAD), uveal melanoma (UVM) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (p < 0.01). NT5E-related immune microenvironment analysis revealed that NT5E is associated positively with the degree of infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells in most cancers. Enrichment analysis of cellular component (CC) demonstrated the critical part of NT5E played in cell-substrate junction, cell-substrate adherens junction, focal adhesion and external side of plasma membrane. Finally, single-cell analysis of NT5E illuminated that EMT function of CAFs was elevated in basal cell carcinoma (BCC), skin cutaneous melanoma (SKCM), HNSC and PAAD. Conclusion: NT5E could serve as a potential prognostic biomarker for cancers. The potential mechanism may be related to the upregulated EMT function of CAFs, which provides novel inspiration for immunotherapy by targeting CAFs with high NT5E expression.

Copyright © 2022 Xue, Liu, Chen, Tao, Liu, Zhou, Zhang, Wang, Jiang, Ding, Shen, Zhang, Yang and Wang.

In plain English

This was a laboratory and database study of a gene called NT5E. It did not study asbestos or asbestos-exposed people, and asbestos is not mentioned. Using public cancer databases (TCGA and GTEx), the authors compared NT5E gene expression in tumors and normal tissue across 31 cancer types and tested its link with survival. They also used single-cell databases and stained supraglottic carcinoma samples, a head and neck cancer, from their hospital. Mesothelioma was one of the cancers analyzed. The article does not say whether it was pleural or peritoneal. Mesothelioma was left out of the tumor-versus-normal comparison because no matching normal tissue data were available. In mesothelioma, higher NT5E expression was associated with worse overall survival (hazard ratio 2.54; confidence interval 1.57 to 4.11; p = 0.001), as it was in several other cancers. NT5E expression was also positively related to estimated infiltration by cancer-associated fibroblasts and endothelial cells in almost all cancers. The authors concluded that NT5E could serve as a prognostic marker. They noted that the database data may carry systematic bias and that their findings need clinical trial validation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics analysis of public gene-expression and survival databases (pan-cancer), with immunofluorescence staining of hospital tumor specimens
• Who was studied: Patients in the TCGA pan-cancer cohort (including mesothelioma) and normal tissues from GTEx, obtained through the UCSC Xena database. Genomic alteration data covered 33 cancer types from cBioPortal. The tumor-versus-normal comparison included 31 tumor types: mesothelioma and uveal melanoma were excluded for lack of normal tissue data. The study also used supraglottic carcinoma specimens from Chinese PLA General Hospital, Beijing. Patient numbers are not given in the text.
• Exposure: No asbestos or fiber exposure was studied. The factor examined was the mRNA expression level of the NT5E gene (which encodes CD73).
• Main results:
  • In univariate Cox regression, NT5E overexpression predicted worse overall survival in PAAD, HNSC, mesothelioma (MESO), STAD, UVM and CESC (p less than 0.01), and in LUAD, BRCA and KIRC (p less than 0.05).
  • In Kaplan-Meier analysis, higher NT5E expression in mesothelioma was associated with poorer survival: HR = 2.54; CI = 1.57 to 4.11; p = 0.001. The high/low cut-off was the point giving the minimum p-value.
  • Mesothelioma was not included in the comparison of tumor versus normal tissue, because normal tissue data were unavailable.
  • Using the EPIC and MCPcounter methods, NT5E expression was positively related to estimated infiltration by cancer-associated fibroblasts (CAFs) and endothelial cells in almost all cancers (p less than 0.01).
  • Single-cell analysis found NT5E mainly in endothelial cells and CAFs in basal cell carcinoma, HNSC, PAAD and skin cutaneous melanoma. EMT function of CAFs was up-regulated in these four cancers.
  • In supraglottic carcinoma specimens (number not stated), NT5E abundance was positively related to T stage. NT5E was co-expressed with the CAF marker alpha-smooth muscle actin.
• The authors' conclusion: The authors concluded that NT5E could serve as a prognostic biomarker across cancers, and that its pro-tumor effect may be related to up-regulated EMT function of cancer-associated fibroblasts.
• Limitations the authors state:
  • The data came from online databases, so systematic bias may be unavoidable.
  • Pan-cancer analysis is affected by heterogeneity between different cancers.
  • The findings need validation in clinical trials.
  • More functional experiments are needed.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Fibroblast, Tumor Microenvironment, Prognosis, Metastasis, Immunotherapy, Overall Survival, Adenocarcinoma.

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