Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity

Vallejo-Ardila, Dora Lucía; Fifis, Theodora; Burrell, Louise M.; Walsh, Katrina A; Christophi, Christopher

doi:10.18632/oncotarget.26174

Cited by 15 publications

(15 citation statements)

References 115 publications

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“…The RAS has been implicated in modulating many aspects of tumor biology and has been extensively investigated by this laboratory and others (Fig. ).…”

Section: Introductionmentioning

confidence: 99%

“…Infusions of ANGII led Tumour recurrence in the regenerating liver to a reduction in HGF and a rise in TGF-β serum levels, ratifying the notion that ANGII modulates LR through HGF and TGF-β. 71 The RAS has been implicated in modulating many aspects of tumor biology and has been extensively investigated by this laboratory and others 69,72 (Fig. 6).…”

Section: Introductionmentioning

confidence: 99%

“…There is evidence that RAS signaling modulates cell proliferation and migration, 73,74 EMT, 74 angiogenesis, 75 ECM remodeling, and the tumor-associated immune response. 72 Components of RAS, particularly the AT1R, are overexpressed in a variety of human cancers. It has been demonstrated that both ACE inhibition and ATR1 blockers significantly reduce CRLM tumor volume in mice compared with controls (P = 0.008 and P = 0.009, respectively).…”

Section: Introductionmentioning

confidence: 99%

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Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

Riddiough

Fifis

Muralidharan

et al. 2019

J of Gastro and Hepatol

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Despite excellent treatment of primary colorectal cancer, the majority of deaths occur as a result of metastasis to the liver. Recent population studies have estimated that one quarter of patients with colorectal cancer will incur synchronous or metachronous colorectal liver metastasis. However, only one quarter of these patients will be eligible for potentially curative resection. Tumor recurrence occurs in reportedly 60% of patients undergoing hepatic resection, and the majority of intrahepatic recurrence occurs within the first 6 months of surgery. The livers innate ability to restore its homeostatic size, and volume facilitates major hepatic resection that currently offers the only chance of cure to patients with extensive hepatic metastases. Experimental and clinical evidence supports the notion that following partial hepatectomy, liver regeneration (LR) paradoxically drives tumor progression and increases the risk of recurrence. It is becoming increasingly clear that the processes that drive liver organogenesis, regeneration, and tumor progression are inextricably linked. This presents a major hurdle in the management of colorectal liver metastasis and other hepatic malignancies because therapies that reduce the risk of recurrence without hampering LR are sought. The processes and pathways underlying these phenomena are multiple, complex, and cross‐communicate. In this review, we will summarize the common mechanisms contributing to both LR and tumor recurrence.

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“…The RAS has been implicated in modulating many aspects of tumor biology and has been extensively investigated by this laboratory and others (Fig. ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

Riddiough

Fifis

Muralidharan

et al. 2019

J of Gastro and Hepatol

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“…The existence of a local renin–angiotensin system in the brain as well as in glioblastoma has been confirmed (Juillerat‐Jeanneret et al , 2004; Paul et al , 2006). This paracrine system regulates cerebral blood flow, and increased activity of the main effector peptide angiotensin II has been shown to reduce cerebral blood perfusion and oxygenation (Kazama et al , 2004; Paul et al , 2006; Vallejo‐Ardila et al , 2018; Wei et al , 2007). Furthermore, angiotensin II signaling has been linked to resistance to bevacizumab‐induced vascular normalization (Johansen et al , 2018; Levin et al , 2017; Stylianopoulos and Jain, 2013).…”

Section: Introductionmentioning

confidence: 99%

Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma

et al. 2020

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Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41-6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy.Abbreviations 95% CI, 95% confidence interval; AGT, angiotensinogen; AUC, area under the receiving operating characteristic curve; CEBP, CCAAT/ enhancer-binding protein; CR, complete response; EIAED, enzyme-inducing anti-epileptic drug; OR, odds ratio; PD, progressive disease; PR, partial response; PS, ECOG performance status; SD, stable disease; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor A. 964Molecular Oncology 14 (2020) 964-973 ª

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“…ANG II has the ability to make the tumor microenvironment immunosuppressive in hypoxic condition . Reprogramming of tumor immune microenvironment has been comprehensively reviewed recently . Further, nuclear accumulation of Angiotensin‐II (A‐II) type 2 receptor, AGTR2, decreased apoptosis, increased proliferation, and invasion in oral squamous cell carcinoma (OSCC) cells.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Connecting Link between Renin–Angiotensin System and Cancer in Barrett's Esophagus by Proteomic Screening

Rao

Husain

Bharti

et al. 2019

Proteomics Clinical Apps

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The renin-angiotensin system (RAS) plays a central role in the regulation of homeostasis and blood pressure. This involves an important enzyme called angiotensin-converting enzyme that leads to the conversion of angiotensin I into angiotensin II. RAS has been reported to show association with inflammation, and in sporadic studies, with cancer. In particular, angiotensin II has been reported to be prevalent in the hypoxic microenvironment and associated with cancer signaling pathways. In a recent study, Bratlie et al. (Proteomics Clin. Appl. 2019, 4, 1800102) is shown to exploit 2D gel electrophoresis, and mass spectrometry (MS) to identify differentially expressed proteins by comparing low-grade dysplasia in Barrett's Esophagus (BE) following administration of agents that interfere with RAS, that is, enalapril and candesartan, and identified specific modulation of HSP60, PDIA3, and PPA1. Though 2D gel coupled with MS is a commonly-used tool for studying proteomes, it still has limitations in terms of a comprehensive analysis due to lack of absolute quantitation in a high-throughput manner. Despite technical limitations and the small size of the study, preliminary data emerging from the investigation show interference caused by clinically approved RAS inhibitors resulting in alteration of molecular markers associated with tumorigenicity. The authors propose potential factors that may influence the progression of the disease. However, these are conspicuous changes in high-abundance proteins only. Therefore, there is a need to carry out detailed experimental studies either using an in vitro labeling technique (isobaric labeling for relative and absolute quantitation) for tissues or an in vivo labeling technique (stable isotope labeling in animal cell culture) coupled with LC-MS/MS to identify differentially-regulated proteins to delineate the role of RAS in BE.

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Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity

Cited by 15 publications

References 115 publications

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma

Discovery of a Novel Connecting Link between Renin–Angiotensin System and Cancer in Barrett's Esophagus by Proteomic Screening

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