Brain metastasis in lung cancer: Building a molecular and systems-level understanding to improve outcomes

Abstract

Lung cancer is a clinically difficult disease with rising disease burden around the world. Unfortunately, most lung cancers present at a clinically advanced stage. Of these cancers, many also present with brain metastasis which complicates the clinical picture. This review summarizes current knowledge on the molecular basis of lung cancer brain metastases. We start from the clinical perspective, aiming to provide a clinical context for a significant problem that requires much deeper scientific investigation. We review new research governing the metastatic process, including tumor cell signaling, establishment of a receptive tumor niches in the brain and evaluate potential new therapeutic options that take advantage of these new scientific advances. Lung cancer remains the largest single cause of cancer mortality in the United States (Siegel et al., 2015). This continues to be the clinical picture despite significant advances in therapy, including the advent of targeted molecular therapies and newly adopted immunotherapies for certain subtypes of lung cancer. In the vast majority of cases, lung cancer presents as advanced disease; in many instances, this advanced disease state is intimately associated with micro and macrometastatic disease (Goldberg et al., 2015). For both non-small cell lung cancer and small cell lung cancer patients, the predominant metastatic site is the brain, with up to 68% of patients with mediastinal lymph node metastasis eventually demonstrating brain metastasis (Wang et al., 2009). The frequency (incidence) of brain metastasis is highest in lung cancers, relative to other common epithelial malignancies (Schouten et al., 2002). Other studies have attempted to predict the risk of brain metastasis in the setting of previously non-metastatic disease. One of the largest studies to do this, analyzing historical data from 1973 to 2011 using the SEER database revealed a 9% risk of patients with previously non-metastatic NSCLC developing brain metastasis over the course of their disease, while 18% of small cell lung cancer patients without previous metastasis went on to develop brain metastasis as their disease progressed (Goncalves et al., 2016). The reasons underlying this predilection for the central nervous system, as well as the recent increase in the frequency of brain metastasis identified in patients remain important questions for both clinicians and basic scientists. More than ever, the question of how brain metastasis develop and how they can be treated and managed requires the involvement of interdisciplinary teams—and more importantly—scientists who are capable of thinking like clinicians and clinicians who are capable of thinking like scientists. This review aims to present a translational perspective on brain metastasis. We will investigate the scope of the problem of brain metastasis and the current management of the metastatic disease process in lung cancer. From this clinical starting point, we will investigate the literature surrounding the molecular underpinnings of lung tumor ...

Global DNA demethylation as an epigenetic marker of human brain metastases

“…The lowest global DNA methylation values were observed in lung, skin, breast, bladder, and endometrial cancer groups. That correlates with clinical observations for melanoma, which is the most easily brain metastasizing tumor [ 8 , 46 ], and for lung cancer, where a large proportion of patients with NSCLC develop metastases during the course of the disease [ 47 , 48 ]. However, brain metastases from endometrial carcinoma, the most common gynecologic malignancy, are rare [ 49 ].…”

Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy

“…However, the most observed change in NSCLC is mutation of the tumour suppressor TP53, which is not a treatment target. Mutations in other tumour suppressor genes such as Liver Kinase B1/Serine Threonine Kinase 11 (LKB1/STK11), neurofibromatosis type 1 (NF1), cyclin-dependent kinase Inhibitor 2A (CDKN2A), SMARCA4 and kelch-like enoyl-CoA hydratase associated protein (KEAP) that cause loss of function also occur [ 13 ]. The heterogeneity of mutations makes treatment difficult due to the frequent occurrence of resistance.…”

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

“…The brain is the most common site of SCLC metastasis; up to 50-80% of all cases of SCLC have metastasis to the brain-a development that is responsible for most SCLCrelated deaths. Conversely, more than 30% of brain metastases originate from SCLC (1). Although many advances have been made in SCLC management, the prognosis of patients with SCLC with brain metastasis has been consistently poor.…”