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Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.

ABSTRACT: The phosphoinositide 3-kinase (PI3K) pathway is a major mediator of growth factor signaling, cell proliferation and metabolism. Somatic gain-of-function mutations in PIK3CA, the catalytic subunit of PI3K, have recently been discovered in a number of vascular anomalies. The timing and origin of these mutations remain unclear although they are believed to occur during embryogenesis. The cellular origin of these lesions likely involves endothelial cells or an early endothelial cell lineage. This review will cover the diseases and syndromes associated with PIK3CA mutations and discuss the cellular origin, pathways and mechanisms. Activating PIK3CA 'hot spot' mutations have long been associated with a multitude of cancers allowing the development of targeted pharmacological inhibitors that are FDA-approved or in clinical trials. Current and future therapeutic approaches for PIK3CA-related vascular anomalies are discussed.

SUBMITTER: Le Cras TD

PROVIDER: S-EPMC7439927 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.

Le Cras Timothy D TD Boscolo Elisa E

Vascular biology (Bristol, England) 20190528 1

The phosphoinositide 3-kinase (PI3K) pathway is a major mediator of growth factor signaling, cell proliferation and metabolism. Somatic gain-of-function mutations in <i>PIK3CA</i>, the catalytic subunit of PI3K, have recently been discovered in a number of vascular anomalies. The timing and origin of these mutations remain unclear although they are believed to occur during embryogenesis. The cellular origin of these lesions likely involves endothelial cells or an early endothelial cell lineage. ...[more]

PMID: 32923951

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Project description:BackgroundPIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.Main bodyPIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).ConclusionManagement of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

Project description:RationaleThe etiology and pathophysiological mechanisms of moyamoya angiopathy (MMA) remain largely unknown. MMA is a progressive, occlusive cerebrovascular disorder characterized by recurrent ischemic and hemorrhagic strokes; with compensatory formation of an abnormal network of perforating blood vessels that creates a collateral circulation; and by aberrant angiogenesis at the base of the brain. Imbalance of angiogenic and vasculogenic mechanisms has been proposed as a potential cause of MMA. Moyamoya vessels suggest that aberrant angiogenic, arteriogenic, and vasculogenic processes may be involved in the pathophysiology of MMA. Circulating endothelial progenitor cells have been hypothesized to contribute to vascular remodeling in MMA. MMA is associated with increased expression of angiogenic factors and proinflammatory molecules. Systemic inflammation may be related to MMA pathogenesis.ObjectiveThis literature review describes the molecular mechanisms associated with cerebrovascular dysfunction, aberrant angiogenesis, and inflammation in MMA and related cerebrovascular diseases along with treatment strategies and future research perspectives.Methods and resultsReferences were identified through a systematic computerized search of the medical literature from January 1, 1983, through July 29, 2022, using the PubMed, EMBASE, BIOSIS Previews, CNKI, ISI web of science, and Medline databases and various combinations of the keywords "moyamoya," "angiogenesis," "anastomotic network," "molecular mechanism," "physiology," "pathophysiology," "pathogenesis," "biomarker," "genetics," "signaling pathway," "blood-brain barrier," "endothelial progenitor cells," "endothelial function," "inflammation," "intracranial hemorrhage," and "stroke." Relevant articles and supplemental basic science articles almost exclusively published in English were included. Review of the reference lists of relevant publications for additional sources resulted in 350 publications which met the study inclusion criteria. Detection of growth factors, chemokines, and cytokines in MMA patients suggests the hypothesis of aberrant angiogenesis being involved in MMA pathogenesis. It remains to be ascertained whether these findings are consequences of MMA or are etiological factors of MMA.ConclusionsMMA is a heterogeneous disorder, comprising various genotypes and phenotypes, with a complex pathophysiology. Additional research may advance our understanding of the pathophysiology involved in aberrant angiogenesis, arterial stenosis, and the formation of moyamoya collaterals and anastomotic networks. Future research will benefit from researching molecular pathophysiologic mechanisms and the correlation of clinical and basic research results.

Dataset Information

Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.

Publications

Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.

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