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

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

doi:10.18632/oncotarget.3643

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.

Highlights

Cancer in pregnancy is on the rise [1]
We examined pregnancy-associated plasma protein-A (PAPPA) mRNA expression by quantitative real-time RT-PCR in a panel of human melanoma cell lines that were derived from resected melanoma metastases and found it to be variably expressed (Figure 1A)
PAPPA protein expression patterns in melanoma tumors were determined by immunohistochemical (IHC) staining of tissue microarrays (TMA) comprising of tumors from 103 patients with stage III and IV metastatic melanoma

Summary

INTRODUCTION

Cancer in pregnancy is on the rise [1]. Melanoma is the most common malignancy encountered during pregnancy and dismal outcomes are recognised to occur in patients who are pregnant at time of diagnosis [1,2,3]. PAPPA is a metalloproteinase that modulates Insulinlike growth factor (IGF) activity It was initially found at high concentration in the plasma of pregnant women and subsequently has been implicated as a multifunctional modulator of a number of pathologic processes [6,7,8,9]. It is the principal physiological regulator of Insulin-like growth factor-binding protein (IGFBP)-4 and cleaves the IGFBP4/IGF1 complex, releasing IGF1 and modulating local IGF1 bioavailability [10]. This may explain the long-recognised, but poorly understood, link between melanoma progression and pregnancy

RESULTS

Melanoma Cell Lines

DISCUSSION