PAPP-A and cancer

Our plain-English summary of PAPP-A and cancer, by C.A. Conover, C. Oxvig (Journal of Molecular Endocrinology, 2018).

The study

• Authors: C.A. Conover, C. Oxvig
• Journal: Journal of Molecular Endocrinology
• Published: 2018;61(1):T1-T10
• Type of article: Review
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The zinc metalloproteinase, PAPP-A, enhances local insulin-like growth factor (IGF) action through cleavage of inhibitory IGF-binding proteins, thereby increasing IGF available for IGF receptor-mediated cell proliferation, migration and survival. In many tumors, enhanced IGF receptor signaling is associated with tumor growth, invasion and metastasis. We will first discuss PAPP-A structure and function, and post-translational inhibitors of PAPP-A expression or proteolytic activity. We will then review the evidence supporting an important role for PAPP-A in many cancers, including breast, ovarian and lung cancer, and Ewing sarcoma.

© 2018 Society for Endocrinology.

In plain English

This article is a review in which two authors summarized published laboratory, animal and patient research on PAPP-A, an enzyme that increases the local activity of insulin-like growth factor (IGF), and its possible role in cancer. It reports no new data and does not discuss asbestos. The authors covered breast, ovarian and lung cancer, malignant pleural mesothelioma, melanoma and Ewing sarcoma. For mesothelioma, they cited one 2013 study (Huang and coworkers). In that study, silencing the PAPP-A gene in mesothelioma cells reduced migration, invasion and growth. Immune-compromised mice injected into the chest cavity with these cells developed no tumors or bloody pleural effusion. In breast cancer, most rodent studies suggested PAPP-A promotes tumors, but one group suggested it suppresses them. Antibodies blocking PAPP-A limited tumor growth in mouse models of ovarian and lung cancer. Under lung cancer, the authors cited a study finding PAPP-A in malignant pleural fluid at about 50-fold serum levels, without linking it to mesothelioma. The authors described targeting PAPP-A as having advantages for treatment. They also noted that several findings conflict and that PAPP-A may have unidentified functions.

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: Narrative review (thematic review) of published studies; no new data
• Who was studied: No study population; the authors reviewed published laboratory, animal and human studies on PAPP-A and several cancers
• Exposure: Not an exposure study. The subject is the enzyme PAPP-A and the IGF system. Asbestos and mineral fibers are not discussed.
• Main results:
  • In a cited study (Huang and coworkers, 2013), PAPP-A was identified as a gene promoting migration and invasion in malignant pleural mesothelioma. Silencing it in mesothelioma cells decreased migration, invasion and proliferation.
  • In the same cited study, immune-compromised mice injected into the pleural cavity with mesothelioma cells carrying PAPP-A shRNA developed no tumors or bloody pleural effusion.
  • In a cited 2017 study discussed under lung cancer (not identified as mesothelioma-specific), PAPP-A was elevated about 50-fold and interleukin-6 more than 100-fold in malignant pleural fluid, compared with serum levels.
  • Breast cancer findings were mixed. Most rodent models suggested PAPP-A acts as an oncogene, but one group suggested it acts as a tumor suppressor.
  • In ovarian cancer patient tumorgrafts in mice ('Avatars'), a PAPP-A-blocking antibody (mAb-PA) worked in Avatars with relatively high PAPP-A but not in those with low PAPP-A.
  • In women with ovarian cancer, PAPP-A in ascites was about 50-fold higher than in serum. Serum PAPP-A did not differ between patients and controls.
  • In a mouse model with A549 lung cancer cells, weekly injections of the PAPP-A-blocking antibody inhibited tumor growth.
• The authors' conclusion: The authors concluded that targeting PAPP-A has the advantage of reducing IGF signaling only in tissues where increased signaling may come from increased PAPP-A activity. They suggested PAPP-A levels might help select patients for therapy.
• Limitations the authors state:
  • Several findings conflict with a simple model in which PAPP-A promotes tumors and the stanniocalcins oppose this by inhibiting PAPP-A.
  • PAPP-A may have substrates or biological activities not yet identified.
  • Data on PAPP-A in cancers other than breast, ovarian and lung cancer, including mesothelioma, are more limited.
  • Earlier reports were biased because the polyclonal antibodies used to detect PAPP-A also reacted with other proteins.

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Lung Cancer, Sarcoma.

Related studies

• Electron microscopy in the diagnosis of percutaneous fine needle aspiration specimens — E.J. Wills, S. Carr, et al. (1987)
• A comparative immunohistochemical study of peritoneal and ovarian serous tumors, and mesotheliomas — N. Khoury, U. Raju, et al. (1990)
• Malignant mesothelioma following radiation exposure — K.H. Antman, J.M. Corson, et al. (1983)
• Calretinin. A selective marker of normal and neoplastic mesothelial cells in serous effusions — M.C. Barberis, M. Faleri, et al. (1997)
• Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies — H.J. Gray, K. Bell-McGuinn, et al. (2018)
• Tumor type influences the effectiveness of pleurodesis in malignant effusions — S. Bielsa, P. Hernández, et al. (2011)

Browse return to medical research.