High expression of insulin receptor on tumour‐associated blood vessels in invasive bladder cancer predicts poor overall and progression‐free survival

Roudnicky, Filip; Poyet, Cédric; Buser, Lorenz; Wild, Peter J.; Tang, Dave; Camenzind, Peter; Ho, Chien Hsien; Otto, Vivianne I.; Detmar, Michael

doi:10.1002/path.4892

Cited by 27 publications

(26 citation statements)

References 59 publications

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“…One study has shown that high BMI in conjunction with negative expression of progesterone receptors serves as an independent risk factor for breast cancer recurrences in patients treated with adjuvant aromatase inhibitors (40). In muscle-invasive bladder cancer, expression of insulin receptors in tumor-associated blood vessels also has correlated with poor overall and progression-free survival (41). Consequently, assay of plasma obesity-related molecules or evaluation of hormonal receptor expression in bladder tumors may help elucidate the mechanism of tumorigenesis encouraged by higher BMI in patients with bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

Optimal body mass index cut‑point for predicting recurrence‑free survival in patients with non‑muscle‑invasive urothelial carcinoma of bladder

et al. 2018

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In Japanese patients with non-muscle-invasive urothelial carcinoma of the bladder, the impact of body mass index (BMI) on recurrence following transurethral resection of bladder tumor (TURBT) is unclear. The present study retrospectively examined data collected from 50 patients diagnosed with primary urothelial carcinoma of the bladder (pTa, pTis, and pT1) who had previously undergone TURBT surgery. Two BMI cut-off points for predicting disease recurrence were evaluated: i) A threshold generated through receiver operating characteristic (ROC) curve analysis; ii) the World Health Organization BMI index (24 kg/m) for overweight status in Japanese populations. Univariate and multivariate analyses were applied to assess individual variables (BMI included) and the effect they had on recurrence-free survival (RFS). Median RFS and BMI values of 19.72 months (range, 3.13-72.13 months) and 23.37 kg/m2 (range, 14.72-36.84 kg/m2), respectively, were recorded. In multivariate analyses, higher continuous BMI was significantly associated with shorter RFS (P=0.019). Based on a ROC-generated BMI cut-off point (23.4 kg/m2), patients were ranked with either a high (≥23.4 kg/m2) or low (<23.4 kg/m2) BMI status. Multivariate analysis indicated that BMI values >23.4 kg/m2 were significantly associated with shorter RFS (P=0.028). Intravesical Bacillus Calmette-Guérin treatment and history of upper-tract urothelial carcinoma were also independently associated (P=0.044 and P=0.010, respectively). However, BMI values >24 kg/m2 (customary cut-off point) had no significant impact on RFS (P=0.066). Thus, a higher BMI status was revealed to be independently predictive of shorter RFS in Japanese patients undergoing TURBT for urothelial carcinoma of the bladder. A greater number of samples are required in order to determine optimal BMI cut-off points in Japanese patients and to investigate whether weight reduction intervention may improve prognosis.

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Section: Discussionmentioning

confidence: 99%

Optimal body mass index cut‑point for predicting recurrence‑free survival in patients with non‑muscle‑invasive urothelial carcinoma of bladder

et al. 2018

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“…To explore the effects of AKT2 dysregulation on endothelial cells, we utilized previously engineered human pluripotent stem cell (hPSC) HUES9 cell lines carrying AKT2 KO and AKT2 E17K mutations [4], along with the corresponding WT cell line, and differentiated each into ECs using a previously published protocol [7,9]. These ECs were then subjected to both molecular profiling studies and functional assays ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…ECs play a central role in the cardiovascular, renal, or neural complications of diabetes mellitus and metabolic syndrome [5]. ECs are an important target of insulin [6,7], and the primary effect of insulin is to activate the kinase AKT1, which then leads to phosphorylation of eNOS and vasodilatation to increase nutrient delivery to tissues [8]. The specific function of the closely related kinase AKT2 in endothelial cells has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype

Roudnicky

Lan

Friesen

et al. 2019

IJMS

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The kinase AKT2 (PKB) is an important mediator of insulin signaling, for which loss-of-function knockout (KO) mutants lead to early onset diabetes mellitus, and dominant active mutations lead to early development of obesity and endothelial cell (EC) dysfunction. To model EC dysfunction, we used edited human pluripotent stem cells (hPSCs) that carried either a homozygous deletion of AKT2 (AKT2 KO) or a dominant active mutation (AKT2 E17K), which, along with the parental wild type (WT), were differentiated into ECs. Profiling of EC lines indicated an increase in proinflammatory and a reduction in anti-inflammatory fatty acids, an increase in inflammatory chemokines in cell supernatants, increased expression of proinflammatory genes, and increased binding to the EC monolayer in a functional leukocyte adhesion assay for both AKT2 KO and AKT2 E17K. Collectively, these findings suggest that vascular endothelial inflammation that results from dysregulated insulin signaling (homeostasis) may contribute to coronary artery disease, and that either downregulation or upregulation of the insulin pathway may lead to inflammation of endothelial cells. This suggests that the standard of care for patients must be expanded from control of metabolic parameters to include control of inflammation, such that endothelial dysfunction and cardiovascular disorders can ultimately be prevented.

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“…Interestingly, we compared pathways predicted with annotations of these six RBPs in GeneCards 6 and found that HSPG2 acted as an anti-angiogenic and anti-tumor peptide that inhibited endothelial cell migration and collagen-induced endothelial tube morphogenesis. Angiogenesis is thought to be a critical procedure of promoting BLCA progression and associated with poor survival ( Bochner et al, 1995 ; Roudnicky et al, 2017 ). Among these prognostic RBPs, HSPG2 demonstrated an anti-angiogenesis effect via binding to α2β1 integrin and interacting with VEGFR2 at the surface of endothelial cells ( Woodall et al, 2008 ; Goyal et al, 2012 ; Poluzzi et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Six-RNA-Binding Protein Signature for Prognosis Prediction in Bladder Cancer

Liu

et al. 2020

Front. Genet.

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RNA-binding proteins (RBPs) are a kind of gene regulatory factor that presents a significant biological effect in the initiation and development of various tumors, including bladder cancer (BLCA). However, the RBP-based prognosis signature for BLCA has not been investigated. In this study, we attempted to develop an RBP-based classifier to predict overall survival (OS) for BLCA based on transcriptome analysis. We extracted data of BLCA patients from The Cancer Genome Atlas database (TCGA) and UCSC Xena. Finally, a total of 398 cases without missing clinical data were enrolled and six RBPs ( FLNA , HSPG2 , AHNAK , FASTKD3 , POU5F1 , and PCSK9 ) associated with OS of BLCA were identified through univariate and multivariate Cox regression analysis. Online analyses and immunohistochemistry validated the prognostic value and expression of six RBPs. Risk scores were calculated to divide patients into high-risk and low-risk level, and patients in the high-risk group tended to have a poor prognosis. In addition, the receiver operating characteristic (ROC) curve analysis was performed to assess the prognostic value of RBPs, and the area under the curve (AUC) values were 0.711 and 0.706, respectively, in the training set and validating set. The findings were further validated in an external validation set. Subsequently, the 6-RBP-based signature and pathological stage were used to construct the nomogram to predict the 3- and 5-years OS of BLCA patients. Also, this 6-RBP-based signature was highly related to recurrence-free survival of BLCA. Weighted co-expression network analysis (WGCNA) combined with functional enrichment analysis contributed to study the potential pathways of six RBPs, including keratinocyte differentiation, RHO GTPases activate PNKs, epithelial tube morphogenesis, establishment or maintenance of cell polarity, and so on. In summary, the 6-RBP-based signature holds the potentiality to serve as a novel prognostic predictor of OS for BLCA.

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High expression of insulin receptor on tumour‐associated blood vessels in invasive bladder cancer predicts poor overall and progression‐free survival

Cited by 27 publications

References 59 publications

Optimal body mass index cut‑point for predicting recurrence‑free survival in patients with non‑muscle‑invasive urothelial carcinoma of bladder

Optimal body mass index cut‑point for predicting recurrence‑free survival in patients with non‑muscle‑invasive urothelial carcinoma of bladder

Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype

Identification of the Six-RNA-Binding Protein Signature for Prognosis Prediction in Bladder Cancer

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