Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis

Our plain-English summary of Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis, by X. Liao, W. Wang, B. Yu, et al (Cancer Cell International, 2022).

The study

• Authors: X. Liao, W. Wang, B. Yu, S. Tan
• Journal: Cancer Cell International
• Published: 2022;22(1):213
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Thrombospondin-2 (THBS2) is a versatile glycoprotein that regulates numerous biological functions, including the apoptosis-proliferation balance in endothelial cells, and it has been linked to tumor angiogenesis. However, the exact role of THBS2 in human cancer remains unknown. This study aimed to determine THBS2 expression in a pan-cancer analysis and its association with pan-cancer prognosis and to further identify its possible roles in tumor immunity and the extracellular matrix (ECM).

Methods: Data on THBS2 expression in cancers and normal tissues were downloaded from the Genotype-Tissue Expression portal and UCSC Xena visual exploration tool and analyzed using the ONCOMINE database, Perl programming language, and Gene Expression Profiling and Interactive Analyses vision 2 webserver. In addition, survival prognosis was analyzed using the survival, survminer, limma, and forestplot packages in R v. 4.0.3.Immune and matrix components were also analyzed using R v. 4.0.3. Most importantly, we partially validated the role and mechanism of THBS2 in pancreatic and gastric cancers in vitro using PANC1 and BGC-823 cell lines.

Results: THBS2 was significantly overexpressed in 17 of the 33 investigated cancers and linked to a poor prognosis in pan-cancer survival analysis. High THBS2 expression was an independent unfavorable prognostic factor in kidney renal papillary cell, mesothelioma, and stomach and pancreatic adenocarcinomas. Immune infiltration and THBS2 expression were also related. THBS2 expression has been linked to immune and stromal scores and immune checkpoint markers in various cancers. The protein-protein interaction network revealed that THBS2 is associated with multiple ECM and immune proteins. THBS2 knockdown decreased the expression of CD47 and matrix metallopeptidase 2 (MMP-2) as well as the proliferation, migration, and invasion of PANC1 and BGC-823 cells in vitro.

Conclusions: Our findings suggested that THBS2 might promote cancer progression by remodeling the tumor microenvironment, affecting CD47-mediated signaling pathways, activating the pro-tumor functions of a disintegrin and metalloproteinase with thrombospondin motifs, and enhancing MMP-2 expression. Furthermore, it functions as a bridge between the ECM and immune infiltration in cancer and serves as a potential prognostic biomarker for several cancers, especially pancreatic and gastric adenocarcinomas.

© 2022. The Author(s).

In plain English

This study analysed public gene databases and ran laboratory tests on cancer cells. It did not study asbestos exposure. Using The Cancer Genome Atlas and other databases, the authors analysed gene-expression (mRNA) levels of thrombospondin-2 (THBS2), a protein, in 33 cancer types, including mesothelioma. In one database comparison, THBS2 expression was significantly higher in 17 cancers than in normal tissue and significantly lower in 14. Higher THBS2 expression was linked with worse overall survival in several cancers, including mesothelioma. For mesothelioma the authors also reported poorer disease-specific survival and progression-free interval with higher THBS2 expression. In multivariate Cox regression analyses that also included tumor stage, high THBS2 expression was an independent unfavorable prognostic factor in mesothelioma and in kidney papillary, pancreatic and stomach cancers. THBS2 expression also correlated with measures of immune cells and connective tissue in tumors. In pancreatic (PANC1) and stomach (BGC-823) cancer cell lines, lowering THBS2 reduced CD47 and MMP-2 protein and slowed cell growth, migration and invasion. The authors concluded that THBS2 might promote cancer progression and may be a potential prognostic biomarker, especially for pancreatic and gastric adenocarcinomas.

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: Bioinformatic (computer-based) pan-cancer analysis of public gene-expression and clinical databases (TCGA, GTEx, ONCOMINE, GEPIA2, UCSC Xena), plus in vitro laboratory experiments on two cancer cell lines
• Who was studied: Database records for 33 cancer types, one of which was mesothelioma (MESO), drawn from The Cancer Genome Atlas, and 34 normal tissues from the GTEx database. The study also used the human pancreatic cancer cell line PANC1 and the stomach cancer cell line BGC-823. The text gives no patient numbers.
• Exposure: No asbestos or fiber exposure was studied. The factor examined was the level of THBS2 gene (mRNA) expression in tumors. In the cell experiments, THBS2 was reduced (knocked down) using small interfering RNA.
• Main results:
  • In the GEPIA2 comparison of tumor and normal tissues, THBS2 expression was significantly higher in 17 cancers (mainly breast, pancreatic and sarcoma) and significantly lower in 14 cancers.
  • THBS2 expression was significantly associated with overall survival in 10 cancer types, including mesothelioma (MESO). Higher THBS2 expression was linked to worse overall survival in all of them except skin cutaneous melanoma.
  • THBS2 expression was associated with disease-specific survival in seven cancer types, including mesothelioma. Increased THBS2 expression was linked to poorer prognosis in these seven.
  • THBS2 expression was associated with progression-free interval in nine cancer types, including mesothelioma. Higher THBS2 expression was linked to a worse progression-free interval in all of them except DLBC (diffuse large B-cell lymphoma).
  • In univariate and multivariate Cox regression, high THBS2 expression was an independent unfavorable prognostic factor for overall survival in kidney renal papillary cell carcinoma, mesothelioma, pancreatic adenocarcinoma and stomach adenocarcinoma. In skin cutaneous melanoma, low THBS2 expression was the unfavorable factor. No hazard ratios are given in the text.
  • THBS2 expression correlated significantly and positively with the StromalScore (a measure of connective-tissue content) in a list of cancers that included mesothelioma.
  • In PANC1 and BGC-823 cells, THBS2 knockdown decreased CD47, MMP-2 and THBS2 protein on western blotting.
  • THBS2 knockdown inhibited proliferation of PANC1 and BGC-823 cells in the CCK8 assay. In transwell and wound healing assays, it also inhibited what the authors called metastasis and invasion of these cells.
• The authors' conclusion: The authors concluded that THBS2 might promote cancer progression by remodeling the tumor microenvironment, affecting CD47-mediated signaling, activating pro-tumor ADAMTS functions and enhancing MMP-2 expression. They added that it may act as a bridge between the extracellular matrix and immune infiltration, and may be a potential prognostic biomarker for several cancers, especially pancreatic and gastric adenocarcinomas.

Topics

Medical terms in this study, explained in our Lexicon: Adenocarcinoma, Glycoprotein, Apoptosis, Angiogenesis, Prognosis, Stomach Cancer, Mesothelioma, Tumor Microenvironment.

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