Low serum mesothelin in pancreatic cancer patients results from retention of shed mesothelin in the tumor microenvironment.
MUC16
Mesothelin
Microenvironment
Pancreatic adenocarcinoma
Journal
Translational oncology
ISSN: 1936-5233
Titre abrégé: Transl Oncol
Pays: United States
ID NLM: 101472619
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
received:
24
02
2022
revised:
06
04
2022
accepted:
23
04
2022
pubmed:
7
5
2022
medline:
7
5
2022
entrez:
6
5
2022
Statut:
ppublish
Résumé
Mesothelin (MSLN) is overexpressed by many cancers, including pancreatic ductal adenocarcinoma (PDAC) and has consequently become a target for anti-cancer therapeutics. Mature, membrane bound MSLN is cleaved by proteases, releasing a shed form that transits to the circulation. Many patients with mesothelioma and ovarian cancer have abnormally high serum MSLN concentration. However, serum MSLN concentration in PDAC patients rarely exceeds levels of healthy controls. Here, serum MSLN concentration in advanced PDAC patients was examined pre- and post-treatment. Serum MSLN did not correlate with tumor MSLN expression, nor with changes in tumor burden as assessed by PDAC serum tumor marker CA19-9. Subsequently, tumor-bearing mouse models were used to investigate the fate of shed MSLN in PDAC versus a control cervical cancer model. Efficiency of MSLN secretion into the serum was cell-line dependent. Tumors from some PDAC lines had poor MSLN secretion efficiency although these lines had similar or higher MSLN shedding rate, total and surface MSLN expression. Measurements of compartment-specific MSLN concentration taken at equilibrium suggested that tumors with poor MSLN secretion efficiency trapped shed MSLN in the tumor microenvironment (TME), a finding confirmed by dynamic experiments using a doxycycline-inducible MSLN expression system. Tumors with the poorest MSLN secretion efficiency had higher collagen density and increased abundance of MSLN binding partner MUC16. The tumor with the worst secretion efficiency could rebind shed MSLN to the cancer cell surface. Altogether, these data suggest that PDAC can trap shed MSLN within the TME. This finding has potential significance for design of MSLN-targeted therapeutics.
Identifiants
pubmed: 35523008
pii: S1936-5233(22)00099-7
doi: 10.1016/j.tranon.2022.101440
pmc: PMC9079715
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
101440Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
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