Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer.
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Biomarkers, Tumor
/ blood
Cell Line, Tumor
Deoxycytidine
/ analogs & derivatives
Drug Resistance, Neoplasm
/ physiology
Humans
Macrophages
/ pathology
Mice
Pancreatic Neoplasms
/ drug therapy
Prognosis
Vascular Cell Adhesion Molecule-1
/ blood
Xenograft Model Antitumor Assays
Gemcitabine
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
03 12 2020
03 12 2020
Historique:
received:
08
03
2020
accepted:
24
11
2020
entrez:
4
12
2020
pubmed:
5
12
2020
medline:
15
4
2021
Statut:
epublish
Résumé
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
Identifiants
pubmed: 33273652
doi: 10.1038/s41598-020-78320-3
pii: 10.1038/s41598-020-78320-3
pmc: PMC7713301
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Biomarkers, Tumor
0
Vascular Cell Adhesion Molecule-1
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
21194Références
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