Pathogenesis of pulmonary arterial hypertension: lessons from cancer

Abstract

Although the causal pathomechanisms contributing to remodelling of the pulmonary vascular bed in pulmonary arterial hypertension (PAH) are still unclear, several analogous features with carcinogenesis have led to the emergence of the cancer-like concept. The major similarities concern the altered crosstalk between cells from different tissue types, unexplained proliferation and survival of pulmonary smooth muscle and endothelial cells, the metabolic (glycolytic) shifts, and the association with the immune system. However, major differences between PAH and cancer exist, including the absence of invasion and metastasis, as well as the pathogenic genes involved and the degrees of angiogenesis impairment and genetic instability. It is clear that PAH is not a cancer, but this cancer-like concept has opened a new field of investigation and raises the possibility that antiproliferative and/or oncological drugs may exert therapeutic effects not only in cancer, but also in PAH. Such analogies and differences are discussed here.

Figure 1.

The “hallmarks of cancer” proposed by Hanahan and Weinberg [20, 21]. a) The six hallmark capabilities originally proposed in 2000 together with the four additional hallmarks proposed in 2011. b) Although pulmonary arterial hypertension (PAH) shares several cancer capabilities, the degree of similarity varies. Furthermore, these capabilities can be markedly different to those observed in cancer; in particular, neither invasion nor metastasis has been observed in PAH. In addition, these features found in PAH also appear to contribute to the disease pathogenesis with different levels of importance.

Figure 2.

Pathogenic concepts of pulmonary arterial hypertension (PAH). The major differences and analogous features between cancer and PAH are highlighted. FGF: fibroblast growth factor; PDGF: platelet-derived growth factor; EGF: epidermal growth factor; BMPR2: bone morphogenetic protein receptor 2; ECM: extracellular matrix; ET-1: endothelin-1; 5-HT: serotonin; NO: nitric oxide; PGI₂: prostacyclin; Th: T-helper cell; Treg: regulatory T-cell; VEGF: vascular endothelial growth factor.