Lung cancer–associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell–immune cell cross-talk

Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had amean pulmo- nary artery diameter of >28mm, indicating pulmonary hypertension (PH). In human lung cancer tissue,we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRasLA2,and cRaf-BxB). In contrast, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing hu- man lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)–mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1model. We conclude that lung cancer–associated PH represents a distinct PH category; targeting inflammation in the micro- environment and PDE5 offers a potential therapeutic option. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works INTRODUCTION