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

Abstract

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.

• Authors: Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Hossein Ardeschir Ghofrani, Gabriele A Krombach, Ludger Fink, Stefan Gattenlöhner, Ulf R Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 416 (Nov 15 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 29141888 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

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

Topics

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