Chapter 19 - Brain Metastasis from Small-Cell Lung Cancer with High Levels of Placental Growth Factor

Abstract

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for brain metastasis (BM) early. Despite efforts and advances in new therapeutics for SCLC, the prognosis of SCLC patients with BM is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important to improve current therapies and design new treatment modalities. However, the molecular pathways of SCLC BM remain largely unknown due to a lack of investigation. We identify the elevated levels of placental growth factor (PLGF) that are associated with SCLC BM and correlated inversely with SCLC clinical outcome. More importantly, our results suggest that SCLC patients with high levels of PLGF in the serum are prone to BM. Using an in vitro blood–brain barrier model, we show that PLGF derived from SCLC cells directly triggers VEGFR1-Rho-ERK1/2 signaling axis activation in brain endothelial cells, resulting in the disassembly of tight junctions, and promotes SCLC cells transendothelial migration. Furthermore, SCLC cells BM in vivo are suppressed by PLGF downregulation. In this context, we document that PLGF secreted by SCLC cells directly triggers the opening of tight junctions for SCLC cells migration through the blood–brain barrier and entry into the brain, which extends beyond traditional roles of PLGF in tumor angiogenesis and progression. Our studies reveal that PLGF is a potential signature of SCLC BM.