Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk.
Sci Transl Med
; 9(416)2017 Nov 15.
Article
de En
| MEDLINE
| ID: mdl-29141888
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Dyspnée
/
Hypertension pulmonaire
/
Tumeurs du poumon
Type d'étude:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Sci Transl Med
Sujet du journal:
CIENCIA
/
MEDICINA
Année:
2017
Type de document:
Article
Pays d'affiliation:
Allemagne