Cancers

Editorial

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5 pages, 234 KiB

Open AccessEditorial

Insights into Urological Cancer

by Claudia Manini and José I. López

Cancers 2021, 13(2), 204; https://doi.org/10.3390/cancers13020204 - 8 Jan 2021

Cited by 4 | Viewed by 2093

Abstract

The year the Covid-19 pandemic appeared has been quite prolific in urological cancer research, and the collection of articles, perspectives, and reviews on renal, prostate, and urinary tract tumors merged in this Urological Cancer 2020 issue is just a representative sample of this [...] Read more.

The year the Covid-19 pandemic appeared has been quite prolific in urological cancer research, and the collection of articles, perspectives, and reviews on renal, prostate, and urinary tract tumors merged in this Urological Cancer 2020 issue is just a representative sample of this assertion [...] Full article

(This article belongs to the Special Issue Urological Cancer 2020)

Research

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29 pages, 55993 KiB

Open AccessArticle

Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures

by Sofia Karkampouna, Maria R. De Filippo, Charlotte K. Y. Ng, Irena Klima, Eugenio Zoni, Martin Spahn, Frank Stein, Per Haberkant, George N. Thalmann and Marianna Kruithof-de Julio

Cancers 2020, 12(12), 3786; https://doi.org/10.3390/cancers12123786 - 15 Dec 2020

Cited by 12 | Viewed by 4209

Abstract

Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether [...] Read more.

Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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11 pages, 1438 KiB

Open AccessArticle

Downstream Neighbor of SON (DONSON) Expression Is Enhanced in Phenotypically Aggressive Prostate Cancers

by Niklas Klümper, Marthe von Danwitz, Johannes Stein, Doris Schmidt, Anja Schmidt, Glen Kristiansen, Michael Muders, Michael Hölzel, Manuel Ritter, Abdullah Alajati and Jörg Ellinger

Cancers 2020, 12(11), 3439; https://doi.org/10.3390/cancers12113439 - 19 Nov 2020

Cited by 8 | Viewed by 2501

Abstract

Downstream neighbor of Son (DONSON) plays a crucial role in cell cycle progression and in maintaining genomic stability, but its role in prostate cancer (PCa) development and progression is still underinvestigated. Methods: DONSON mRNA expression was analyzed with regard to clinical-pathological parameters and [...] Read more.

Downstream neighbor of Son (DONSON) plays a crucial role in cell cycle progression and in maintaining genomic stability, but its role in prostate cancer (PCa) development and progression is still underinvestigated. Methods: DONSON mRNA expression was analyzed with regard to clinical-pathological parameters and progression using The Cancer Genome Atlas (TCGA) and two publicly available Gene Expression Omnibus (GEO) datasets of PCa. Afterwards, DONSON protein expression was assessed via immunohistochemistry on a comprehensive tissue microarray (TMA). Subsequently, the influence of a DONSON-knockdown induced by the transfection of antisense-oligonucleotides on proliferative capacity and metastatic potential was investigated. DONSON was associated with an aggressive phenotype in the PCa TCGA cohort, two GEO PCa cohorts, and our PCa TMA cohort as DONSON expression was particularly strong in locally advanced, metastasized, and dedifferentiated carcinomas. Thus, DONSON expression was notably upregulated in distant and androgen-deprivation resistant metastases. In vitro, specific DONSON-knockdown significantly reduced the migration capacity in the PCa cell lines PC-3 and LNCaP, which further suggests a tumor-promoting role of DONSON in PCa. In conclusion, the results of our comprehensive expression analyses, as well as the functional data obtained after DONSON-depletion, lead us to the conclusion that DONSON is a promising prognostic biomarker with oncogenic properties in PCa. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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20 pages, 6497 KiB

Open AccessFeature PaperArticle

CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer

by Molishree Joshi, Jihye Kim, Angelo D’Alessandro, Emily Monk, Kimberley Bruce, Hanan Elajaili, Eva Nozik-Grayck, Andrew Goodspeed, James C. Costello and Isabel R. Schlaepfer

Cancers 2020, 12(11), 3431; https://doi.org/10.3390/cancers12113431 - 18 Nov 2020

Cited by 27 | Viewed by 3718

Abstract

Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell [...] Read more.

Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. Transcriptomic analysis identified ER stress, serine biosynthesis and lipid catabolism as significantly upregulated pathways in the OE versus KD cells. On the other hand, androgen response was significantly downregulated in OE cells. These changes associated with increased acyl-carnitines, serine synthesis and glutathione precursors in OE cells. Unexpectedly, OE cells showed increased mitochondrial ROS but when challenged with fatty acids and no androgens, the Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better antioxidant defenses with excess CPT1A expression. Public databases also showed decreased androgen response correlation with increased serine-related metabolism in advanced PCa. Lastly, worse progression free survival was observed with increased lipid catabolism and decreased androgen response. Excess CPT1A is associated with a ROS-mediated stress phenotype that can support PCa disease progression. This study provides a rationale for targeting lipid catabolic pathways for therapy in hormonal cancers. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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11 pages, 1508 KiB

Open AccessArticle

Epidemiological Characteristics and Survival in Patients with De Novo Metastatic Prostate Cancer

by Carlo Cattrini, Davide Soldato, Alessandra Rubagotti, Linda Zinoli, Elisa Zanardi, Paola Barboro, Carlo Messina, Elena Castro, David Olmos and Francesco Boccardo

Cancers 2020, 12(10), 2855; https://doi.org/10.3390/cancers12102855 - 3 Oct 2020

Cited by 16 | Viewed by 3948

Abstract

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results [...] Read more.

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results (SEER) Research Data (2000–2017) were analyzed using the SEER*Stat software. The Kaplan–Meier method and Cox regression were used. Patients with de novo mPCa were allocated to three cohorts based on the year of diagnosis: A (2000–2003), B (2004–2010), and C (2011–2014). The maximum follow-up was fixed to 5 years. Overall, 26,434 patients were included. Age, race, and metastatic stage (M1) significantly affected OS and CSS. After adjustment for age and race, patients in Cohort C showed a 9% reduced risk of death (hazard ratio (HR): 0.91 (95% confidence interval [CI] 0.87–0.95), p < 0.001) and an 8% reduced risk of cancer-specific death (HR: 0.92 (95% CI 0.88–0.96), p < 0.001) compared with those in Cohort A. After adjustment for age, race, and metastatic stage, patients in Cohort C showed an improvement in OS and CSS compared with Cohort B (HR: 0.94 (95% CI 0.91–0.97), p = 0.001; HR: 0.89 (95% CI 0.85–0.92), p < 0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between Cohorts B and C. In conclusion, the real-world survival of de novo mPCa remains poor, with a median OS and CSS improvement of only 4 months in the latest years. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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13 pages, 720 KiB

Open AccessArticle

Analysis of CXCL9, PD1 and PD-L1 mRNA in Stage T1 Non-Muscle Invasive Bladder Cancer and Their Association with Prognosis

by Jennifer Kubon, Danijel Sikic, Markus Eckstein, Veronika Weyerer, Robert Stöhr, Angela Neumann, Bastian Keck, Bernd Wullich, Arndt Hartmann, Ralph M. Wirtz, Helge Taubert and Sven Wach

Cancers 2020, 12(10), 2794; https://doi.org/10.3390/cancers12102794 - 29 Sep 2020

Cited by 16 | Viewed by 2932

Abstract

Non-muscle invasive bladder cancer (NMIBC), which is characterized by a recurrence rate of approximately 30% and very long treatment times, remains a major unresolved problem for patients and the health care system. The immunological interplay between tumor cells and the immune environment is [...] Read more.

Non-muscle invasive bladder cancer (NMIBC), which is characterized by a recurrence rate of approximately 30% and very long treatment times, remains a major unresolved problem for patients and the health care system. The immunological interplay between tumor cells and the immune environment is important for tumor development. Therefore, we analyzed the mRNA of three immune markers, CXCL9, PD1 and PD-L1, in NMIBC by qRT-PCR. The results were subsequently correlated with clinicopathological parameters and prognostic data. Altogether, as expected, higher age was an independent prognostic factor for overall survival (OS) and disease-specific survival (DSS), but not for recurrence-free survival (RFS). Lower CXCL9 mRNA was observed in multivariate Cox’s regression analysis to be an independent prognostic parameter for reduced OS (relative risk; RR = 2.08; p = 0.049), DSS (RR = 4.49; p = 0.006) and RFS (RR = 2.69; p = 0.005). In addition, PD-L1 mRNA was an independent prognostic factor for DSS (RR = 5.02; p = 0.042) and RFS (RR = 2.07; p = 0.044). Moreover, in univariate Cox’s regression analysis, the stratification of patients revealed that low CXCL9 or low PD1 mRNA was associated with reduced RFS in the younger patient group (≤71 years), but not in the older patient group (>71 years). In addition, low CXCL9 or low PD-L1 was associated with shorter RFS in patients with higher tumor cell proliferation and in patients without instillation therapy. In conclusion, the characterization of mRNA levels of immune markers differentiates NIMBC patients with respect to prognosis. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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15 pages, 883 KiB

Open AccessArticle

Dual-Time Point [⁶⁸Ga]Ga-PSMA-11 PET/CT Hybrid Imaging for Staging and Restaging of Prostate Cancer

by Manuela A. Hoffmann, Hans-Georg Buchholz, Helmut J Wieler, Florian Rosar, Matthias Miederer, Nicolas Fischer and Mathias Schreckenberger

Cancers 2020, 12(10), 2788; https://doi.org/10.3390/cancers12102788 - 28 Sep 2020

Cited by 27 | Viewed by 2949

Abstract

Routine [⁶⁸Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [...] Read more.

Routine [⁶⁸Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [⁶⁸Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher (p < 0.001) comparing early and late PET/CT. High positivity rates from routine [⁶⁸Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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11 pages, 1164 KiB

Open AccessArticle

The Role of Daily Adaptive Stereotactic MR-Guided Radiotherapy for Renal Cell Cancer

by Shyama U. Tetar, Omar Bohoudi, Suresh Senan, Miguel A. Palacios, Swie S. Oei, Antoinet M. van der Wel, Berend J. Slotman, R. Jeroen A. van Moorselaar, Frank J. Lagerwaard and Anna M. E. Bruynzeel

Cancers 2020, 12(10), 2763; https://doi.org/10.3390/cancers12102763 - 25 Sep 2020

Cited by 35 | Viewed by 4175

Abstract

Novel magnetic-resonance-guided radiotherapy (MRgRT) permits real-time soft-tissue visualization, respiratory-gated delivery with minimal safety margins, and time-consuming daily plan re-optimisation. We report on early clinical outcomes of MRgRT and routine plan re-optimization for large primary renal cell cancer (RCC). Thirty-six patients were treated with [...] Read more.

Novel magnetic-resonance-guided radiotherapy (MRgRT) permits real-time soft-tissue visualization, respiratory-gated delivery with minimal safety margins, and time-consuming daily plan re-optimisation. We report on early clinical outcomes of MRgRT and routine plan re-optimization for large primary renal cell cancer (RCC). Thirty-six patients were treated with MRgRT in 40 Gy/5 fractions. Prior to each fraction, re-contouring of tumor and normal organs on a pretreatment MR-scan allowed daily plan re-optimization. Treatment-induced toxicity and radiological responses were scored, which was followed by an offline analysis to evaluate the need for such daily re-optimization in 180 fractions. Mean age and tumor diameter were 78.1 years and 5.6 cm, respectively. All patients completed MRgRT with an average fraction duration of 45 min. Local control (LC) and overall survival rates at one year were 95.2% and 91.2%. No grade ≥3 toxicity was reported. Plans without re-optimization met institutional radiotherapy constraints in 83.9% of 180 fractions. Thus, daily plan re-optimization was required for only a minority of patients, who can be identified upfront by a higher volume of normal organs receiving 25 Gy in baseline plans. In conclusion, stereotactic MRgRT for large primary RCC showed low toxicity and high LC, while daily plan re-optimization was required only in a minority of patients. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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28 pages, 4290 KiB

Open AccessArticle

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

by Megan Crumbaker, Eva K. F. Chan, Tingting Gong, Niall Corcoran, Weerachai Jaratlerdsiri, Ruth J. Lyons, Anne-Maree Haynes, Anna A. Kulidjian, Anton M. F. Kalsbeek, Desiree C. Petersen, Phillip D. Stricker, Christina A. M. Jamieson, Peter I. Croucher, Christopher M. Hovens, Anthony M. Joshua and Vanessa M. Hayes

Cancers 2020, 12(5), 1178; https://doi.org/10.3390/cancers12051178 - 7 May 2020

Cited by 7 | Viewed by 5162

Abstract

Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for [...] Read more.

Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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19 pages, 7137 KiB

Open AccessArticle

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

by Juan Li, Baotong Zhang, Mingcheng Liu, Xing Fu, Xinpei Ci, Jun A, Changying Fu, Ge Dong, Rui Wu, Zhiqian Zhang, Liya Fu and Jin-Tang Dong

Cancers 2020, 12(3), 748; https://doi.org/10.3390/cancers12030748 - 21 Mar 2020

Cited by 16 | Viewed by 4424

Abstract

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. [...] Read more.

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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20 pages, 4191 KiB

Open AccessArticle

Role of Microtubule-Associated Protein 1b in Urothelial Carcinoma: Overexpression Predicts Poor Prognosis

by Tsu-Ming Chien, Ti-Chun Chan, Steven Kuan-Hua Huang, Bi-Wen Yeh, Wei-Ming Li, Chun-Nung Huang, Ching-Chia Li, Wen-Jeng Wu and Chien-Feng Li

Cancers 2020, 12(3), 630; https://doi.org/10.3390/cancers12030630 - 9 Mar 2020

Cited by 19 | Viewed by 3183

Abstract

We sought to examine the relationship between microtubule-associated proteins (MAPs) and the prognosis of urothelial carcinoma by assessing the microtubule bundle formation genes using a reappraisal transcriptome dataset of urothelial carcinoma (GSE31684). The result revealed that microtubule-associated protein 1b (MAP1B) is [...] Read more.

We sought to examine the relationship between microtubule-associated proteins (MAPs) and the prognosis of urothelial carcinoma by assessing the microtubule bundle formation genes using a reappraisal transcriptome dataset of urothelial carcinoma (GSE31684). The result revealed that microtubule-associated protein 1b (MAP1B) is the most significant upregulated gene related to cancer progression. Real-time reverse-transcription polymerase chain reaction was used to measure MAP1B transcription levels in urothelial carcinoma of the upper tract (UTUC) and the bladder (UBUC). Immunohistochemistry was conducted to detect MAP1B protein expression in 340 UTUC and 295 UBUC cases. Correlations of MAP1B expression with clinicopathological status, disease-specific survival, and metastasis-free survival were completed. To assess the oncogenic functions of MAP1B, the RTCC1 and J82 cell lines were stably silenced against their endogenous MAP1B expression. Study findings indicated that MAP1B overexpression was associated with adverse clinical features and could independently predict unfavorable prognostic effects, indicating its theranostic value in urothelial carcinoma. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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20 pages, 3395 KiB

Open AccessArticle

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

by Matthias Schnetz, Julia K. Meier, Claudia Rehwald, Christina Mertens, Anja Urbschat, Elisa Tomat, Eman A. Akam, Patrick Baer, Frederik C. Roos, Bernhard Brüne and Michaela Jung

Cancers 2020, 12(3), 530; https://doi.org/10.3390/cancers12030530 - 25 Feb 2020

Cited by 25 | Viewed by 4555

Abstract

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role [...] Read more.

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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Review

Jump to: Editorial, Research, Other

13 pages, 3176 KiB

Open AccessFeature PaperReview

Unusual Faces of Bladder Cancer

by Claudia Manini and José I. López

Cancers 2020, 12(12), 3706; https://doi.org/10.3390/cancers12123706 - 10 Dec 2020

Cited by 6 | Viewed by 4168

Abstract

The overwhelming majority of bladder cancers are transitional cell carcinomas. Albeit mostly monotonous, carcinomas in the bladder may occasionally display a broad spectrum of histological features that should be recognized by pathologists because some of them represent a diagnostic problem and/or lead prognostic [...] Read more.

The overwhelming majority of bladder cancers are transitional cell carcinomas. Albeit mostly monotonous, carcinomas in the bladder may occasionally display a broad spectrum of histological features that should be recognized by pathologists because some of them represent a diagnostic problem and/or lead prognostic implications. Sometimes these features are focal in the context of conventional transitional cell carcinomas, but some others are generalized across the tumor making its recognition a challenge. For practical purposes, the review distributes the morphologic spectrum of changes in architecture and cytology. Thus, nested and large nested, micropapillary, myxoid stroma, small tubules and adenoma nephrogenic-like, microcystic, verrucous, and diffuse lymphoepithelioma-like, on one hand, and plasmacytoid, signet ring, basaloid-squamous, yolk-sac, trophoblastic, rhabdoid, lipid/lipoblastic, giant, clear, eosinophilic (oncocytoid), and sarcomatoid, on the other, are revisited. Key histological and immunohistochemical features useful in the differential diagnosis are mentioned. In selected cases, molecular data associated with the diagnosis, prognosis, and/or treatment are also included. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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20 pages, 3465 KiB

Open AccessReview

Consensus Definition and Prediction of Complexity in Transurethral Resection or Bladder Endoscopic Dissection of Bladder Tumours

by Mathieu Roumiguié, Evanguelos Xylinas, Antonin Brisuda, Maximillian Burger, Hugh Mostafid, Marc Colombel, Marek Babjuk, Joan Palou Redorta, Fred Witjes and Bernard Malavaud

Cancers 2020, 12(10), 3063; https://doi.org/10.3390/cancers12103063 - 20 Oct 2020

Cited by 8 | Viewed by 2633

Abstract

Ten senior urologists were interrogated to develop a predictive model based on factors from which they could anticipate complex transurethral resection of bladder tumours (TURBT). Complexity was defined by consensus. Panel members then used a five-point Likert scale to grade those factors that, [...] Read more.

Ten senior urologists were interrogated to develop a predictive model based on factors from which they could anticipate complex transurethral resection of bladder tumours (TURBT). Complexity was defined by consensus. Panel members then used a five-point Likert scale to grade those factors that, in their opinion, drove complexity. Consensual factors were highlighted through two Delphi rounds. Respective contributions to complexity were quantitated by the median values of their scores. Multivariate analysis with complexity as a dependent variable tested their independence in clinical scenarios obtained by random allocation of the factors. The consensus definition of complexity was “any TURBT/En-bloc dissection that results in incomplete resection and/or prolonged surgery (>1 h) and/or significant (Clavien-Dindo ≥ 3) perioperative complications”. Logistic regression highlighted five domains as independent predictors: patient’s history, tumour number, location, and size and access to the bladder. Receiver operating characteristic (ROC) analysis confirmed good discrimination (AUC = 0.92). The sum of the scores of the five domains adjusted to their regression coefficients or Bladder Complexity Score yielded comparable performance (AUC = 0.91, C-statistics, p = 0.94) and good calibration. As a whole, preoperative factors identified by expert judgement were organized to quantitate the risk of a complex TURBT, a crucial requisite to personalise patient information, adapt human and technical resources to individual situations and address TURBT variability in clinical trials. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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26 pages, 1282 KiB

Open AccessFeature PaperReview

Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research

by Sirin Saranyutanon, Sachin Kumar Deshmukh, Santanu Dasgupta, Sachin Pai, Seema Singh and Ajay Pratap Singh

Cancers 2020, 12(9), 2651; https://doi.org/10.3390/cancers12092651 - 17 Sep 2020

Cited by 32 | Viewed by 10225

Abstract

We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to [...] Read more.

We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to be complex, and histological findings often do not provide an accurate assessment of disease aggressiveness and future course. Moreover, we also witness tremendous racial disparity in prostate cancer incidence and clinical outcomes necessitating a deeper understanding of molecular and mechanistic bases of prostate cancer. Biological research heavily relies on model systems that can be easily manipulated and tested under a controlled experimental environment. Over the years, several cancer cell lines have been developed representing diverse molecular subtypes of prostate cancer. In addition, several animal models have been developed to demonstrate the etiological molecular basis of the prostate cancer. In recent years, patient-derived xenograft and 3-D culture models have also been created and utilized in preclinical research. This review is an attempt to succinctly discuss existing information on the cellular and molecular progression of prostate cancer. We also discuss available model systems and their tested and potential utility in basic and preclinical prostate cancer research. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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21 pages, 681 KiB

Open AccessReview

Angiogenesis Inhibition in Prostate Cancer: An Update

by Chandrani Sarkar, Sandeep Goswami, Sujit Basu and Debanjan Chakroborty

Cancers 2020, 12(9), 2382; https://doi.org/10.3390/cancers12092382 - 23 Aug 2020

Cited by 36 | Viewed by 6624

Abstract

Prostate cancer (PCa), like all other solid tumors, relies on angiogenesis for growth, progression, and the dissemination of tumor cells to other parts of the body. Despite data from in vitro and in vivo preclinical studies, as well as human specimen studies indicating [...] Read more.

Prostate cancer (PCa), like all other solid tumors, relies on angiogenesis for growth, progression, and the dissemination of tumor cells to other parts of the body. Despite data from in vitro and in vivo preclinical studies, as well as human specimen studies indicating the crucial role played by angiogenesis in PCa, angiogenesis inhibition in clinical settings has not shown significant benefits to patients, thus challenging the inclusion and usefulness of antiangiogenic agents for the treatment of PCa. However, one of the apparent reasons why these antiangiogenic agents failed to meet expectations in PCa can be due to the choice of the antiangiogenic agents, because the majority of these drugs target vascular endothelial growth factor-A (VEGFA) and its receptors. The other relevant causes might be inappropriate drug combinations, the duration of treatment, and the method of endpoint determination. In this review, we will first discuss the role of angiogenesis in PCa growth and progression. We will then summarize the different angiogenic growth factors that influence PCa growth dynamics and review the outcomes of clinical trials conducted with antiangiogenic agents in PCa patients and, finally, critically assess the current status and fate of antiangiogenic therapy in this disease. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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17 pages, 2244 KiB

Open AccessReview

Applications of Artificial Intelligence to Prostate Multiparametric MRI (mpMRI): Current and Emerging Trends

by Michelle D. Bardis, Roozbeh Houshyar, Peter D. Chang, Alexander Ushinsky, Justin Glavis-Bloom, Chantal Chahine, Thanh-Lan Bui, Mark Rupasinghe, Christopher G. Filippi and Daniel S. Chow

Cancers 2020, 12(5), 1204; https://doi.org/10.3390/cancers12051204 - 11 May 2020

Cited by 41 | Viewed by 6076

Abstract

Prostate carcinoma is one of the most prevalent cancers worldwide. Multiparametric magnetic resonance imaging (mpMRI) is a non-invasive tool that can improve prostate lesion detection, classification, and volume quantification. Machine learning (ML), a branch of artificial intelligence, can rapidly and accurately analyze mpMRI [...] Read more.

Prostate carcinoma is one of the most prevalent cancers worldwide. Multiparametric magnetic resonance imaging (mpMRI) is a non-invasive tool that can improve prostate lesion detection, classification, and volume quantification. Machine learning (ML), a branch of artificial intelligence, can rapidly and accurately analyze mpMRI images. ML could provide better standardization and consistency in identifying prostate lesions and enhance prostate carcinoma management. This review summarizes ML applications to prostate mpMRI and focuses on prostate organ segmentation, lesion detection and segmentation, and lesion characterization. A literature search was conducted to find studies that have applied ML methods to prostate mpMRI. To date, prostate organ segmentation and volume approximation have been well executed using various ML techniques. Prostate lesion detection and segmentation are much more challenging tasks for ML and were attempted in several studies. They largely remain unsolved problems due to data scarcity and the limitations of current ML algorithms. By contrast, prostate lesion characterization has been successfully completed in several studies because of better data availability. Overall, ML is well situated to become a tool that enhances radiologists’ accuracy and speed. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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11 pages, 768 KiB

Open AccessPerspective

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

by Meredith Mihalopoulos, Zachary Dovey, Maddison Archer, Talia G. Korn, Kennedy E. Okhawere, William Nkemdirim, Hassan Funchess, Ami Rambhia, Nihal Mohamed, Steven A. Kaplan, Reza Mehrazin, Dara Lundon, Che-Kai Tsao, Ketan K. Badani and Natasha Kyprianou

Cancers 2020, 12(9), 2442; https://doi.org/10.3390/cancers12092442 - 28 Aug 2020

Cited by 7 | Viewed by 3439

Abstract

Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but [...] Read more.

Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but inevitably resistance develops for those with metastatic disease, and novel treatment strategies are urgently needed. Emerging molecular and epidemiological evidence suggests that quinazoline-based α1-adrenoceptor-antagonists may have both chemopreventive and direct therapeutic actions in the treatment of urological cancers, including renal cancer. In human renal cancer cell models, quinazoline-based α1-adrenoceptor antagonists were shown to significantly reduce the invasion and metastatic potential of renal tumors by targeting focal adhesion survival signaling to induce anoikis. Mechanistically these drugs overcome anoikis resistance in tumor cells by targeting cell survival regulators AKT and FAK, disrupting integrin adhesion (α5β1 and α2β1) and engaging extracellular matrix (ECM)-associated tumor suppressors. In this review, we discuss the current evidence for the use of quinazoline-based α1-adrenoceptor antagonists as novel therapies for renal cell carcinoma (RCC) and highlight their potential therapeutic action through overcoming anoikis resistance of tumor epithelial and endothelial cells in metastatic RCC. These findings provide a platform for future studies that will retrospectively and prospectively test repurposing of quinazoline-based α1-adrenoceptor-antagonists for the treatment of advanced RCC and the prevention of metastasis in neoadjuvant, adjuvant, salvage and metastatic settings. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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