Embryonic Stem Cell-like Population within Venous Malformation Expresses the Renin–Angiotensin System

Tan, Elysia M S; Brasch, Helen D.; Davis, Paul F.; Itinteang, Tinte; Tan, Swee T.

doi:10.1097/gox.0000000000002170

Cited by 8 publications

(8 citation statements)

References 5 publications

(9 reference statements)

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“…Further studies with a larger sample size including functional experiments are required to confirm our findings. Components of the renin–angiotensin system (RAS) have been shown to be expressed by similar populations in infantile hemangioma ( 41 ), pyogenic granuloma ( 42 ), and venous malformation ( 43 , 44 ). Investigation into the expression of RAS on a primitive population in extracranial AVM may lead to novel targeting of the population using available medications.…”

Section: Discussionmentioning

confidence: 99%

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

et al. 2021

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Objectives: Arteriovenous malformation (AVM) consists of a nidus with poorly formed low-resistance vessels in place of a functional capillary network. The role of somatic mutations in embryonic stem cells (ESCs) and vascular anomalies and the presence of primitive populations in vascular anomalies led us to investigate the presence of a primitive population in extracranial AVM.Methods: Extracranial AVM tissue samples from 12 patients were stained for stemness-associated markers OCT4, SOX2, NANOG, KLF4, and c-MYC using immunohistochemical staining. In situ hybridization (ISH) was performed on six tissue samples to determine transcript expression. Western blotting and RT-qPCR were performed on two AVM-derived primary cell lines to determine protein and transcript expression of these markers, respectively. Immunofluorescence staining was performed on two tissue samples to investigate marker co-localization.Results: Immunohistochemical staining demonstrated the expression of OCT4, SOX2, KLF4, and c-MYC on the endothelium and media of lesional vessels and cells within the stroma of the nidus in all 12 AVM tissue samples. ISH and RT-qPCR confirmed transcript expression of all five markers. Western blotting showed protein expression of all markers except NANOG. Immunofluorescence staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ population within the endothelium and media of the lesional vessels and cells within the stroma of the AVM nidus.Conclusions: Our findings may suggest the presence of a primitive population within the AVM nidus. Further investigation may lead to novel therapeutic targeting of this population.

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Section: Discussionmentioning

confidence: 99%

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

et al. 2021

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“…Cells expressing stemness-associated markers have been identified in vascular tumors such as IH ( 74 ) and pyogenic granuloma ( 14 ), and vascular malformations, including VM ( 16 ), verrucous venous malformation ( 17 ), LM ( 75 ), AVM ( 15 ), and PWS ( 18 ). Components of the RAS are expressed by these ESC-like cells in IH ( 76 ), pyogenic granuloma ( 77 ), VM ( 78 , 79 ) and LM ( 80 ). This article focuses on the recent paradigm shift in the understanding and treatment of IH and discusses emerging findings of the role of ESC-like cells and the RAS in other VAs.…”

Section: Embryonic Stem Cell-like Cells and The Renin-angiotensin Sys...mentioning

confidence: 99%

“…Components of the RAS are expressed by cells expressing stemness-associated markers in other types of VAs including pyogenic granuloma ( 77 ), VM ( 78 ), and LM ( 80 ).…”

Section: Embryonic Stem Cell-like Cells and The Renin-angiotensin Sys...mentioning

confidence: 99%

“…Multiple gain-of-function gene mutations affecting these pathways that cause over-activity, have been identified in a number of VAs ( 1 , 94 , 109 – 111 ). The central role of the RAS in regulating hematopoietic cells, MSCs and angiogenesis, and the presence of components of the RAS ( 77 , 78 , 80 , 102 ) and its bypass loops on ESC-like cells in VAs ( 103 , 112 – 114 ), suggests possible therapeutic targeting of the ESC-like cells with RASIs in VAs ( 1 ).…”

Section: Embryonic Stem Cell-like Cells and The Renin-angiotensin Sys...mentioning

confidence: 99%

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Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System

Kilmister

Tan

2022

Front. Surg.

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Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) – a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.

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“…Populations of cells expressing stemness-associated markers within several types of VAs express components of the RAS ( 7 , 52 , 53 ). The classical RAS ( Figure 3 ) is an endocrine cascade that is crucial for blood volume and blood pressure homeostasis ( 54 ).…”

Section: Introductionmentioning

confidence: 99%

Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies

et al. 2021

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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.

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Embryonic Stem Cell-like Population within Venous Malformation Expresses the Renin–Angiotensin System

Abstract: Supplemental Digital Content is available in the text.

Cited by 8 publications

References 5 publications

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

Stemness-Associated Markers Are Expressed in Extracranial Arteriovenous Malformation

Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System

Cell Populations Expressing Stemness-Associated Markers in Vascular Anomalies

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