Table 1.
Comparison of the cancer hallmarks with PAH hallmarks
| Hallmarks of Cancer (65) | Hallmarks of PAH |
|---|---|
| General aspects | General aspects |
| “Evolution gone awry” (66)* | “Wound healing gone awry” (42)** |
| Systemic disease*** | Small lung vessels, but PAH can be a manifestation of systemic diseases or heart diseases and there are systemic disease manifestations (115, 159) |
| Sustained proliferative signaling | |
| Growth factors, survival factors | Endothelial cell and vascular smooth muscle cell growth (31, 134, 138, 174) |
| Hormones, increased levels of receptor proteins, anti-apoptotic mechanisms (including survivin expression) | Increased sensitivity to growth factors (76, 78, 175) |
| Akt/PKB, Ras, c-MYC, c-KIT, p53, HIF-1α, HIF-2α, p27Kip1, FHIT (80), HSP90 (16), NFAT, β-catenin, FGF, MDRP (144), MRP4 (85), PDGF, 5-LO (89) | Increased expression of HIF-1α, HIF-2α, ARNT, VEGF, KDR (175), NFAT (15), 5-LO (190), β-catenin (138), MDRP (138), MRP4 (67) |
| Survivin (103, 138), loss of p27, Kip1 (31), HSP90 (19), c-KIT (38, 45, 46, 60, 108), FHIT (41) | |
| Genome instability, mutations | |
| Mutations (including BMPR2, BMP9, SOX2, KDR):“corruption of the TGF-β pathway,” PARP (65), many other gene mutations (KRAS, HRAS, BRAF, BRCA, PTEN, p53) (86, 157), KDR (170) | Mutations: BMPR2 (4), BMP9, SOX2 (60), aquaporin 1, CAV1 (177), SMAD9, ACVRL1, ENG, EIF2, AK4, KCN5, KCN3, PARP (103), KDR (44) |
| Chromosomal abnormalities | Chromosomal abnormalities (2) |
| Insensitivity to growth suppressors | |
| Cyclin-dependent kinases | Cyclin-dependent kinases (187) |
| Prostacyclin induces VSMC apoptosis via ERK1/2 (97), decreased BMPR2 signaling (4, 43) | |
| Resisting cell death | |
| Bcl-2 family, Bax, Bim, Puma, survivin | Decreased BMPR2 signaling (4, 43) Increased survivin expression (103, 138) |
| Loss of p53 function? Bax mutation (193) | |
| Enabling replicative immortality | |
| Telomerase (23) | Telomerase expression in PAH (111) supports hyper-proliferation of endothelial cells |
| Involvement in proliferation via the β-catenin/LEF transcriptional complex? (138) | |
| Sustained angiogenesis | |
| Upregulated by hypoxia and oncogenes; endogenous angiogenesis inhibitors Bone marrow-derived vascular progenitors |
VEGF, KDR (175) upregulated by hypoxia and oncogenes VEGF produced by inflammatory cells Angiogenic/anti-angiogenic imbalance Endostatin (39, 72), sFLT (148) and others |
| IL-32 (195) | IL-32 (119) |
| Phenotypic instability | |
| Epithelial mesenchymal transition | Endothelial mesenchymal transition (73, 87, 139) |
| 5-Lipoxygenase expression (107) | 5-Lipoxygenase expression (190), loss of TGF-β receptor 2 (193) |
| Microenvironment and inflammation providing growth signals and contributing to clonal expansion (33, 34, 156) | |
| Smoldering inflammation, presence of cells that provide growth and survival factors (181, 182) | |
| Il-1α, IL-1β (90) | IL-1α, IL-1β (180) |
| Stem cell niche? (171) Obesity (151), leptin (151) Red blood cell distribution width |
Stem cells (7, 48, 196) Obesity (23), leptin (75), dyslipidemia (70) Red blood cell distribution width |
| Reprogramming energy metabolism | |
| Glycolytic switch (Warburg effect) (191), glutaminolysis | Hypoxia upregulates HIF-1α and HIF-2α, which upregulate glycolysis (Warburg effect) (5, 19, 43, 196), upregulation of GLUT1 |
| Cancer stem cells (171) | |
| Bone marrow-derived stem cells (7), vessel wall stem cells (48, 155), circulating endothelial cell precursors (7, 22) | |
| Evasion of immune destruction | |
| Deficiency in development or function of cytotoxic CD8+ CD4+ Th1 helper cells Secretion of immunosuppressive TGF-β (66) |
Immunosuppressive T regs? (163) |
ACVRL1, activin A receptor like type 1; AK4, adenylate kinase 4; BMP9, bone morphogenetic protein 9; BMPR2, bone morphogenic protein receptor type II; CAV1, caveolin 1; EIF2, eukaryotic initiation factor 2; ENG, endoglin; GLUT1, glucose transporter 1; HIF-1α, hypoxia-inducible factor-1α; HIF-2α, hypoxia-inducible factor-2α; HSP90, heat shock protein 90; KDR, VEGF receptor 2; MDRP, multiple drug resistance protein; PAH, pulmonary arterial hypertension; PARP, poly (ADP-ribose) polymerase; PTEN, phosphatase and tensin homolog; sFlt, soluble VEGF receptor 1; SMAD9, SMAD family member 9; TGF, transforming growth factor.
This concept relates to a process “formally analogous to a Darwinian evolution, in which a succession of genetic changes, each conferring one or another growth advantage, leads to progressive conversion of normal human cells” (65).
“Wound healing gone awry” (42); injury to the endothelium is not repaired with a return to a normal endothelial cell monolayer; instead, exuberant endothelial cell growth (174) occurs, leading to lumen obliteration and fibrosis; inflammatory and immune cells participate in this process (174).
Although metastatic spread turns cancer into a systemic disease, some cancers can remain localized.
Although stem cells in PAH are not “cancer” stem cells, they may nevertheless participate in the formation of complex vascular lesions.