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Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion

2015; Impact Journals LLC; Volume: 6; Issue: 18 Linguagem: Inglês

10.18632/oncotarget.3643

1949-2553

Prashanth Prithviraj, Matthew Anaka, Sonja J. McKeown, Michael Permezel, Marzena Walkiewicz, Jonathan Cebon, Andreas Behren, Aparna Jayachandran,

Cancer Cells and Metastasis

// Prashanth Prithviraj 1, 2, 3 , Matthew Anaka 1 , Sonja J McKeown 5 , Michael Permezel 6 , Marzena Walkiewicz 1, 2 , Jonathan Cebon 1, 2, 3, 4, * , Andreas Behren 1, 2, 3, 4, * , Aparna Jayachandran 1, 2, 3, 4, * 1 Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia 2 Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia 3 Department of Medicine, University of Melbourne, Victoria, Australia 4 School of Cancer Medicine, La Trobe University, Victoria, Australia 5 Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia 6 Mercy Hospital for Women, Heidelberg, VIC, Australia * These authors have contributed equally to this work Correspondence to: Andreas Behren, e-mail: andreas.behren@onjcri.org.au Keywords: PAPPA, melanoma, pregnancy, EMT, invasion Received: February 01, 2015 Accepted: March 23, 2015 Published: April 10, 2015 ABSTRACT Melanoma is the most common cancer diagnosed in pregnant women and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. Here, we report that melanoma migration, invasiveness and progression are promoted by Pregnancy-Associated Plasma Protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of IGF1 by cleaving it from a circulating complex formed with IGFBP4. We show that PAPPA is widely expressed by metastatic melanoma tumors and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in vivo within the embryonic chicken neural tube. PAPPA-enriched pregnancy serum treatment enhanced melanoma motility in vitro . Furthermore, we report that IGF1 can induce the phenotypic and functional effects of epithelial-to-mesenchymal transition (EMT) in melanoma cells. In this study, we establish a clear relationship between a pregnancy-associated protein PAPPA, melanoma and functional effects mediated through IGF1 that provides a plausible mechanism for accelerated melanoma progression during pregnancy. This opens the possibility of targeting the PAPPA/IGF1 axis therapeutically.