Research ArticleCancer

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

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Science Translational Medicine  15 Nov 2017:
Vol. 9, Issue 416, eaai9048
DOI: 10.1126/scitranslmed.aai9048

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A tense environment

Lung cancer remains the most common cause of death worldwide, but some of the biology underlying the symptoms of this disease is still not well understood. In particular, the frequent occurrence of dyspnea in patients with advanced lung cancer remained to be explained. Pullamsetti et al. demonstrated that lung cancer drives vascular remodeling in its microenvironment, resulting in the development of pulmonary hypertension, helping to explain the patients’ symptoms. The authors showed evidence of this phenomenon in human patients, as well as in three different mouse models, where they also examined the mechanism underlying this condition.

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-Prkdcscid Il2rgtm1Wjl/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.

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