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Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk.
- Source :
-
Anticancer research [Anticancer Res] 2024 Jun; Vol. 44 (6), pp. 2497-2509. - Publication Year :
- 2024
-
Abstract
- Background/aim: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells.<br />Materials and Methods: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated β-galactosidase (SA-β-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets.<br />Results: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-β, whereas DGC cells induced SA-β-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients.<br />Conclusion: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.<br /> (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Cell Movement
Stomach Neoplasms pathology
Stomach Neoplasms metabolism
Interleukin-8 metabolism
Peritoneal Neoplasms secondary
Peritoneal Neoplasms metabolism
Cellular Senescence
Cancer-Associated Fibroblasts metabolism
Cancer-Associated Fibroblasts pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1791-7530
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Anticancer research
- Publication Type :
- Academic Journal
- Accession number :
- 38821603
- Full Text :
- https://doi.org/10.21873/anticanres.17056