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

1. Pulmonary hypertension in
lung cancer
J. Roig Cutillas
Pulmonary Department
Clínica Creu Blanca
Barcelona
Mini Keynote Symposium on Translational Research
Primers in Cancer

3. 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

4. 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.

5. Fig. 4
Thaichman D. Clinics in Chest Medicine 2013; Forfia P. Am J Crit Care Med 2006

6. 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

7. 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

8. 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

9. Pullamsetti et al. Sci. Transl. Med 2017

10. Pullamsetti et al. Sci. Transl. Med 2017

11. © 2017 Global Initiative for Chronic Obstructive Lung Disease

13. Fig. 4
Choudhury G. Clinics in Chest Medicine 2014

14. Fig. 6
Choudhury G. Clinics in Chest Medicine 2014

15. 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

16. 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

17. 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

18. Proposed
mechanism of PH
development in
lung cancer
Pullamsetti et al. Sci Transl Med 2017

19. 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

20. 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

21. 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

22. Current strategies to address variability (genetic, molecular, cellular and
response to therapy) among PH patients - Personalized medicine.
Seeger W. Pulm Circ 2013