Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion
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Prashanth Prithviraj1,2,3, Matthew Anaka1, Sonja J McKeown5, Michael Permezel6, Marzena Walkiewicz1,2, Jonathan Cebon1,2,3,4,*, Andreas Behren1,2,3,4,*, Aparna Jayachandran1,2,3,4,*
1Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia
2Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia
3Department of Medicine, University of Melbourne, Victoria, Australia
4School of Cancer Medicine, La Trobe University, Victoria, Australia
5Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia
6Mercy Hospital for Women, Heidelberg, VIC, Australia
*These authors have contributed equally to this work
Andreas Behren, e-mail: email@example.com
Keywords: PAPPA, melanoma, pregnancy, EMT, invasion
Received: February 01, 2015 Accepted: March 23, 2015 Published: April 10, 2015
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.
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