Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk.
Soni Savai PullamsettiBaktybek KojonazarovSamantha StornHenning GallYlia SalazarJanine WolfAndreas WeigertNefertiti El-NikhelyHossein Ardeschir GhofraniGabriele A KrombachLudger FinkStefan GattenlöhnerUlf R RappRalph Theo SchermulyWerner SeegerPublished in: Science translational medicine (2018)
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.
Keyphrases
- pulmonary hypertension
- pulmonary artery
- oxidative stress
- computed tomography
- pulmonary arterial hypertension
- endothelial cells
- cell therapy
- single cell
- coronary artery
- cell cycle arrest
- induced apoptosis
- magnetic resonance
- peripheral blood
- magnetic resonance imaging
- transcription factor
- mouse model
- adipose tissue
- palliative care
- bone marrow
- skeletal muscle
- cell proliferation
- pi k akt
- advanced cancer