Genetic Basis and Therapies for Vascular Anomalies

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Abstract

Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies.

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URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2015-001703-32.

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ERK/MAPK signalling pathway and tumorigenesis

Yan-Jun Guo, Wei-Wei Pan, Sheng-Bing Liu … (2020)

Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

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Growing roles for the mTOR pathway.

Dos Sarbassov, Siraj M. Ali, David Sabatini (2005)

The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.

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PI3K/AKT/mTOR Pathway in Angiogenesis

Jayashree Karar, Amit Maity (2011)

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is activated in the majority of human cancers. This pathway is known to play a key role in numerous cellular functions including proliferation, adhesion, migration, invasion, metabolism, and survival, but in the current review we focus on its role in angiogenesis. PI3K activation may occur via RAS mutation, loss of phosphatase and tensin homolog (PTEN), or by increased expression of growth factor receptors such as epidermal growth factor receptor. There is a connection between the PI3K pathway and angiogenesis. Hypoxia leads to HIF-1α stabilization and is a major stimulus for increased vascular endothelial growth factor (VEGF) production by tumor cells. However, activation of the PI3K/AKT pathway in tumor cells can also increase VEGF secretion, both by hypoxia-inducible factor 1 (HIF-1) dependent and independent mechanisms. The PI3K/AKT pathway also modulates the expression of other angiogenic factors such as nitric oxide and angiopoietins. Numerous inhibitors targeting the PI3K/AKT/mTOR pathway have been developed, and these agents have been shown to decrease VEGF secretion and angiogenesis. The effect of these inhibitors on tumor vasculature can be difficult to predict. The vasculature of tumors is aberrant, leading to sluggish bloodflow and elevated interstitial blood pressure, which can be perpetuated by the high levels of VEGF. Hence, decreasing VEGF expression can paradoxically lead to vascular normalization and improved bloodflow in some tumors. In addition to its importance in cancer, the PI3K pathway also plays an essential role in the formation of normal blood vessels during development. Embryos with kinase-dead p110α catalytic subunit of PI3K develop vascular defects. Stimulation of endothelial cells by VEGF leads to activation of the PI3K pathway within these cells, which is important for cell migration. Sustained endothelial activation of AKT1 has been shown to induce the formation of structurally abnormal blood vessels that recapitulate the aberrations of tumor vessels. Hence, the PI3K pathway plays an important role in regulating angiogenesis both in normal tissues and in cancers.

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Author and article information

Contributors

Angela Queisser: (View ORCID Profile)

Emmanuel Seront: (View ORCID Profile)

Laurence M. Boon: (View ORCID Profile)

Miikka Vikkula: (View ORCID Profile)

Journal

Title: Circulation Research

Abbreviated Title: Circ Res

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 0009-7330

ISSN (Electronic): 1524-4571

Publication date Created: June 25 2021

Publication date (Print): June 25 2021

Volume: 129

Issue: 1

Pages: 155-173

Affiliations

[1 ]Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium (A.Q., L.M.B., M.V.), University of Louvain, Brussels, Belgium (M.V.).

[2 ]Centre for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc Brussels, Belgium (E.S., L.M.B., M.V.)

[3 ]Institut Roi Albert II, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium (E.S.)

[4 ]VASCERN VASCA European Reference Centre Cliniques Universitaires Saint-Luc, Brussels, Belgium (E.S., L.M.B., M.V.).

[5 ]University of Louvain, Brussels, Belgium (M.V.).

[6 ]Walloon Excellence in Life Sciences and Biotechnology (WELBIO), University of Louvain, Brussels, Belgium (M.V.).

Article

DOI: 10.1161/CIRCRESAHA.121.318145

PubMed ID: 34166070

SO-VID: c3912eba-2e43-4982-9385-0561636d63ee

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Genetic Basis and Therapies for Vascular Anomalies

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Vascular Biology

Most cited references 165

ERK/MAPK signalling pathway and tumorigenesis

Growing roles for the mTOR pathway.

PI3K/AKT/mTOR Pathway in Angiogenesis

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Cited by 51

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