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Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.
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.
Afiliación
  • Tindall RR; Department of Surgery.
  • Faraoni EY; Department of Anesthesiology, Critical Care and Pain Medicine.
  • Li J; Department of Surgery.
  • Zhang Y; Department of Surgery.
  • Ting SM; Department of Neurology.
  • Okeugo B; Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • Zhao X; Department of Neurology.
  • Liu Y; Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • Younes M; Department of Pathology, George Washington University, Washington, DC 20037, USA.
  • Shen Q; Department of Interdisciplinary Oncology, Louisiana State Univ. Health Sciences Center, New Orleans, LA 70112, USA.
  • Bailey-Lundberg JM; Department of Anesthesiology, Critical Care and Pain Medicine.
  • Cao Y; Department of Surgery.
  • Ko TC; Department of Surgery.
Pancreas ; 2024 Jun 04.
Article en En | MEDLINE | ID: mdl-38829570
ABSTRACT

OBJECTIVE:

The pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts (CAFs) 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 adequately defined.

METHODS:

We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas (TCGA) RNA-sequencing data and characterized the 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 (P < 0.05). Immunohistochemistry detected Grem1 protein in PDAC tumor cells and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in CAFs suppressed transforming growth factor (TGF)-ß-induced extracellular matrix proteins (P < 0.05). Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages (P < 0.05).

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.

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Pancreas Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Pancreas Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article