Megakaryocytic potentiating factor and mature mesothelin stimulate the growth of a lung cancer cell line in the peritoneal cavity of mice

Our plain-English summary of Megakaryocytic potentiating factor and mature mesothelin stimulate the growth of a lung cancer cell line in the peritoneal cavity of mice, by J. Zhang, T.K. Bera, W. Liu, et al (PloS One, 2014).

The study

• Authors: J. Zhang, T.K. Bera, W. Liu, X. Du, C. Alewine, R. Hassan, I. Pastan
• Journal: PloS One
• Published: 2014;9(8):e104388
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The mesothelin (MSLN) gene encodes a 71 kilodalton (kDa) precursor protein that is processed into megakaryocytic potentiating factor (MPF), a 31 kDa protein that is secreted from the cell, and mature mesothelin (mMSLN), a 40 kDa cell surface protein. The mMSLN binds to CA125, an interaction that has been implicated in the intra-cavitary spread of mesothelioma and ovarian cancer. To better define the role of MPF and mMSLN, growth of the lung cancer cell line A549 was evaluated in immuno-deficient mice with inactivation of the Msln gene. We observed that Msln-/- mice xenografted with intraperitoneal A549 tumors survive significantly long than tumor-bearing Msln+/+ mice. When tumor-bearing Msln-/- mice are supplemented with recombinant MPF (and to a lesser extent mMSLN), most of this survival advantage is lost. These studies demonstrate that MPF and mMSLN have an important role in the growth of lung cancer cells in vivo and raise the possibility that inactivation of MPF may be a useful treatment for lung and other MSLN expressing cancers.

In plain English

This was a laboratory experiment in mice. The authors bred athymic nude mice in which the Msln gene was inactivated (Fox N null/Msln–/–), confirmed loss of Msln protein in lung tissue by immunohistochemistry, and injected two million human A549 lung cancer cells into the peritoneal cavity of Msln–/– and Msln+/+ mice. Median survival was 31 days in Msln+/+ mice and 46 days in Msln–/– mice (p<0.0001), with about 25% of Msln–/– mice surviving over four months. No such survival difference appeared with A431 epidermoid cancer cells (negative for MSLN and CA125), and subcutaneously injected A549 tumours grew at the same rate in Msln–/– and Msln+/+ mice. Giving Msln–/– mice recombinant MPF-rFc reduced median survival to 31 days (p<0.0001) and mMSLN-rFc to 42 days (p=0.016), while control CD22-rFc remained 46 days (p=0.388). Forced MPF expression in A549 cells produced no statistical difference in soft-agar colony formation. The authors concluded that MPF is the more potent factor in their model, suggesting its effect is not direct on the tumour but perhaps works indirectly on other cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mouse xenograft study with gene-knockout mice, plus in vitro cell assays)
• Who was studied: Female athymic nude mice (NCr-nu/nu) and Fox N null/Msln–/– mice, weight 15–20 g and age 7–10 weeks, bearing human A549 lung cancer or A431 epidermoid cancer xenografts; recombinant-protein experiment used 41 PBS, 21 MPF-rFc, 21 CD22-rFc and 20 mMSLN-rFc Msln(–/–) mice; NIH laboratory
• Exposure: Presence or absence of the mouse Msln gene, and intraperitoneal injection of recombinant MPF-rFc, mMSLN-rFc or control CD22-rFc fusion proteins (25 µg per injection) in tumour-bearing Msln–/– mice; no asbestos exposure was studied
• Main results:
  • Median survival after intraperitoneal A549 cells was 31 days in Msln+/+ mice and 46 days in Msln–/– mice; nearly 25% of Msln–/– mice survived over four months while all Msln+/+ mice died within 50 days
  • In Msln(–/–) mice bearing A549 tumours, median survival was 46 days with PBS (41 mice), 31 days with MPF-rFc (21 mice, p<0.0001), 46 days with CD22-rFc (21 mice, p=0.388) and 42 days with mMSLN-rFc (20 mice, p=0.016)
  • No survival advantage for Msln–/– mice was seen with intraperitoneal A431 cells, which express neither MSLN nor CA125
  • With subcutaneous A549 injection, tumours in Msln–/– and Msln+/+ mice grew at the same rate
  • A549 cells had low mesothelin (average 3.5x10^3 mMSLN binding sites per cell) but robust CA125 expression; the intraperitoneal A549 tumours stained negative for MSLN and positive for CA125
  • A549 cells stably transfected with MPF (producing about 400 ng MPF in 48 hours) showed no statistical difference in soft-agar colony formation versus vector control (means 66.1 versus 63.1)
• The authors' conclusion: The authors concluded that MPF and mMSLN have an important role in in vivo growth of these lung cancer cells, that MPF is the more potent of the two in their model and may act indirectly on other cells rather than directly on the tumour, and they suggested that inhibiting MPF might be useful against some cancers growing in the peritoneal cavity
• Limitations the authors state:
  • The observations were made using a single cell type
  • The cell type responsible for mediating the MPF effect was not identified

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Mesothelin, Lung Cancer, Peritoneal Cavity, Mesothelioma, Ovarian Cancer.

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