Expression of Cathepsins B, D, and G in Microcystic Lymphatic Malformation

Mehrotra, Shreeja; Schaijik, Bede van; Boyes, Kendra; Bockett, Nicholas; Brasch, Helen D.; Davis, Paul F.; Itinteang, Tinte; Tan, Swee T.

doi:10.1089/lrb.2020.0047

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…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%

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

confidence: 99%

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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“…1). The cathepsins are expressed in several diseases, including keloid disorder [65,66], Dupuytren's disease [67], vascular tumors [68], vascular malformations [69] and benign and malignant solid tumors including meningioma [70], GB [71], metastatic colon adenocarcinoma to the liver [72], and cutaneous [73] and oral cavity [74] squamous cell carcinoma (SCC). Similarly, chymase-a ubiquitous serine protease with a strong ability to catalyze the formation of ATII, is found in many disorders [75].…”

Section: Bypass Loops Of the Rasmentioning

confidence: 99%

The renin-angiotensin system in central nervous system tumors and degenerative diseases

Haron

Kilmister

Davis

et al. 2021

Front. Biosci. (Landmark Ed)

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Despite their differences, central nervous system (CNS) tumors and degenerative diseases share important molecular mechanisms underlying their pathologies, due to their common anatomy. Here we review the role of the renin-angiotensin system (RAS) in CNS tumors and degenerative diseases, to highlight common molecular features and examine the potential merits in repurposing drugs that inhibit the RAS, its bypass loops, and converging signaling pathways. The RAS consists of key components, including angiotensinogen, (pro)renin receptor (PRR), angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (AT1R), ATII receptor 2 (AT2R) and the Mas receptor (MasR). The RAS is integral to systemic and cellular pathways that regulate blood pressure and body fluid equilibrium and cellular homeostasis. The main effector of the RAS is ATII which exerts its effect by binding to AT1R and AT2R through two competitive arms: an ACE1/ATII/AT1R axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/AT2R and/or ATII/ACE2/Ang(1-7)/MasR axis that potentiates neuroprotection pathways. Alterations of these axes are associated with cellular dysfunction linked to CNS diseases. The generation of ATII is also influenced by proteases that constitute bypass loops of the RAS. These bypass loops include cathepsins B, D and G and chymase and aminopeptidases. The RAS is also influenced by converging pathways such as the Wnt/β-catenin pathway which sits upstream of the RAS via PRR, a key component of the RAS. We also discuss the co-expression of components of the RAS and markers of pluripotency, such as OCT4 and SOX2, in Parkinson’s disease and glioblastoma, and their potential influences on transduction pathways involving the Wnt/β-catenin, MAPK/ERK, PI3K/AKT and vacuolar (H+) adenosine triphosphatase (V-ATPase) signaling cascades. Further research investigating modulation of the ACE1/ATII/AT1R and ACE2/Ang(1-7)/MasR axes with RAS inhibitors may lead to novel treatment of CNS tumors and degenerative diseases. The aim of this review article is to discuss and highlight experimental and epidemiological evidence for the role of the RAS, its bypass loops and convergent signaling pathways in the pathogenesis of CNS tumors and degenerative diseases, to direct research that may lead to the development of novel therapy.

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Lymphatic vessels and the renin-angiotensin-system

Bertoldi

Caputo

Calò

et al. 2023

American Journal of Physiology-Heart and Circulatory Physiology

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The lymphatic system is an integral part of the circulatory system and plays an important role in the fluid homeostasis of the human body. Accumulating evidence has recently suggested the involvement of lymphatic dysfunction in the pathogenesis of cardio-reno-vascular (CRV) disease. However, how the sophisticated contractile machinery of lymphatic vessels is modulated, and possibly impaired in CRV disease, remains largely unknown. In particular, little attention has been paid to the effect of the renin-angiotensin-system (RAS) on lymphatics, despite the high concentration of RAS mediators that these tissue-draining vessels are exposed to and the established role of the RAS in the development of classic microvascular dysfunction and overt CRV disease. We herein review recent studies linking RAS to lymphatic function and/or plasticity, and further highlight RAS-specific signaling pathways - previously shown to drive adverse arterial remodeling and CRV organ damage - that have potential for direct modulation of the lymphatic system.

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Expression of Cathepsins B, D, and G in Microcystic Lymphatic Malformation

Cited by 4 publications

References 41 publications

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

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

The renin-angiotensin system in central nervous system tumors and degenerative diseases

Lymphatic vessels and the renin-angiotensin-system

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