Prithviraj Prashanth, Anaka Matthew, McKeown Sonja J, Permezel Michael, Walkiewicz Marzena, Cebon Jonathan, Behren Andreas, Jayachandran Aparna
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.
Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.
Oncotarget. 2015 Jun 30;6(18):15953-65. doi: 10.18632/oncotarget.3643.
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.
黑色素瘤是孕妇中最常见的诊断出的癌症，通常在孕期或产后不久会出现侵袭性病程且预后较差。其潜在机制尚不清楚。在此，我们报告妊娠相关血浆蛋白A（PAPPA）可促进黑色素瘤的迁移、侵袭和进展，PAPPA是胎盘产生的一种妊娠相关金属蛋白酶，它通过从与胰岛素样生长因子结合蛋白4（IGFBP4）形成的循环复合物中切割IGF1来增加其生物利用度。我们发现PAPPA在转移性黑色素瘤肿瘤中广泛表达，并且在表现出间充质、侵袭性和标记保留表型的黑色素瘤细胞中升高。值得注意的是，抑制PAPPA可显著降低黑色素瘤细胞在体外以及鸡胚神经管内的侵袭和迁移。富含PAPPA的妊娠血清处理可增强黑色素瘤细胞在体外的运动能力。此外，我们报告IGF1可诱导黑色素瘤细胞发生上皮-间充质转化（EMT）的表型和功能效应。在本研究中，我们确立了一种妊娠相关蛋白PAPPA、黑色素瘤以及通过IGF1介导的功能效应之间的明确关系，这为孕期黑色素瘤加速进展提供了一种合理的机制。这为治疗性靶向PAPPA/IGF1轴开辟了可能性。
