Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis
Joshua D.G. LeachNikola VlahovPetros TsantoulisRachel A. RidgwayDustin J. FlanaganKathryn GilroyNathalie SphyrisEster Gil VazquezDavid F. VincentWilliam J. FallerMichael C. HodderAlexander RavenSigrid K. FeyArafath K. NajumudeenDouglas StrathdeeColin NixonMark HughesWilliam ClarkRobin ShawTim MaughanManuel Salto‐TellezPhilip QuirkeViktor H. KoelzerPhilip D. DunneAndrew D. BeggsPeter J. CampbellFrancesca M. BuffaChris HolmesRichard KaplanLouise BrownMark LawlerJoshua HordernIan TomlinsonSimon J. LeedhamDion MortonSander R. van HooffDavid J. HuelsJan Paul MedemaSimon T. BarryMargaret C. FrameAsier Unciti‐BrocetaSimon J. LeedhamGareth J. InmanRené JackstadtBarry J. ThompsonAndrew D. CampbellSabine TejparOwen J. Sansom
58
Citation
84
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype ( Ly6a/Sca1 + ) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF -mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.Keywords:
ACVRL1
IntroductionHereditary hemorrhagic telangiectasia (HHT), also referred to as the Osler-Weber-Rendu syndrome, is a rare autosomal dominant hereditary disease that results in abnormal vasculogenesis in the skin, mucous membranes, and visceral organs such as the liver, lungs, and brain [1]. The prevalence of HHT ranges from one in every 5,000 people to one in every 8,000 people with an estimated 85,000 cases in Europe [2, 3] and the rate of diagnosis is lower in lower socioeconomic groups [4].Four important genes, including ENG (endoglin), ACVRL1 (activin receptor-like kinase 1), SMAD4 (mothers against decapentaplegic homolog 4), and GDF2 (growth differentiation factor 2), have recently been linked to the underlying mechanism of HHT [5]. Arterio-venous malformations (AVMs) are caused by mutations in these genes that interfere with the TGF-β (transforming growth factor)-beta signaling pathways in vascular endothelial cells, which impair cell division [5]. Heterozygous mutations are the common cause of the two primary kinds of HHT. Endoglin (ENG) is mutated in HHT1. Patients, especially women, with this type are more likely to develop pulmonary and cerebral AVMs. Activin A receptor-like type 1 (ACVRL1), commonly referred to as ALK1, is mutated in HHT2. Of the mutations known to cause HHT, ENG makes up around 61% and ACVRL1 makes up about 37% [7, 8].About 90% of those with the condition experience recurrent nosebleeds, which usually begin in childhood. Other symptoms include gastrointestinal bleeding (25–30%), which can cause melena and severe symptomatic microcytic anemia; pulmonary AVMs (50%) that can cause dyspnea, hemoptysis, paradoxical emboli, and cerebral abscesses; cerebral AVMs (10%) that can cause headache, seizures, and focal neurological deficits; and hepatic AVM (40–70%), which are typically asymptomatic but might show signs of high output cardiac failure and hepatic decompensation, ultimately necessitating liver transplantation [9].Clinical diagnosis of HHT is made using the Curacao criteria, which include first-degree family history of HHT, visceral involvement, recurrent spontaneous nosebleeds, and mucocutaneous telangiectasias. If three or more criteria are met, the diagnosis is considered to be conclusive; if only two criteria are met, the diagnosis is considered to be suspected HHT [10] [Table 1]. If less than two criteria are met, the diagnosis is considered to be unlikely HHT.Table 1 Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasias
ACVRL1
Microcytic anemia
Cite
Citations (0)
Studies of rare genetic diseases frequently reveal genes that are fundamental to life, and the familial vascular disorder HHT (hereditary haemorrhagic telangiectasia) is no exception. The majority of HHT patients are heterozygous for mutations in either the ENG (endoglin) or the ACVRL1 (activin receptor-like kinase 1) gene. Both genes are essential for angiogenesis during development and mice that are homozygous for mutations in Eng or Acvrl1 die in mid-gestation from vascular defects. Recent development of conditional mouse models in which the Eng or Acvrl1 gene can be depleted in later life have confirmed the importance of both genes in angiogenesis and in the maintenance of a normal vasculature. Endoglin protein is a co-receptor and ACVRL1 is a signalling receptor, both of which are expressed primarily in endothelial cells to regulate TGFβ (transforming growth factor β) signalling in the cardiovasculature. The role of ACVRL1 and endoglin in TGFβ signalling during angiogenesis is now becoming clearer as interactions between these receptors and additional ligands of the TGFβ superfamily, as well as synergistic relationships with other signalling pathways, are being uncovered. The present review aims to place these recent findings into the context of a better understanding of HHT and to summarize recent evidence that confirms the importance of endoglin and ACVRL1 in maintaining normal cardiovascular health.
ACVRL1
Telangiectases
Cite
Citations (52)
Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level.Areas covered: Pathogenic mutations in genes coding for the TGF-β receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed.Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.
Telangiectases
ACVRL1
Haploinsufficiency
Cite
Citations (89)
Hereditary haemorrhagic telangiectasia (HHT) (OMIM 187300) is an autosomal dominant disorder caused by mutations in either of two genes, endoglin ( ENG , OMIM 131195) (HHT1) and activin A receptor type II-like 1 ( ACVRL1 , OMIM 601284) (HHT2). Evidence for a third locus has also been reported.1
The product of the ACVRL1 gene is a type I receptor for the TGF-beta group of ligands; it is associated with the TGF-beta or activin type II receptors and the complex binds TGF-beta or activin. It is highly expressed in endothelial cells, lung, and placenta, as endoglin, mutations of which are observed in HHT1; endoglin is supposed to sequester TGF-beta and present the ligand to activin A receptor type II-like 1 plus a type II receptor.2 Mutations in ENG and ACVRL1 may cause HHT1 or HHT2, respectively, by disrupting this complex.
The clinical presentation, indistinguishable between HHT1 and HHT2, typically includes epistaxis and telangiectasia, and the diagnosis can be considered to be confirmed, according to the proposal of Shovlin et al ,3 if three of the four suggested diagnostic criteria (epistaxis, telangiectasia, visceral lesions, positive family history) are present. The phenotype is highly variable and penetrance is complete by the age of 40 years.4
Arteriovenous (AV) fistulae are frequently observed in the liver (8% of patients),5 lungs (20%),6 and brain5 and may cause severe life threatening complications. Neurological complications (strokes, cerebral abscesses, seizures) may be prevented with appropriate treatment of the pulmonary arteriovenous malformations (PAVMs). A higher risk for lung involvement has been suggested in patients carrying mutations in the ENG gene,7 while in some families with a peculiar liver involvement, mutations in ACVRL1 have been described.8 The involvement of the latter gene has also been reported in a single patient with a pituitary tumour …
ACVRL1
Penetrance
Telangiectases
Cite
Citations (63)
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in
ACVRL1
Compound heterozygosity
Cite
Citations (6)
遺伝性出血性末梢血管拡張症(hereditary hemorrhagic telangiectasia : HHT/Rendu-Osler-Weber syndrome)は反復する鼻出血で気づかれる常染色体優性遺伝性の血管奇形である。HHT患者の多くで血管内皮細胞由来のTransforming growth factor (TGF)-βスーパーファミリーシグナル調節蛋白をコードするendoglin 遺伝子(ENG)もしくはactivin receptor-like kinase 1遺伝子(ACVRL 1)の変異が認められている。本邦におけるHHT患者からはENG変異の報告しかない。症例は39歳の男性。幼少時から鼻出血を繰り返し, 6年前より難治となった。硬口蓋や舌に点状の紅色丘疹が多数みられた。口唇の紅色丘疹の病理組織像では真皮上層に拡張した毛細血管が確認された。同時に左肺動静脈瘻と小脳静脈奇形, 小腸の毛細血管拡張が認められた。遺伝子解析にてENGの変異が認められ, HHT 1型と診断された。
ACVRL1
Activin receptor
Cite
Citations (0)
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic-angiostatic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic-angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.
Telangiectases
ACVRL1
Haploinsufficiency
Pathogenesis
Cite
Citations (49)
A decade ago, it was recognized that mutations in the ENDOGLIN (ENG) (1) and ACTIVIN RECEPTOR-LIKE KINASE 1 (ACVRL1) (2) genes cause an autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2, respectively. The predominant expression of the corresponding proteins, endoglin and ALK1, on vascular endothelial cells (ECs) and their function as transforming growth factor (TGF)-β receptors indicated that HHT is likely associated with perturbations in TGF-β signaling in ECs. Mice heterozygous for either gene develop HHT (3–6), and can be used to gain insight into the mechanisms of disease, highlighting the role of TGF-β in maintaining vascular integrity and unraveling the potential contribution of other pathways to HHT pathogenesis. Mice totally deficient in either endoglin (3–5) or ALK1 (6) do not survive past midgestation, and their analysis has revealed an essential role for these receptors in vascular development. This chapter provides an overview of HHT as a disorder of the vascular endothelium associated with the generation of abnormal structures such as telangiectases and arteriovenous malformations (AVMs), and discusses the current model of HHT pathogenesis.
ACVRL1
Telangiectases
Pathogenesis
Cite
Citations (1)
Hereditary haemorrhagic telangiectasia (HHT) is a vascular hereditary autosomic dominant disease associated with epistaxis, telangiectases, gastrointestinal haemorrhages and arteriovenous malformations in lung, liver and brain. It affects 1-2 in 10,000 people. There are at least three different genes mutated in HHT, ENG, ACVRL1 and MADH4 that encode endoglin, activin receptor-like kinase (ALK1) and Smad4 proteins, respectively. These proteins are involved in the transforming growth factor (TGF)-β superfamily signalling pathway of vascular endothelial cells. Mutations in ENG (HHT1) and ACVRL1 (HHT2) account for more than 90% of all HHT mutations. In this article, we review the underlying molecular and cellular bases and the therapeutic approaches that have been addressed in our laboratory in recent years.
Telangiectases
ACVRL1
Activin receptor
Cite
Citations (18)
Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/or function of the cardiovasculature. Hereditary Haemorrhagic Telangiectasia is a familial disease of this type. The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage. ENG and ACVRL1 encode receptors for the TGFβ superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood. Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations. Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice. Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations. These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation. We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo. Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia. We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity.
ACVRL1
Telangiectases
Cite
Citations (126)