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

Introduction

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing early. About 10% of patients with SCLC develop brain metastasis at the time of diagnosis, and the majority of these patients will be symptomatic. The progressive growth of metastasis in the brain is often associated with the terminal stage of the disease, and the prognosis of most patients is consistently poor, with median survival duration of 4–6 months. Additionally, brain metastasis (BM) occurs during the course of the disease in over 50% of SCLC patients surviving 2 years or more ( ). Obviously, it is necessary to prevent BM in SCLC management. Although BM can be surgically removed without producing severe neurologic complications, the prognosis of the disease is still very poor. Therefore, a better understanding of the mechanisms of SCLC metastasis to the brain is important to improve current therapies and design new treatment modalities.

The brain is a common site of metastasis in SCLC. It is important for successful BM formation that SCLC cells migrate across the blood–brain barrier (BBB), which is constituted with the endothelium and the surrounding cells. The unique anatomical structure of BBB isolates central cells from peripheral tissue and maintains highly stable conditions ( ). Owing to the existence of the BBB, the mechanism of SCLC metastasis to the brain is believed to be different from that to other tissues. SCLC cells adhesion to and migration through this barrier require complex molecular interactions, and the detailed understanding of these events may lead the way to target inhibition of BM formation. However, in-depth knowledge about these mechanisms is largely lacking. In many patients, the BBB has failed to block the invasion of metastatic SCLC cells into brain parenchyma, suggesting the presence of some mechanisms that facilitate invasion of cancer cells into the brain parenchyma through the BBB. Moreover, the BBB is breached in metastases as evidenced by magnetic resonance imaging, which shows that more than 70% of SCLC brain metastases have leakage of contrast agent from blood vessels ( ). It is likely that the increased BBB permeability plays a crucial role in the process. However, the detailed mechanism remains a mystery.

A major anatomical feature regulating BBB permeability is the presence of closely associated areas called tight junctions (TJs) between opposing endothelial cells. The TJs are the main components that confer the low paracellular permeability and high electrical resistance. TJs function both as a “zipper” and a “fence” that limit paracellular permeability and are composed of transmembrane proteins, such as claudins and occludin, joining the cytoskeleton via cytoplasmic proteins, such as zonula occludin proteins (ZO-1 and ZO-2). Thus, the regulation of TJ protein expression and/or subcellular distribution plays a key role in the alteration of the BBB permeability.

Our previous studies had clearly indicated that SCLCs could trigger the disassembly of TJs between brain microvascular endothelial cells resulting in the enhancement of the BBB permeability ( ). So, the “opening” of TJs seemed to be a key event in SCLC cell transendothelial migration. Then, how do SCLC cells “open” the TJs between brain endothelium? Recent investigations were beginning to provide insight into how several cytokines and their signaling pathways participate in breast cancer and melanoma cell metastatic colonization in the brain. A variety of the factors were postulated to be involved in altering BBB permeability when these tumor cells metastasized to brain. , performed comparative genome-wide expression analysis on breast cancer cell brain metastatic variants and identified the cyclooxygenase COX2, as a critical mediator of extravasation through the blood–brain barrier; determined that stromal cell-derived factor 1α (SDF-1α) induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells. Overexpression of transforming growth factor-β2 (TGF-β2) in murine B16 melanoma cells induced parenchymal micrometastases but had no effect on the leptomeningeal lesions ( ). It was reported that vascular endothelial growth factor (VEGF) is an important regulator for breast cancer cell migration across the brain endothelial cells ( ). In a brain metastatic variant of MDA-MB-231 cells, there was a significant increase in VEGF production, and inhibition of VEGFR activity significantly reduced brain tumor burden after intracarotid injection in mice ( ). However, some studies demonstrated that VEGF expression was not sufficient for BM production. When lung adenocarcinoma cells (PC14PE6) transfected with antisense VEGF165 were injected into the carotid artery of nude mice, the formation of brain metastases was substantially decreased compared with untransfected cells. However, in lung squamous carcinoma cells (H226) transfected with VEGF121 or VEGF165, no increase in metastasis was observed ( ). Therefore, another vascular permeability factor beside VEGF might facilitate tumor cell migration across the BBB and metastasize to the brain. The alteration of BBB permeability between brain endothelium was an important biological event during SCLC cell transendothelial migration. However, the detailed molecular mechanism which contributes to the pathological process needs to be elucidated.

Placental Growth Factor