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

Autorenliste: Pullamsetti, Soni Savai; Kojonazarov, Baktybek; Storn, Samantha; Gall, Henning; Salazar, Ylia; Wolf, Janine; Weigert, Andreas; El-Nikhely, Nefertiti; Ghofrani, Hossein Ardeschir; Krombach, Gabriele A.; Fink, Ludger; Gattenlohner, Stefan; Rapp, Ulf R.; Schermuly, Ralph Theo; Grimminger, Friedrich; Seeger, Werner; Savai, Rajkumar

Jahr der Veröffentlichung: 2017

Zeitschrift: Science Translational Medicine

Bandnummer: 9

Heftnummer: 416

ISSN: 1946-6234

eISSN: 1946-6242

DOI Link: https://doi.org/10.1126/scitranslmed.aai9048

Verlag: American Association for the Advancement of Science

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, KRas(LA2), and cRaf-BxB). In contrast, NOD. Cg-Prkdc(scid) 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 micro-environment and PDE5 offers a potential therapeutic option.

Zitierstile

Harvard-Zitierstil: Pullamsetti, S., Kojonazarov, B., Storn, S., Gall, H., Salazar, Y., Wolf, J., et al. (2017) Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk, Science Translational Medicine, 9(416), Article eaai9048. https://doi.org/10.1126/scitranslmed.aai9048

APA-Zitierstil: Pullamsetti, S., Kojonazarov, B., Storn, S., Gall, H., Salazar, Y., Wolf, J., Weigert, A., El-Nikhely, N., Ghofrani, H., Krombach, G., Fink, L., Gattenlohner, S., Rapp, U., Schermuly, R., Grimminger, F., Seeger, W., & Savai, R. (2017). Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk. Science Translational Medicine. 9(416), Article eaai9048. https://doi.org/10.1126/scitranslmed.aai9048

Zitierstile

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