Neoplastic features in the pathobiology of pulmonary arterial hypertension


 ... that the pathobiology of pulmonary arterial hypertension (PAH) has neoplastic features?

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, characterized by vascular narrowing leading to progressive elevations in artery pressures and, ultimately, right heart failure.1 In 1891, Von Romberg discovered pulmonary vascular lesions, which he named “pulmonary vascular sclerosis”.2 In PAH, vascular lesions involve a distinct constellation of lesions known clinically, as “plexogenic pulmonary arteriopathy”. One of them, the plexiform lesion (Figure 1), is considered the histological hallmark of this arteriopathy.3 However, the etiology of vascular lesion remains controversial. Although vascular lesions involve three components: smooth muscle layer, adventitia and the endothelium4 , much of the research performed over years focused on the smooth muscle component. This was due to studies with rats exposed to chronic hypoxia or treated with monocrotaline that suggested pulmonary vasoconstriction as the cause of vascular remodeling.5 Although investigations into this vasoconstrictive theory of PAH have yielded a number of drugs currently used to treat the disease, it has now been shown that less than 10% of PAH patients respond to vasodilators.7 Thus, the development of new theories has become necessary.

 In 1994, Tuder, using immunohistochemistry, described augmented endothelial cell proliferation leading to complicated capillary-like channels (angio-proliferation), as the main component of the plexiform lesion.

Capture2.JPG (3)

Figure 1: A, Plexiform lesion from a patient with severe PAH demonstrating complete obliteration of the vessel by proliferated cells. B, Normal small pulmonary artery.4

In 1998, the discovery of endothelial monoclonality in plexiform lesions of primary pulmonary hypertension4 , led Voelkel and collaborators to formulate that year, the neoplastic hypothesis of the disease.5

Neoplasia is understood to be an abnormal proliferation of cells that results in tumor formation without metastasis. Two important events occur during tumor formation; uncontrolled angio-proliferation and inhibition of apoptosis.5, 7 In the last 15 years of research, several mutations have been linked to both events in endothelial cells from plexiform lesions. For instance, alterations in transforming growth factor-β (TGF-β) receptor II may turn endothelial cell insensitive to the cell growth-controlling effects of TGF-β5. Interestingly, mutations in bone morphogenic protein receptor II (BMPRII), a member of the TGF-β receptor family, are responsible for the familial forms of PAH1. Moreover, expression of anti-apoptotic protein surviving which inhibits activation of caspases 3 and 7 has been reported in PAH plexiform lesions.4 Consistent with these findings, endothelial cells isolated from pulmonary arteries of patients with PAH are hyperproliferative and apoptosis-resistant.5 In addition to mutations effecting apoptosis resistance, tumor cells suppress mitochondrial function which also prevents apoptosis and gives them a proliferative advantage.7 As a consequence, a shift from oxidative phosphorylation to aerobic glycolysis occurs, which is known as the Warburg effect.8 The Warburg effect, originally described in tumor cells, is characterized by decreased oxygen consumption and increased glucose uptake.8 Recently, this phenomenon has been described in pulmonary artery endothelial cells from patients with PAH.9 Clinically, the most striking evidence supporting the neoplastic hypothesis and the involvement of the Warburg effect is a study using positron emission tomography scan in PAH patients.9 This technique is utilized to detect tumors, based on the faculty of tumor cells to actively consume glucose at high rates. Higher fluoro-deoxy-D-glucose (labeled glucose analog) uptake was found in PAH lungs compared with healthy controls9 indicative of the Warburg effect.

Current therapies used in the treatment of PAH have limited effectiveness and do not prevent mortality. Most of these therapies are targeted against the vasoconstriction component of PAH. Furthermore, diagnosis of the disease requires invasive techniques. Exploration into the neoplastic theory of PAH opens the door to develop new diagnostic techniques and targeted therapies against the vascular remodeling component.



1. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):13S-24S.

2. Fishman AP. Primary pulmonary arterial hypertension: a look back. J Am Coll Cardiol. 2004;43(12 Suppl S):2S-4S.

 3. Fishman AP. Changing concepts of the pulmonary plexiform lesion. Physiol Res. 2000;49(5):485-492.

 4. Cool CD, Groshong SD, Oakey J, Voelkel NF. Pulmonary hypertension: cellular and molecular mechanisms. Chest. 2005;128(6 Suppl):565S-571S.

 5. Rai PR, Cool CD, King JA, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(6):558-564.

6. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144(2):275-285.

7. Michelakis ED, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation. 2008;118(14):1486-1495.

8. Warburg O. On the origin of cancer cells. Science (New York, N.Y. 1956;123(3191):309-314.

9. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RM, Stuehr DJ, Erzurum SC. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A. 2007;104(4):1342-1347.


Pulmonary Arterial Hypertension

Published in:

PVRI Chronicle Vol 1: Issue 1 cover image

June 2014

PVRI Chronicle Vol 1: Issue 1

More from this Journal

Explore the PC Journal

Pulmonary Circulation allows diverse knowledge of research, techniques, and case studies to reach a wide readership of specialists in order to improve patient care and treatment outcomes.