Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies

Abstract

Treatment of vascular anomalies (VAs) is mostly empirical and, in many instances unsatisfactory, as the pathogeneses of these heterogeneous conditions remain largely unknown. There is emerging evidence of the presence of cell populations expressing stemness-associated markers within many types of vascular tumors and vascular malformations. The presence of these populations in VAs is supported, in part, by the observed clinical effect of the mTOR inhibitor, sirolimus, that regulates differentiation of embryonic stem cells (ESCs). The discovery of the central role of the renin-angiotensin system (RAS) in regulating stem cells in infantile hemangioma (IH) provides a plausible explanation for its spontaneous and accelerated involution induced by β-blockers and ACE inhibitors. Recent work on targeting IH stem cells by inhibiting the transcription factor SOX18 using the stereoisomer R(+) propranolol, independent of β-adrenergic blockade, opens up exciting opportunities for novel treatment of IH without the β-adrenergic blockade-related side effects. Gene mutations have been identified in several VAs, involving mainly the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways. Existing cancer therapies that target these pathways engenders the exciting possibility of repurposing these agents for challenging VAs, with early results demonstrating clinical efficacy. However, there are several shortcomings with this approach, including the treatment cost, side effects, emergence of treatment resistance and unknown long-term effects in young patients. The presence of populations expressing stemness-associated markers, including transcription factors involved in the generation of induced pluripotent stem cells (iPSCs), in different types of VAs, suggests the possible role of stem cell pathways in their pathogenesis. Components of the RAS are expressed by cell populations expressing stemness-associated markers in different types of VAs. The gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways interact with different components of the RAS, which may influence cell populations expressing stemness-associated markers within VAs. The potential of targeting these populations by manipulating the RAS using repurposed, low-cost and commonly available oral medications, warrants further investigation. This review presents the accumulating evidence demonstrating the presence of stemness-associated markers in VAs, their expression of the RAS, and their interaction with gene mutations affecting the PI3K/AKT/mTOR and/or the Ras/RAF/MEK/ERK pathways, in the pathogenesis of VAs.

Keywords: embryonic stem cells; gene mutations; induced pluripotent stem cells; renin-angiotensin system; stemness-associated markers; vascular anomalies; vascular malformation; vascular tumor.

Figure 1

The International Society for the Study of Vascular Anomalies classification of vascular anomalies. Vascular anomalies (VAs) are categorized as vascular tumors, vascular malformations and unclassified VAs. Vascular tumors are categorized as being benign, locally aggressive or borderline, or malignant. Vascular malformations are categorized as simple malformations, combined malformations, of major named vessels, or are associated with other anomalies. Simple and combined malformations can be either high- or low-flow. AVF, arterio-venous fistula; AVM, arterio-venous malformation; CAVM, capillary-arteriovenous malformation; CLAVM, capillary-lymphatic-arteriovenous malformation; CLOVES, congenital lipomatous overgrowth-vascular malformation—epidermal nevi-spinal anomaly syndrome; CLVM, capillary-lymphatic-venous malformation; CM, capillary malformation; CVM, capillary-venous malformation; KTS, Klippel-Trénaunay syndrome; LM, lymphatic malformation; LVM, lymphatic venous malformation; PWS, port-wine stain; SWS, Sturge-Weber syndrome; VM, venous malformation.

Figure 2

A proposed model for the role of gene mutations involving the Ras/BRAF/MEK/ERK and the PI3KCA/AKT/mTOR pathways by their interaction with different components of the renin-angiotensin system, leading to the induction and/or maintenance of cells that express stemness-associated markers in vascular anomalies. AH, anastomosing hemangioma; ATII, angiotensin II; AT₁R, angiotensin II receptor 1; AT₂R, angiotensin II receptor 2; PRR, pro-renin receptor; AVF, arteriovenous fistula; AVM, arterio-venous malformation; CM, capillary malformation; CM-AVM, capillary malformation—arterio-venous malformation; CM-AVM2, capillary malformation—arterio-venous malformation 2; CLOVES, congenital lipomatous overgrowth with vascular—epidermal and skeletal anomalies; HPWS, hypertrophic port-wine stain; P-W syndrome, Parkes-Weber syndrome; PWS, port-wine stain; KTS, Klippel-Trénaunay syndrome; LM, lymphatic malformation; NICH, non-involuting congenital hemangioma; PG, pyogenic granuloma; PICH, partially involuting congenital hemangioma; RICH, rapidly involuting congenital hemangioma; SWS, Sturge-Weber syndrome; VEGF, vascular endothelial growth factor; VM, venous malformation; VVM, verrucous venous malformation.

Figure 3

A Schema demonstrating the classical renin-angiotensin system, with cathepsins B, D, and G, acting as bypass loops. Activation of pro-renin occurs upon binding with pro-renin receptor. Renin then converts angiotensinogen into angiotensin I (ATI), which is cleaved by angiotensin-converting enzyme (ACE) to produce the active peptide angiotensin II (ATII). The actions of ATII are mediated through interactions with ATII receptor 1 (AT₁R) and ATII receptor 2 (AT₂R). Cathepsin B and cathepsin D contribute to renin activation. Cathepsin D and chymase mediates conversion of angiotensinogen into ATI. Cathepsin G promotes generation of ATII from ATI or directly from angiotensinogen. Reproduced with permission from Expert Rev Clin Pharmacol (6).

Figure 4

A proposed model portraying how gene mutations identified within vascular anomalies affect the expression of the stemness-associated markers OCT4, SOX2, NANOG, KLF4, and c-MYC. OCT4, SOX2, and NANOG are upregulated through Wnt signaling, and NANOG is down regulated through BMP-signaling. KLF4 and c-MYC are upregulated by ERK activation under the influence of GNAQ, VEGF, and RAS signaling via activation of angiotensin II receptor 1 (AT₁R) and pro-renin receptor (PRR).