Irreversible and sustained upregulation of endothelin axis during oncogene-associated pancreatic inflammation and cancer

Gupta, Suprit; Prajapati, Avi; Gulati, Mansi; Gautam, Shailendra K.; Kumar, Sushil; Dalal, Vipin; Talmon, Geoffrey A.; Rachagani, Satyanarayana; Jain, Maneesh

doi:10.1016/j.neo.2019.11.001

Cited by 18 publications

(12 citation statements)

References 51 publications

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“…The ET axis in the ductal and stromal cells has been proposed to have a potential role in the initiation and progression of PDAC at the background of mutant KRAS, promoted by various inflammatory stimuli in the environment. Especially, ET-1 binds to its dual receptors, ETAR and ETBR, interconnecting the interactions among epithelial cells, TAMs, CAFs, and other immune cells ( Gupta et al, 2020 ). Besides, TAMs predominantly enhance the expression of heparin-binding EGFR ligand in pre-neoplastic lesions to facilitate ADM ( Kumar et al, 2015 ).…”

Section: The Role Of Tams In Pdacmentioning

confidence: 99%

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

Yang

Liu

Liao

2021

Front. Cell Dev. Biol.

120

114

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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. PDAC is only cured by surgical resection in its early stage, but there remains a relatively high possibility of recurrence. The development of PDAC is closely associated with the tumor microenvironment. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the pancreatic tumor stroma. TAMs are inclined to M2 deviation in the tumor microenvironment, which promotes and supports tumor behaviors, including tumorigenesis, immune escape, metastasis, and chemotherapeutic resistance. Herein, we comprehensively reviewed the latest researches on the origin, polarization, functions, and reprogramming of TAMs in PDAC.

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Section: The Role Of Tams In Pdacmentioning

confidence: 99%

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

Yang

Liu

Liao

2021

Front. Cell Dev. Biol.

120

114

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“…In addition, macrophages were depicted by Mac-3 staining within the plaque border ( Figure S1C). Macrophages express components of the endothelin system including ET A R, but are also capable of inducing ET-1 secretion and ET receptor expression in vitro in a variety of cell types including HUVECs [30,42,43]. Moreover, neutrophils also express ET A R [43], so the observed, SMA-independent ET A R staining might arise from these inflammatory cells We showed that qPCR analysis of SMA gene expression confirms the histological observation as it shows an increase after 22 weeks of high-fat diet.…”

Section: Discussionmentioning

confidence: 99%

“…The prominent ET A R signal from the adventitia in Figure 1C might at least in part be due to the presence of adventitial fibroblasts, which are known to contribute to increased levels of collagen type I expression associated with fibrosis, increased vessel stiffness and VSMC migration by ET-1 signaling [29]. Mac-3 staining for macrophages shows an enhanced presence of immune cells within the plaque wall ( Figure S1C), which might also be a source of ET A R probe fluorescence [30]. Analysis of ET A R, SMA and MMP-9 mRNA expression during the diet-induced progression of atherosclerosis reveals marked differences between ApoE −/− and control animals ( Figure 1D-F).…”

Section: Apoe −/− Mice Show Enhanced Et a R Expression After High-fatmentioning

confidence: 99%

Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis

et al. 2020

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Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ETAR) in the course of atherogenesis to reveal possible time frames for targeted imaging and interventions. We used the ApoE−/− mice model and human specimens and evaluated ETAR expression by quantitative rtPCR (qPCR), histology and fluorescence molecular imaging. We found a significant upregulation of ETAR after 22 weeks of high-fat diet in the aortae of ApoE−/− mice. With regard to translation to human disease, we applied the fluorescent probe to fresh explants of human carotid and femoral artery specimens. The findings were correlated with qPCR and histology. While ETAR is upregulated during the progression of early atherosclerosis in the ApoE−/− mouse model, we found that ETAR expression is substantially reduced in advanced human atherosclerotic plaques. Moreover, those expression changes were clearly depicted by fluorescence imaging using our in-house designed ETAR-Cy 5.5 probe confirming its specificity and potential use in future studies.

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“…The ET-1/ET-1R axis hyper-activation endows cells with malignant potential conferring upon them a landscape of features associated with changes in cell fate and acquisition of aggressive traits. ET-1, and other components of the ET-1 axis, is highly expressed in many human malignancies and their expression is associated with tumoral advanced stages [ 5 , 6 ]. Clinically relevant, in many tumor contexts [ 5 , 33 ] high levels of ET-1R are associated with a worst prognosis, proving the unfavorable prognostic role of ET-1R.…”

Section: The Et-1-driven Signaling Network In Tumor Cells and Tumor‐mmentioning

confidence: 99%

“…Defining the mechanistic dynamics related to GPCR signaling in tumor and microenvironmental contexts is an endeavor for the rational design of high-efficacy cancer therapeutics [ 4 ]. Among the GPCR, the endothelin-1 (ET-1) receptors (ET-1R), ET A receptor (ET A R) and ET B receptor (ET B R), are pervasively expressed in many human malignances and their activation confers to tumor cells peculiar malignant traits, orchestrating the signaling network involved in cell proliferation, cell invasion and migration, drug resistance, angiogenesis and lymphangiogenesis, and metastatization [ 5 , 6 ]. The binding of 21-amino acid small vasoactive peptides known as endothelins (ETs) activates ET-1R.…”

Section: Introductionmentioning

confidence: 99%

YAP and endothelin-1 signaling: an emerging alliance in cancer

Tocci

Blandino²,

Bagnato

2021

J Exp Clin Cancer Res

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The rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.

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Irreversible and sustained upregulation of endothelin axis during oncogene-associated pancreatic inflammation and cancer

Cited by 18 publications

References 51 publications

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis

YAP and endothelin-1 signaling: an emerging alliance in cancer

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