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胰腺导管腺癌中Gremlin1表达增加促进促纤维生成的基质微环境形成。

Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.

作者信息

Tindall Rachel R, Faraoni Erika Y, Li Jiajing, Zhang Yinjie, Ting Shun-Ming, Okeugo Beanna, Zhao Xiurong, Liu Yuying, Younes Mamoun, Shen Qiang, Bailey-Lundberg Jennifer M, Cao Yanna, Ko Tien C

机构信息

From the Department of Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX.

Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX.

出版信息

Pancreas. 2024;53(10):e808-e817. doi: 10.1097/MPA.0000000000002378. Epub 2024 Jun 4.

DOI:10.1097/MPA.0000000000002378
PMID:38829570
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11615151/
Abstract

OBJECTIVE

Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not defined.

MATERIALS AND METHODS

We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas RNA-sequencing data and characterized expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies.

RESULTS

Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts. Immunohistochemistry detected Grem1 protein in PDAC tumor and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in cancer-associated fibroblasts suppressed transforming growth factor β-induced extracellular matrix proteins. Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages.

CONCLUSIONS

Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.

摘要

目的

胰腺导管腺癌（PDAC）微环境主要由癌症相关成纤维细胞和免疫细胞组成。Gremlin1（Grem1）是一种促纤维化因子，可促进多种癌症的肿瘤发生。然而，Grem1在PDAC微环境中的作用尚未明确。

材料与方法

我们使用癌症基因组图谱RNA测序数据，将Grem1水平与人类PDAC中活化的基质和免疫细胞进行关联，并对胰腺细胞系和PDAC组织中Grem1转录本和异构体的表达进行了表征。我们通过体外研究评估了Grem1在微环境中的作用。

结果

Grem1表达与活化的基质以及M1和M2巨噬细胞的增加相关。在人类胰腺细胞中仅可检测到全长Grem1变体1和异构体1，并且在胰腺成纤维细胞中观察到非常高水平的Grem1。免疫组织化学检测到PDAC肿瘤和基质细胞中的Grem1蛋白，这与PDAC肿瘤中浸润的巨噬细胞相关。癌症相关成纤维细胞中的Grem1敲低抑制了转化生长因子β诱导的细胞外基质蛋白。体外Grem1重组蛋白处理增加了M1和M2巨噬细胞。

结论

Grem1通过调节成纤维细胞和巨噬细胞在PDAC微环境中作为促纤维化因子发挥作用。Grem1可能有潜力被开发为PDAC的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/5134dc4f57db/nihms-1996436-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/cde88476d994/nihms-1996436-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/01722c486168/nihms-1996436-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/352f88c39b8a/nihms-1996436-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/a862b79b3150/nihms-1996436-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/a0d57d878053/nihms-1996436-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/5134dc4f57db/nihms-1996436-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/cde88476d994/nihms-1996436-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/01722c486168/nihms-1996436-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/352f88c39b8a/nihms-1996436-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/a862b79b3150/nihms-1996436-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/a0d57d878053/nihms-1996436-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0272/11615151/5134dc4f57db/nihms-1996436-f0006.jpg

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The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.
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