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Article ; Online: The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

Rafia S. Al-Lamki / Nicholas J. Hudson / John R. Bradley / Anne Y. Warren / Tim Eisen / Sarah J. Welsh / Antony C. P. Riddick / Fiach C. O’Mahony / Arran Turnbull / Thomas Powles / SCOTRRCC Collaborative / Antonio Reverter / David J. Harrison / Grant D. Stewart

Biology, Vol 9, Iss 74, p

2020 Volume 74

Abstract: Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards ... ...

Abstract	Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
Keywords	renal cancer ; kidney cancer ; sunitinib ; PHAX ; organ culture ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90

Alex Henke / Omar E. Franco / Grant D. Stewart / Antony C.P. Riddick / Elad Katz / Simon W. Hayward / Axel A. Thomson

Cancers, Vol 8, Iss 9, p

2016 Volume 77

Abstract: Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer ... ...

Abstract	Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay; Results: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF; Conclusions: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.
Keywords	prostate cancer ; cancer associated fibroblast ; heat shock protein ; contractility ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma

Tobias Klatte / Kevin M. Gallagher / Luca Afferi / Alessandro Volpe / Nils Kroeger / Silvia Ribback / Alan McNeill / Antony C. P. Riddick / James N. Armitage / Tevita F. ‘Aho / Tim Eisen / Kate Fife / Axel Bex / Allan J. Pantuck / Grant D. Stewart

BMC Medicine, Vol 17, Iss 1, Pp 1-

development and evaluation using the ASSURE prospective clinical trial cohort

2019 Volume 10

Abstract: Abstract Background The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply ... ...

Abstract	Abstract Background The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery. Methods We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1–4, N0–1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups. Results We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups. Conclusions We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could ...
Keywords	Recurrence ; Papillary ; Prognosis ; Adjuvant ; Surveillance ; Localised ; Medicine ; R
Subject code	610
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential expression of prognostic proteomic markers in primary tumour, venous tumour thrombus and metastatic renal cell cancer tissue and correlation with patient outcome.

Alexander Laird / Fiach C O'Mahony / Jyoti Nanda / Antony C P Riddick / Marie O'Donnell / David J Harrison / Grant D Stewart

PLoS ONE, Vol 8, Iss 4, p e

2013 Volume 60483

Abstract: Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ... ...

Abstract	Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ensures predicting metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been shown to have prognostic significance, including Ki67, p53, vascular endothelial growth factor receptor 1 (VEGFR1) and ligand D (VEGFD), SNAIL and SLUG. Previous pathway analysis has been from study of the primary tumour, with little attention to the metastatic tumours which are the focus of targeted molecular therapies. As such, in this study a tissue microarray from 177 patients with primary renal tumour, renal vein tumour thrombus and/or RCC metastasis has been created and used with Automated Quantitative Analysis (AQUA) of immunofluorescence to study the prognostic significance of these markers in locally advanced and metastatic disease. Furthermore, this has allowed assessment of differential protein expression between the primary tumours, renal vein tumour thrombi and metastases. The results demonstrate that clinico-pathological parameters remain the most significant predictors of cancer specific survival; however, high VEGFR1 or VEGFD can predict poor cancer specific survival on univariate analysis for locally advanced and metastatic disease. There was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared with the primary tumours and renal vein tumour thrombi. With the exception of p53, these differences in protein expression have not been shown previously in RCC. This confirms the importance of proliferation, angiogenesis and epithelial to mesenchymal transition in the pathogenesis and metastasis of RCC. Importantly, this work highlights the need for further ...
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1

Brigid Orr / O. Cathal Grace / Pam Brown / Antony C. P. Riddick / Grant D. Stewart / Omar E. Franco / Simon W. Hayward / Axel A. Thomson

Disease Models & Mechanisms, Vol 6, Iss 2, Pp 530-

2013 Volume 536

Abstract: SUMMARY Human prostatic cancer-associated fibroblasts (CAFs) can elicit malignant changes in initiated but non-tumorigenic human prostate epithelium, demonstrating that they possess pro-tumorigenic properties. We set out to reduce the pro-tumorigenic ... ...

Abstract	SUMMARY Human prostatic cancer-associated fibroblasts (CAFs) can elicit malignant changes in initiated but non-tumorigenic human prostate epithelium, demonstrating that they possess pro-tumorigenic properties. We set out to reduce the pro-tumorigenic activity of patient CAFs using the Dlk1 and SCUBE1 molecules that we had previously identified in prostate development. Our hypothesis was that mesenchymally expressed molecules might reduce CAF pro-tumorigenic activity, either directly or indirectly. We isolated primary prostatic CAFs and characterised their expression of CAF markers, expression of Notch2, Dlk1 and SCUBE1 transcripts, and confirmed their ability to stimulate BPH1 epithelial cell proliferation. Next, we expressed Dlk1 or SCUBE1 in CAFs and determined their effects upon tumorigenesis in vivo following recombination with BPH1 epithelia and xenografting in SCID mice. Tumour size was reduced by about 75% and BPH1 proliferation was reduced by about 50% after expression of Dlk1 or SCUBE1 in CAFs, and there was also a reduction in invasion of BPH1 epithelia into the host kidney. Inhibition of Notch signalling, using inhibitor XIX, led to a reduction in BPH1 cell proliferation in CAF-BPH1 co-cultures, whereas inhibition of Dlk1 in NIH3T3-conditioned media led to an increase in BPH1 growth. Our results suggest that pro-tumorigenic CAF activity can be reduced by the expression of developmental pathways.
Keywords	Medicine ; R ; Pathology ; RB1-214
Subject code	570
Language	English
Publishing date	2013-03-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer.

Alexander Henke / O Cathal Grace / George R Ashley / Grant D Stewart / Antony C P Riddick / Henry Yeun / Marie O'Donnell / Richard A Anderson / Axel A Thomson

PLoS ONE, Vol 7, Iss 8, p e

2012 Volume 42516

Abstract: During prostate development, mesenchymal-epithelial interactions regulate organ growth and differentiation. In adult prostate, stromal-epithelial interactions are important for tissue homeostasis and also play a significant role in prostate cancer. In ... ...

Abstract	During prostate development, mesenchymal-epithelial interactions regulate organ growth and differentiation. In adult prostate, stromal-epithelial interactions are important for tissue homeostasis and also play a significant role in prostate cancer. In this study we have identified molecules that show a mesenchymal expression pattern in the developing prostate, and one of these showed reduced expression in prostate cancer stroma.Five candidate molecules identified by transcript profiling of developmental prostate mesenchyme were selected using a wholemount in situ hybridisation screen and studied Decorin (Dcn), Semaphorin6D (Sema6D), SPARC/Osteonectin (SPARC), Sprouty1 (Spry-1) and Tsukushi (Tsku). Expression in rat tissues was evaluated using wholemount in situ hybridisation (postnatal day (P) 0.5) and immunohistochemistry (embryonic day (E) E17.5, E19.5; P0.5; P6; 28 & adult). Four candidates (Decorin, SPARC, Spry-1, Tsukushi) were immunolocalised in human foetal prostate (weeks 14, 16, 19) and expression of Decorin was evaluated on a human prostate cancer tissue microarray. In embryonic and perinatal rats Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi were expressed with varying distribution patterns throughout the mesenchyme at E17.5, E19.5, P0.5 and P6.5. In P28 and adult prostates there was either a decrease in the expression (Semaphorin6D) or a switch to epithelial expression of SPARC, and Spry-1, whereas Decorin and Tsukushi were specific to mesenchyme/stroma at all ages. Expression of Decorin, SPARC, Spry-1 and Tsukushi in human foetal prostates paralleled that in rat. Decorin showed mesenchymal and stromal-specific expression at all ages and was further examined in prostate cancer, where stromal expression was significantly reduced compared with non-malignant prostate.We describe the spatio-temporal expression of Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi in developing prostate and observed similar mesenchymal expression patterns in rat and human. Additionally, Decorin showed reduced expression in prostate cancer stroma compared to non-malignant prostate stroma.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The use of automated quantitative analysis to evaluate epithelial-to-mesenchymal transition associated proteins in clear cell renal cell carcinoma.

Fiach C O'Mahony / Dana Faratian / James Varley / Jyoti Nanda / Marianna Theodoulou / Antony C P Riddick / David J Harrison / Grant D Stewart

PLoS ONE, Vol 7, Iss 2, p e

2012 Volume 31557

Abstract: Epithelial-to-mesenchymal transition (EMT) has recently been implicated in the initiation and progression of renal cell carcinoma (RCC). Some mRNA gene expression studies have suggested a link between the EMT phenotype and poorer clinical outcome from ... ...

Abstract	Epithelial-to-mesenchymal transition (EMT) has recently been implicated in the initiation and progression of renal cell carcinoma (RCC). Some mRNA gene expression studies have suggested a link between the EMT phenotype and poorer clinical outcome from RCC. This study evaluated expression of EMT-associated proteins in RCC using in situ automated quantitative analysis immunofluorescence (AQUA) and compared expression levels with clinical outcome.Unsupervised hierarchical cluster analysis of pre-existing RCC gene expression array data (GSE16449) from 36 patients revealed the presence of an EMT transcriptional signature in RCC [E-cadherin high/SLUG low/SNAIL low]. As automated immunofluorescence technology is dependent on accurate definition of the tumour cells in which measurements take place is critical, extensive optimisation was carried out resulting in a novel pan-cadherin based tumour mask that distinguishes renal cancer cells from stromal components. 61 patients with ccRCC and clinical follow-up were subsequently assessed for expression of EMT-associated proteins (WT1, SNAIL, SLUG, E-cadherin and phospho-β-catenin) on tissue microarrays. Using Kaplan-Meier analysis both SLUG (p = 0.029) and SNAIL (p = 0.024) (log rank Mantel-Cox) were significantly associated with prolonged progression free survival (PFS). Using Cox regression univariate and multivariate analysis none of the biomarkers were significantly correlated with outcome. 14 of the 61 patients expressed the gene expression analysis predicted EMT-protein signature [E-cadherin high/SLUG low/SNAIL low], which was not found to be associated to PFS when measured at the protein level. A combination of high expression of SNAIL and low stage was able to stratify patients with greater significance (p = 0.001) then either variable alone (high SNAIL p = 0.024, low stage p = 0.029).AQUA has been shown to have the potential to identify EMT related protein targets in RCC allowing for stratification of patients into high and low risk groups, as well the ability to ...
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors

Christopher G. Smith / Tina Moser / Florent Mouliere / Johanna Field-Rayner / Matthew Eldridge / Anja L. Riediger / Dineika Chandrananda / Katrin Heider / Jonathan C. M. Wan / Anne Y. Warren / James Morris / Irena Hudecova / Wendy N. Cooper / Thomas J. Mitchell / Davina Gale / Andrea Ruiz-Valdepenas / Tobias Klatte / Stephan Ursprung / Evis Sala /

Antony C. P. Riddick / Tevita F. Aho / James N. Armitage / Samantha Perakis / Martin Pichler / Maximilian Seles / Gabriel Wcislo / Sarah J. Welsh / Athena Matakidou / Tim Eisen / Charles E. Massie / Nitzan Rosenfeld / Ellen Heitzer / Grant D. Stewart

Genome Medicine, Vol 12, Iss 1, Pp 1-

2020 Volume 17

Abstract: Abstract Background Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods Here, a combination of untargeted and targeted sequencing methods, applied to ... ...

Abstract	Abstract Background Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
Keywords	Renal cancer ; Cell-free tumor DNA (ctDNA) ; Personalized analysis ; Predictive biomarker ; Heterogeneity ; Medicine ; R ; Genetics ; QH426-470
Subject code	610 ; 616
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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