Intratumoral Fibrosis in Facilitating Renal Cancer Aggressiveness: Underlying Mechanisms and Promising Targets

Intratumoral fibrosis is a histologic manifestation of fibrotic tumor stroma. The interaction between cancer cells and fibrotic stroma is intricate and reciprocal, involving dysregulations from multiple biological processes. Different components of tumor stroma are implicated via distinct manners. In the kidney, intratumoral fibrosis is frequently observed in renal cell carcinoma (RCC). However, the underlying mechanisms remain largely unclear. In this review, we recapitulate evidence demonstrating how fibrotic stroma interacts with cancer cells and mechanisms shared between RCC tumorigenesis and renal fibrogenesis, providing promising targets for future studies.

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Effect of host immunity on metastatic potential in renal cell carcinoma: the assessment of optimal in vivo models to study metastatic behavior of renal cancer cells

Tumor Biology ◽

10.1007/s13277-011-0300-4 ◽

2012 ◽

Vol 33 (2) ◽

pp. 551-559 ◽

Cited By ~ 3

Author(s):

Minoru Kobayashi ◽

Tatsuo Morita ◽

Nicole A. L. Chun ◽

Aya Matsui ◽

Masafumi Takahashi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cancer ◽

Renal Cell ◽

Metastatic Potential ◽

Host Immunity ◽

In Vivo Models ◽

Metastatic Behavior

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Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan

PLoS ONE ◽

10.1371/journal.pone.0242429 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0242429

Author(s):

Shian-Ying Sung ◽

Trang Thi Huynh Le ◽

Jin- Hua Chen ◽

Teng-Fu Hsieh ◽

Chia-Ling Hsieh

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Research Database ◽

Antihypertensive Medications ◽

Increased Risk ◽

Underlying Mechanisms

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22–2.18) or absence (HR: 2.31, 95% CI = 1.40–3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

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The Significance of INHBE Expression in the Cancer Cells of Clear-Cell Renal Cell Carcinoma

Urologia Internationalis ◽

10.1159/000518161 ◽

2021 ◽

pp. 1-11

Author(s):

Zi-Bin Xu ◽

Mei-Fu Gan ◽

Hong-Yuan Yu ◽

Li-Cai Mo ◽

Yu-Hui Xia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Tumor Tissue ◽

Transforming Growth Factor ◽

Clear Cell ◽

Tumor Promoter ◽

Sequencing Data ◽

Cell Renal Cell Carcinoma

Background: Activins and inhibins are structurally related dimeric glycoprotein hormones belonging to the transforming growth factor-β superfamily but whether they are also involved in malignancy is far from clear. No study has reported the expression of INHBE in kidney cancer. The purpose of this study was to examine the expressions of INHBE in the tumor tissue of patients with clear-cell renal cell carcinoma (ccRCC) and to explore the pathologic significance. Methods: The INHBE mRNA expression in the tumor tissue of ccRCC patients was analyzed by using RNA sequencing data from the TCGA database. To examine the expression of inhibin βE protein, 241 ccRCC patients were recruited and immunohistochemistry was performed on the tumor tissue of these patients along with 39 normal renal samples. The association between the inhibin βE expression level and patient’s clinicopathological indices was evaluated. Results: In the normal renal tissue, inhibin βE was found to be expressed mainly by renal tubular epithelial cells. In the tumor tissue, inhibin βE was expressed mainly in cancer cells. The expressions of INHBE mRNA and protein in the tumor tissue of ccRCC patients increased significantly compared with those in normal renal samples. There was a significant correlation between the level of inhibin βE in the tumor tissue and tumor grade. Patients with a lower inhibin βE expression in the tumor tissue were found to have a longer overall survival and disease-specific survival. Conclusions: INHBE might be involved in the pathogenesis of ccRCC and function as a tumor promoter.

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Combining differential expression, chromosomal and pathway analyses for the molecular characterization of renal cell carcinoma

Canadian Urological Association Journal ◽

10.5489/cuaj.64 ◽

2012 ◽

Vol 1 (2S) ◽

Cited By ~ 1

Author(s):

Kyle A. Furge ◽

Karl Dykema ◽

David Petillo ◽

Michael Westphal ◽

Zhongfa Zhang ◽

...

Keyword(s):

Gene Expression ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Gene Expression Profiling ◽

Cancer Cells ◽

Expression Profiling ◽

Renal Cell ◽

Molecular Signatures ◽

Genetic Makeup ◽

Papillary Rcc

Using high-throughput gene-expression profiling technology, we can now gaina better understanding of the complex biology that is taking place in cancer cells. This complexity is largely dictated by the abnormal genetic makeup ofthe cancer cells. This abnormal genetic makeup can have profound effectson cellular activities such as cell growth, cell survival and other regulatory processes. Based on the pattern of gene expression, or molecular signatures of the tumours, we can distinguish or subclassify different types of cancers according to their cell of origin, behaviour, and the way they respond to therapeuticagents and radiation. These approaches will lead to better molecularsubclassification of tumours, the basis of personalized medicine. We have, todate, done whole-genome microarray gene-expression profiling on several hundredsof kidney tumours. We adopt a combined bioinformatic approach, based on an integrative analysis of the gene-expression data. These data are used toidentify both cytogenetic abnormalities and molecular pathways that are deregulatedin renal cell carcinoma (RCC). For example, we have identified the deregulationof the VHL-hypoxia pathway in clear-cell RCC, as previously known,and the c-Myc pathway in aggressive papillary RCC. Besides the more commonclear-cell, papillary and chromophobe RCCs, we are currently characterizingthe molecular signatures of rarer forms of renal neoplasia such ascarcinoma of the collecting ducts, mixed epithelial and stromal tumours, chromosomeXp11 translocations associated with papillary RCC, renal medullarycarcinoma, mucinous tubular and spindle-cell carcinoma, and a group of unclassified tumours. Continued development and improvement in the field of molecular profiling will better characterize cancer and provide more accurate diagnosis, prognosis and prediction of drug response.

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Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

Metabolites ◽

10.3390/metabo10120509 ◽

2020 ◽

Vol 10 (12) ◽

pp. 509

Author(s):

Giuseppe Lucarelli ◽

Matteo Ferro ◽

Davide Loizzo ◽

Cristina Bianchi ◽

Daniela Terracciano ◽

...

Keyword(s):

Fatty Acids ◽

Renal Cell Carcinoma ◽

Lipid Metabolism ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Chemotherapy Resistance ◽

Neoplastic Tissue ◽

Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

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Circular RNA circMTO1 Suppresses RCC Cancer Cell Progression via miR9/LMX1A Axis

Technology in Cancer Research & Treatment ◽

10.1177/1533033820914286 ◽

2020 ◽

Vol 19 ◽

pp. 153303382091428

Author(s):

Kecheng Li ◽

Cheng-Liang Wan ◽

Yan Guo

Keyword(s):

Renal Cell Carcinoma ◽

Cell Proliferation ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cancer ◽

Renal Cell ◽

Target Genes ◽

Cell Function ◽

Circular Rnas ◽

Promoting Effect

Renal cell carcinoma is one of the most common kidney cancer, which accounts almost 90% of the adult renal malignancies worldwide. In recent years, a new class of endogenous noncoding RNAs, circular RNAs, exert important roles in cell function and certain types of pathological responses, especially in cancers, generally by acting as a microRNA sponge. Circular RNAs could act as sponge to regulate the microRNA and the target genes. However, the knowledge about circular RNAs in renal cell carcinoma remains unclear so far. In the research, we selected a highly expressed novel circular RNAs named circMTO1 in renal cell carcinomas. We investigated the roles of circMTO1 and found that circMTO1 overexpression could suppress cell proliferation and metastases in both A497 and 786-O renal cancer cells, while silencing of circMTO1 could promote the progression in SN12C and OS-RC-2 renal cancer cells. The study showed that circMTO1 acted as miR9 and miR223 sponge and inhibited their levels. Furthermore, silencing of circMTO1 in renal cell carcinoma could downregulate LMX1A, the target of miR-9, resulting in the promotion of renal cell carcinoma cell proliferation and invasion. In addition, LMX1A expression suppression induced by transfection of miR9 mimics confirmed that miR9 exerted its function in renal cell carcinoma by regulating LMX1A expression. What’s more, miR9 inhibitor and LMX1A overexpression could block the tumor-promoting effect of circMTO1 silencing. In conclusion, circMTO1 suppresses renal cell carcinoma progression by circMTO1/miR9/ LMX1A, indicating that circMTO1 may be a potential target in renal cell carcinoma therapy.

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Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma

Oncotarget ◽

10.18632/oncotarget.25102 ◽

2018 ◽

Vol 9 (28) ◽

pp. 20058-20074 ◽

Cited By ~ 8

Author(s):

Lucile Broncy ◽

Basma Ben Njima ◽

Arnaud Méjean ◽

Christophe Béroud ◽

Khaled Ben Romdhane ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Genetic Analysis ◽

Cell Carcinoma ◽

Single Cell ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Circulating Cancer Cells

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CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p

Molecular Cancer ◽

10.1186/s12943-019-0997-z ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 27

Author(s):

Lu Wang ◽

Guang Yang ◽

Danfeng Zhao ◽

Jiaqi Wang ◽

Yang Bai ◽

...

Keyword(s):

Stem Cells ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Lung Metastasis ◽

Renal Cell ◽

Clear Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

Abstract Background Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. Methods The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. Results CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ᅟ

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Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21145042 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5042

Author(s):

Seon-Hyeong Lee ◽

Joon Hee Kang ◽

Ji Sun Ha ◽

Jae-Seon Lee ◽

Su-Jin Oh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Extracellular Matrix ◽

Endothelial Cells ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Nuclear Translocation ◽

Xenograft Model ◽

Transglutaminase 2 ◽

P300 Binding

Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular matrix, and endothelial cells. TGase 2 stabilizes VEGF in the extracellular matrix and promotes VEGFR-2 nuclear translocation in endothelial cells. However, the role of TGase 2 in angiogenesis in the cancer cell domain remains unclear. Hypoxia-inducible factor (HIF)-1α-mediated VEGF production underlies the induction of angiogenesis in cancer cells. In this study, we show that p53 downregulated HIF-1α in RCC, and p53 overexpression decreased VEGF production. Increased TGase 2 promoted angiogenesis by inducing p53 degradation, leading to the activation of HIF-1α. The interaction of HIF-1α and p53 with the cofactor p300 is required for stable transcriptional activation. We found that TGase 2-mediated p53 depletion increased the availability of p300 for HIF-1α-p300 binding. A preclinical xenograft model suggested that TGase 2 inhibition can reverse angiogenesis in RCC.

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