scholarly journals Somatic PIK3CA mutations as a driver of sporadic venous malformations

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra42-332ra42 ◽  
Author(s):  
Pau Castel ◽  
F. Javier Carmona ◽  
Joaquim Grego-Bessa ◽  
Michael F. Berger ◽  
Agnès Viale ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Vascular Malformations ◽  
Akt Pathway ◽  
Venous Malformations ◽  
Phosphatidylinositol 3 Kinase ◽  
Pik3ca Mutations ◽  
Downstream Signaling ◽  
Clinical Challenge ◽  
Substantial Morbidity ◽  
Over Time

Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.

scholarly journals Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

2021 ◽  
Vol 7 (6) ◽  
pp. a006147
Author(s):  
Sarah E. Sheppard ◽  
Victoria R. Sanders ◽  
Abhay Srinivasan ◽  
Laura S. Finn ◽  
Denise Adams ◽  
...  
Keyword(s):  
Arteriovenous Malformations ◽  
Mapk Pathway ◽  
Vascular Malformations ◽  
Lymphatic Vessels ◽  
Catalytic Subunit ◽  
Venous Malformations ◽  
Phosphatidylinositol 3 Kinase ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Cerebral Vascular Malformations

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

scholarly journals Mouse Models for Exploring the Biological Consequences and Clinical Significance of PIK3CA Mutations

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 158 ◽  
Author(s):  
Camilla B. Mitchell ◽  
Wayne A. Phillips
Keyword(s):  
Clinical Significance ◽  
Mouse Models ◽  
Vascular Malformations ◽  
Pi3k Pathway ◽  
Model Systems ◽  
Therapeutic Interventions ◽  
Phosphatidylinositol 3 Kinase ◽  
Gene Encoding ◽  
Pik3ca Mutations ◽  
Regulate Cell Growth

The phosphatidylinositol 3-kinase (PI3K) pathway is involved in a myriad of cellular signalling pathways that regulate cell growth, metabolism, proliferation and survival. As a result, alterations in the PI3K pathway are frequently associated with human cancers. Indeed, PIK3CA—the gene encoding the p110α catalytic subunit of PI3K—is one of the most commonly mutated human oncogenes. PIK3CA mutations have also been implicated in non-malignant conditions including congenital overgrowth syndromes and vascular malformations. In order to study the role of PIK3CA mutations in driving tumorigenesis and tissue overgrowth and to test potential therapeutic interventions for these conditions, model systems are essential. In this review we discuss the various mouse models currently available for preclinical studies into the biological consequences and clinical significance of PIK3CA mutations.

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

2017 ◽  
Vol 63 (4) ◽  
pp. 545-556
Author(s):  
Natalya Oskina ◽  
Aleksandr Shcherbakov ◽  
Maksim Filipenko ◽  
Nikolay Kushlinskiy ◽  
L. Ovchinnikova
Keyword(s):  
Genetic Disease ◽  
Intracellular Signaling ◽  
Somatic Mutations ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Phosphatidylinositol 3 Kinase ◽  
Intracellular Signaling Pathway ◽  
Metabolic Activities ◽  
Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

Phosphatidylinositol 3-Kinase/AKT Pathway Activation in Human Vestibular Schwannoma

2008 ◽  
Vol 29 (1) ◽  
pp. 58-68 ◽  
Author(s):  
Abraham Jacob ◽  
Tina X. Lee ◽  
Brian A. Neff ◽  
Shyra Miller ◽  
Bradley Welling ◽  
...  
Keyword(s):  
Vestibular Schwannoma ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Pathway Activation ◽  
Phosphatidylinositol 3

scholarly journals The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1219
Author(s):  
Yan Teng ◽  
Yibin Fan ◽  
Jingwen Ma ◽  
Wei Lu ◽  
Na Liu ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Akt Pathway ◽  
Skin Disorders ◽  
Phosphatidylinositol 3 Kinase ◽  
Skin Development ◽  
Wide Range ◽  
Malignant Skin ◽  
Solid Foundation ◽  
And Migration ◽  
Poor Outcomes

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway regulates cell proliferation, differentiation, and migration, along with angiogenesis and metabolism. Additionally, it could mediate skin development and homeostasis. There is much evidence to suggest that dysregulation of PI3K/Akt pathway is frequently associated with several human cutaneous malignancies like malignant melanoma (MM), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC), as well as their poor outcomes. Nevertheless, emerging roles of PI3K/Akt pathway cascade in a group of common non-malignant skin disorders including acne and psoriasis, among others, have been recognized. The enhanced understanding of dysfunction of PI3K/Akt pathway in patients with these non-malignant disorders has offered a solid foundation for the progress of updated therapeutic targets. This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies.

scholarly journals Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85α, androgen receptor, and Src.

2016 ◽  
Vol 291 (43) ◽  
pp. 22841-22841
Author(s):  
Mei Sun ◽  
Lin Yang ◽  
Richard I. Feldman ◽  
Xia-meng Sun ◽  
Kapil N. Bhalla ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals The phosphatidylinositol-3 kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12 cells

2003 ◽  
Vol 8 (8) ◽  
pp. 657-669 ◽  
Author(s):  
Maiko Higuchi ◽  
Keisuke Onishi ◽  
Norihisa Masuyama ◽  
Yukiko Gotoh
Keyword(s):  
Pc12 Cells ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Branch Formation ◽  
Phosphatidylinositol 3
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