Details

Autor(en) / Beteiligte

• Zhang, Xianyu
• Yu, Yunkai
• Peer, Cody J.
• Landsman, Rebekah
• Skorupan, Nebojsa
• Cao, Liang
• Alewine, Christine

Titel

Low serum mesothelin in pancreatic cancer patients results from retention of shed mesothelin in the tumor microenvironment

Ist Teil von

• Translational oncology, 2022-07, Vol.21, p.101440-101440, Article 101440

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• •Pancreas ductal adenocarcinoma (PDAC) frequently expresses mesothelin.•No elevation in serum mesothelin was observed in PDAC patients.•Shed mesothelin transit from intratumoral fluid to serum compartments is slowed in PDAC. 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.