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

Sci Transl Med. 2017 Nov 15;9(416):eaai9048. doi: 10.1126/scitranslmed.aai9048.


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 a mean pulmonary artery diameter of >28 mm, 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-PrkdcscidIl2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human 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 LLC1 model. We conclude that lung cancer-associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Dendritic Cells
  • Dyspnea / immunology
  • Dyspnea / physiopathology*
  • Echocardiography
  • Humans
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / immunology*
  • Hypertension, Pulmonary / physiopathology*
  • Immunohistochemistry
  • In Vitro Techniques
  • Inflammation / immunology
  • Inflammation / physiopathology
  • Lung Neoplasms / complications
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / physiopathology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • T-Lymphocytes / metabolism


  • NF-kappa B
  • Cyclic Nucleotide Phosphodiesterases, Type 5