Editors' ChoicePulmonary Hypertension

Is Pulmonary Arterial Hypertension a Cancer?

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Science Translational Medicine  24 Apr 2013:
Vol. 5, Issue 182, pp. 182ec71
DOI: 10.1126/scitranslmed.3006349

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by narrowing of the pulmonary arteries because of muscular thickening and intimal proliferation. The hyperplasia of pulmonary artery smooth-muscle cells (PA-SMCs) is the main pathological change responsible for the vascular remodeling observed in this disease. Little is known about the origin of this growth dysregulation; however, in the past decade investigations have found similarities between PAH and cancer, such as the expression of malignant cell biomarkers and the resistance to programmed cell death. Resistance to cell death is a major hallmark of cancer that permits tumor growth and resistance to treatment.

One of the mechanisms that cancer cells use to escape cellular aging and subsequent death is the inactivation of the tumor suppressor p53. Treatments that activate p53 are a novel and attractive strategy to reverse proliferative disorders such as PAH. Mouraret et al. studied the effects of inducing growth arrest in PA-SMCs with Nutlin-3a, a cis-imidazoline analog that stabilizes p53 by inhibiting the binding of MDM2 (murine double minute 2), a negative regulator of p53. The authors showed that Nutlin-3a attenuated the development of PAH in three distinct experimental mouse models of the disease [transgenic mice overexpressing the serotonin transporter in smooth muscle cells, chronic hypoxia, and hypoxia plus Semaxinib (SU5416), a vascular endothelial growth factor and tyrosine kinase antagonist that produces obliterative pulmonary vascular remodeling] by inducing PA-SMC growth arrest but not apoptosis. Nutlin-3a stabilized the lung p53 protein and increased the expression of p21, a cell-cycle regulator involved in cell growth arrest. Conversely, Nutlin-3a failed to prevent the development of PAH in mice with deletions of the p53 (p53–/–) or p21 (p21–/–) gene.

This study suggests that Nutlin-3a, a selective antagonist of the p53-MDM2 interaction, induced PA-SMC growth arrest and attenuated or reversed PAH in mouse models. The present investigation continues to approximate the pathobiology of cancer and PAH and demonstrates that induction of cell-growth arrest is a promising therapeutic option for this disease, a cancer-like pulmonary vascular condition.

N. Mouraret et al., Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension. Circulation, published online 19 March 2013 (10.1161/circulationaha.113.002434). [Abstract]

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