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Pulmonary hypertension in lung cancer

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Mini Keynote Symposium on Translational Research
Primers in Cancer
Institut de Recerca Contra la Leucèmia Josep Carreras Auditorium
December 14th, 2017

Published in: Health & Medicine
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Pulmonary hypertension in lung cancer

  1. 1. Pulmonary hypertension in lung cancer J. Roig Cutillas Pulmonary Department Clínica Creu Blanca Barcelona Mini Keynote Symposium on Translational Research Primers in Cancer
  2. 2. Known causes of pulmonary hypertension in lung cancer • Associated COPD-emphysema Choudhury G. Clin Chest Med 2014 • Associated Sleep Apnea Syndrome Wong HS. Curr Opin Pulm Med 2017; Li L. Oncotarget 2017 • Pulmonary thromboembolism-cancer related venous thrombosis Wieshammer S. Thromb J 2016 • Massive tumor cells capillary embolization He XW. Angiology 1989 • Lung toxicity caused by drugs Roig J. Clin Pulm Med 2006 Roig J. Open Resp Med Rev 2007
  3. 3. Fig. 2 Lange TJ. Pulm Circ 2013 Forfia PR. Clinics in Chest Medicine 2013 Measurement of parameters of interest on axial CT. AA: ascending aorta; LPAD: left pulmonary artery diameter; MPAD: main pulmonary artery diameter; RPAD: right pulmonary artery diameter; VB: vertebral body.
  4. 4. Fig. 4 Thaichman D. Clinics in Chest Medicine 2013; Forfia P. Am J Crit Care Med 2006
  5. 5. RV dilation changes LV geometry decreasing LV preload and worsening diastolic function. If acute, RV dilation may contribute to pericardial constraint, limiting filling of both ventricles. IPAH = idiopathic pulmonary arterial hypertension; LV = left ventricle; RV = right ventricle. Reproduced with permission from Voelkel NF . Circulation 2006. Brittain EL. Pulm Circ 2012
  6. 6. Contrasting hypotheses regarding origin and perpetuation of vascular remodeling and inflammation. A. “Inside/Out” response centered on endothelial injury, cell recruitment to the intima, activation of medial smooth muscle cells. B. “Outside-In” hypothesis: dendritic cells, macrophages and lymphocytes + fibroblasts immune cells occurs early and persists in the adventitia. Fibroblast activation, leukocyte and progenitor cell accumulation and retention lead to remodeling not only of the adventitia, but cause subsequent changes in the media and ultimately even the intima. Senmark KR. Pulm Circ 2012
  7. 7. 1 Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany. 2 Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus Liebig University, Giessen 35392, Germany. 3 Department of Radiology, UGMLC, member of the DZL, Justus Liebig University, Giessen 35392, Germany. 4 Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt 60438, Germany. 5 Department of Medicine, Imperial College, London SW7 2AZ, UK. 6 Institute of Pathology and Cytology, Wetzlar 35578, Germany. 7Department of Pathology, UGMLC, member
  8. 8. Pullamsetti et al. Sci. Transl. Med 2017
  9. 9. Pullamsetti et al. Sci. Transl. Med 2017
  10. 10. © 2017 Global Initiative for Chronic Obstructive Lung Disease
  11. 11. Fig. 4 Choudhury G. Clinics in Chest Medicine 2014
  12. 12. Fig. 6 Choudhury G. Clinics in Chest Medicine 2014
  13. 13. PA enlargement and pulmonary vascular remodeling detected in patients with lung cancer Medial wall thickness of pulmonary vessels from biopsies obtained from lung cancer patients with COPD (n = 10) grouped by stage of COPD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with nontumor regions of SCC or AC. Pullamsetti et al. Sci Transl Med 2017
  14. 14. Tumor cell and immune cell cross-talk driving pulmonary vascular remodeling Proliferation and migration of human donor PASMCs (Pulmonary Arterial Smooth Muscle Cells) and PAAFs (Adventitial Fibroblasts) subjected to CM and derived from AC tumor cells (A549), macrophages, or AC tumor cells cocultured with macrophages as indicated. Scale bars, 20 mm; n = 3. **P < 0.01 compared with Sftpc-cRaf-BxB. Pullamsetti et al. Sci Transl Med 2017
  15. 15. Role of PDE5 up-regulation in lung cancer–associated PH Expression of PDE5 mRNA in (A) PASMCs and (B) PAAFs that were stimulated with basal medium (BM) or indicated cytokines for 24 hours (n = 4). Scale bars, 20 mm; n = 4. *P < 0.05, **P < 0.01 ***p < 0.001 Pullamsetti et al. Sci Transl Med 2017
  16. 16. Proposed mechanism of PH development in lung cancer Pullamsetti et al. Sci Transl Med 2017
  17. 17. The constitutively activated “imprinted” phenotype of fibroblasts is due, at least in part, to increased HDAC (histone deacytelase) activity. Stenmark KM. Pulm Circ 2012 Targeting the adventitial microenvironment in pulmonary hypertension: A potential approach to therapy that considers epigenetic change
  18. 18. Schematic of the mechanisms of epigenetic regulation. DNA methylation, histone modifications, and RNA- mediated gene silencing constitute three distinct mechanisms of epigenetic regulation. Kim GH. Pulm Circ 2011 Epigenetic mechanisms of pulmonary hypertension
  19. 19. Schematic representation approaches undertaken to address right heart remodeling and failure. NO: Nitric oxide; sGC: soluble guanylate cyclase. Schematic showing the theoretical progression of pulmonary vascular disease and the subsequent effect on RV function from normal physiological conditions (top) to severe pulmonary vascular remodeling and subsequent RV failure (bottom). Seeger W. Pulm Circ 2013
  20. 20. Current strategies to address variability (genetic, molecular, cellular and response to therapy) among PH patients - Personalized medicine. Seeger W. Pulm Circ 2013

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