The cancer theory of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress, pseudo-hypoxia, and more. After inducing an initial death of the endothelial cells, these environmental stresses contribute with time to the development of hyper-proliferative and apoptotic resistant clone of cells including pulmonary artery smooth muscle cells, fibroblasts, and even pulmonary artery endothelial cells allowing vascular remodeling and PAH development. Molecularly, these cells exhibit many features common to cancer cells offering the opportunity to exploit therapeutic strategies used in cancer to treat PAH. In this review, we outline the signaling pathways and mechanisms described in cancer that drive PAH cells' survival and proliferation and discuss the therapeutic potential of antineoplastic drugs in PAH.

Keywords: apoptosis; cell survival; neoplasia; proliferation; vascular remodeling.

Fig. 1

Schematic representation of PAH. In an advance stage of the disease, obliteration of the vascular lumen due to vasoconstriction and excessive proliferation and resistance of apoptosis of resident cells (adventitial fibroblasts, pulmonary artery smooth muscle cells, pulmonary artery endothelial cells) increases PVR resulting in right ventricular adaptation (right ventricle hypertrophy). Initial compensation is followed by progressive and irreversible right ventricular enlargement leading to right ventricular failure.

Fig. 2

Acquisition of cancer traits by pulmonary vascular cells during PAH progression (figure adapted from Guignabert et al. and Hanahan and Weinberg). During disease progression, the vast majority of cancer hallmarks described by Hanahan and Weinberg (excepted tissue invasion and metastasis) are also shared by pulmonary vascular cells from PAH patients. Solid arrows within the outer circle represent high degree of similarity between cancer and PAH. Hatched arrows represent low/medium degree of similarity between cancer and PAH.

Fig. 3

Scheme depicting the major intracellular signaling pathways implicated in the hyperproliferative phenotype of PAH cells. [Ca²⁺]_cyt, cytosolic calcium concentration; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AKT, protein kinase B; FGF2, fibroblast growth factor-2; ERK1/2, extracellular signal-regulated kinases 1/2; FOXO1, forkhead box protein O1; IGF, insulin growth factor; IL-6, interleukin 6; JAK, janus kinase; LATS1/2, large tumor suppressor kinases 1/2; MDM2, mouse double minute 2 homolog; MEK1/2, mitogen-activated protein kinase/ERK kinases 1/2; MST1/2, mammalian sterile 20-like kinases 1/2; mTOR, mechanistic target of rapamycin; NFAT, nuclear factor of activated T-cells; PDGF, platelet-derived growth factor; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PIM-1, proviral integration site for Moloney murine leukemia virus-1; PIP3, phosphatidylinositol 3,4,5 triphosphate; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RTK, receptor tyrosine kinase; S6K1, ribosomal protein S6 kinase beta-1; STAT3, signal transducer and activator of transcription 3; TAZ, transcriptional coactivator with PDZ-binding motif; YAP, yes-associated protein.

Fig. 4

Pathogenic concepts of PAH. Like cancer cells, PAH cells are exposed to stressful conditions. To deal with these insults causing initial cell death, PAH cells have developed adaptive mechanisms allowing them to survive and proliferate over time and leading to vascular remodeling of distal pulmonary arteries. Given that PAH and cancer cells share numerous similarities, therapeutic strategies used in cancer are exploited to treat PAH. “Anticancer” drugs showing beneficial effects in experimental PAH models and are tested in PAH clinical trials are highlighted within the dotted boxes.