© 2008 American Thoracic Society doi: 10.1164/rccm.200806-867ED
Severe Pulmonary Arterial HypertensionA Forme Fruste of Cancer?
Université Paris-Sud 11
Hannover Medical School Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary vascular resistance, eventually leading to right ventricular failure and ultimately death (1). Although imbalance between pulmonary artery vasoconstriction and vasodilatation may contribute to the pathophysiology of the disease, it is now widely recognized that remodeling of small pulmonary arteries represents the main pathologic finding related to pulmonary arterial hypertension, with marked proliferation of pulmonary artery smooth muscle and endothelial cells resulting in the obstruction of resistant pulmonary arteries (1, 2). In this issue of the Journal (pp. 558–564), Rai and colleagues elaborate on the hypothesis that pulmonary arterial hypertension shows many features of a neoplastic, angioproliferative disorder, which might benefit from novel treatment strategies derived from oncology (3). At first examination, pulmonary arterial hypertension is not cancer (3, 4). The vascular lesions of severe pulmonary arterial hypertension exhibit only some of the classic characteristics of malignancy. As cancer-like processes, these lesions are angiogenic, apoptotic cells are rarely found, and antiapoptotic proteins are overexpressed. However, some major characteristics of cancer are missing, most importantly tissue invasion and metastasis. As stated by the authors, the lesions characteristic of pulmonary arterial hypertension are not cancerous in the true meaning of word, but they show many features of neoplastic proliferation in that there is a process of abnormal and uncontrolled cell growth (3). Impaired transforming growth factor (TGF)-β and bone morphogenetic protein signaling render the pulmonary artery endothelial and smooth muscle cells insensitive to the growth-controlling effects of these molecules, leading to proliferation and selection of apoptosis- resistant cells (1, 5, 6). Among the most relevant recent discoveries in pulmonary arterial hypertension, recognition of germline mutations in the genes coding for receptor members of the TGF-β superfamily in familial and idiopathic cases has emphasized the potential role of growth factors in the development of the disease (7, 8). The most important genetic defect identified in patients with familial or idiopathic disease affects the gene coding for bone morphogenetic protein receptor type II (BMPR2), a member of the superfamily of the TGF-β receptor, which is involved in pulmonary artery endothelial and smooth muscle cell growth (7, 8). As stated by Rai and colleagues, the set of genes that account for the susceptibility to develop severe pulmonary arterial hypertension are those normally responsible for maintaining the orderly, nonproliferating replacement of apoptotic pulmonary vascular cells (3). Thus, proliferation of the pulmonary vascular wall might lead to a neoplastic-like pulmonary vascular disease corresponding to severe angioproliferative pulmonary hypertension. Interestingly, recent descriptions of the disease phenotype of BMPR2 mutation carriers with pulmonary arterial hypertension have demonstrated that they present approximately 10 years earlier than noncarriers with more severe hemodynamic compromise at diagnosis, highlighting the concept that such genetic defects may in turn be responsible for a more aggressive form of the disease (8). In susceptible individuals, multiple events will presumably promote pulmonary vascular remodeling and pulmonary arterial hypertension. Such events may include viral infection or exposure to drugs and toxins (9–13). Of note, a multiple hit process has been well described in the evolution of cancer and may indeed apply to proliferative pulmonary vascular disease. Among the molecules and growth factors that could contribute to vascular cell proliferation in pulmonary arterial hypertension, platelet-derived growth factor has been identified as a novel possible therapeutic target (14, 15). Successful treatment in experimental models of pulmonary hypertension as well as case reports of successful platelet-derived growth factor receptor tyrosine kinase inhibition in subjects displaying refractory pulmonary arterial hypertension despite best standard of care support the idea that platelet-derived growth factor–targeted therapies should be tested in future clinical trials in human pulmonary arterial hypertension (14–16). In contrast to the currently available treatments for pulmonary arterial hypertension, such drugs offer the perspective of "reverse remodeling" (i.e., the regression of established pulmonary vascular lesions) (14). The potential utility of other drugs currently developed in oncology for pulmonary arterial hypertension remains uncertain (16). In any case, safety will be a major issue if such agents are tested in groups of patients with severe cardiovascular compromise. Indeed, concerns have arisen about potential cardiotoxic effects of tyrosine kinase inhibitors, especially in patients with preexisting cardiac conditions (16). Safety and efficacy of several tyrosine kinase inhibitors are currently being evaluated in multicenter randomized trials, emphasizing the relevance of the concepts discussed in the article by Rai and colleagues (3, 16). FOOTNOTES
Conflict of Interest Statement: M.H. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.M.H. has served as a site Principal Investigator for the imatinib trial sponsored by Novartis. Fees of REFERENCES
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100,000 in 2008 have been paid to his institution, Hannover Medical School, relating to this clinical trial. 
