Renal cell carcinoma: a review of biology and pathophysiology

Nabi, Shahzaib; Kessler, Elizabeth R.; Bernard, Brandon; Flaig, Thomas W.; Lam, Elaine T.

doi:10.12688/f1000research.13179.1

Cited by 113 publications

(108 citation statements)

References 50 publications

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“…The most common gene involved in the pathogenesis of ccRCC is the von Hippel-Lindau gene (VHL) [14]. One of the major functions of the VHL gene product is regulation of the levels of hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A and HIF2A) [15]. In ccRCC, inactivation or loss of VHL leads to aberrant accumulation of HIF proteins, which in turn results in angiogenesis, glycolysis, apoptosis, and lipid deposition in ccRCC [2,16].…”

Section: Discussionmentioning

confidence: 99%

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications

Kim¹,

Kim²,

Lim³

et al. 2020

J. Cancer

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Background: Cytochrome P-450 4A11 (CYP4A11) and peroxisome proliferator-activated receptor-α (PPARα) are expressed at high levels in renal proximal tubules, and upregulation of CYP4A11 protein levels is known to be influenced by PPAR agonists. The goal of this study was to evaluate the clinicopathological role of CYP4A11 expression in renal cell carcinoma (RCC). Methods: We performed immunohistochemical analysis of CYP4A11, CYP4A22 and PPARα and correlated the results with the clinicopathological features of RCC (n=139). Reverse transcription digital droplet polymerase chain reaction (RT-ddPCR) against CYP4A11 and CYP4A22 was also performed. Results: CYP4A11 mRNA expression levels were higher in non-neoplastic kidney tissues than in matched tumor tissues in 12 matched pairs of freshly frozen primary clear-cell RCC (ccRCC) and nontumor tissue (p=0.002). Immunohistochemical staining showed that CYP4A11 expression was significantly lower in ccRCC than in non-ccRCCs, including papillary, chromophobe, and unclassified RCCs (p<0.001). CYP4A11 expression was associated with PPARα expression, males and high nuclear histologic grades (p=0.001, p=0.018 and p<0.001). Univariate and multivariate analyses revealed that CYP4A11 expression was correlated with short overall survival (p=0.007 and p=0.010). Conclusion: These findings suggest that CYP4A11 expression is a potential poor prognostic factor of RCC. The considerable decrease in CYP4A11 expression is a predictive diagnostic factor of ccRCC, and CYP4A11 metabolism in ccRCC might be different from that in non-ccRCCs.

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Section: Discussionmentioning

confidence: 99%

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications

Kim¹,

Kim²,

Lim³

et al. 2020

J. Cancer

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“…These growth factors are currently targeted by specific inhibitors (e.g. sunitinib and pazopanib) as first-line therapy option for metastatic ccRCC 13 .…”

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confidence: 99%

CREB1 is affected by the microRNAs miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p and correlates with adverse clinicopathological features in renal cell carcinoma

Friedrich

Heimer

Stoehr

et al. 2020

Sci Rep

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The transcription factor cAMP response element-binding protein (CREB1) has been shown to be involved in diverse biological pathways including the regulation of cell proliferation, apoptosis, cell cycle progression, and metastasis. In this context, aberrant expression of CREB1 and the functional consequences are well investigated in a number of hematopoietic and solid tumors. However, CREB1 expression and underlying control mechanisms are only poorly analyzed in renal cell carcinoma (RCC). The present study confirmed a deregulation of CREB1 protein in the clear cell type of RCC (ccRCC) and analysis of in-house ccRCC cell lines suggested a post-transcriptional control. The combination of miRNA enrichment assay, in silico analysis and molecular biological approaches revealed four novel CREB1-regulating miRNAs, namely miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p. Categorizing RCC samples as CREB1 negative or positive, respectively, the expression of these miRNAs was found to be inversely correlated with CREB1 protein levels. Analyzing 453 consecutive RCC tumors by immunohistochemistry, weakly negative, but significant correlations of CREB1 with tumor stage and grade, vascular invasion (V1) and lymphovascular invasion (L1) were found. In this respect, ccRCC might differ from other solid tumors like esophageal squamous-cell carcinoma or glioma.Renal cell carcinoma (RCC) is a kidney cancer originating in the lining of proximal renal tubular epithelial cells and can be histologically subtyped into clear cell type (ccRCC, 75%), papillary (pRCC, 13-15%), chromophobe type (chRCC, 5%), and several rare subtypes 1,2 . Globally, RCC is listed as the sixth most frequently diagnosed form of cancer in men and the tenth in women, with highest rates described in North America and the Czech Republic 3,4 . Noteworthy, RCC incidence was shown to be increasing and frequently accompanied by several risk factors including smoking, hypertension, obesity, chronic analgesic use, and diabetes 5,6 . Early treatment options for RCC are quite limited and usually involve partial or complete resection of the affected kidney(s) 7 since this type of tumor is considerably resistant to chemotherapy and radiotherapy 8 . However, immunotherapy as well as biologic or targeted therapy has shown to be an efficient option for RCC treatment 9 . Thus, it is important to characterize molecular targets responsible for the formation and development of this disease. Probably best analyzed is the alteration of the tumor suppressive Von Hippel-Lindau (VHL) gene that has a crucial value in the origin and development of ccRCC and can be found to be affected in up to 90% of all ccRCC cases 10 . Situated in a complex pathway, VHL is ultimately responsible for the regulation of the transcription factors hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A, HIF2A) 11,12 . The deregulation of HIF1A and HIF2A results in the up-regulation of various growth factors like vascular endothelial growth factor (VEGF), platelet-derived growth factor beta

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“…Obesity is associated with insulin resistance and increased levels of growth factors such as insulin‐like growth factor (IGF)‐I. The IGF pathway may be especially important for clear cell RCC which is strongly related to the von Hippel–Lindau (VHL) tumour suppressor gene, which in turn helps regulate IGF‐I‐mediated cell signalling . VHL is a critical player in renal carcinogenesis, especially for clear cell type.…”

Section: Discussionmentioning

confidence: 99%

“…The IGF pathway may be especially important for clear cell RCC which is strongly related to the von Hippel-Lindau (VHL) tumour suppressor gene, which in turn helps regulate IGF-I-mediated cell signalling. 22 VHL is a critical player in renal carcinogenesis, especially for clear cell type. The VHL gene is directly related to IGF-I-mediated cell signalling, which in turn is inhibited in the presence of the intact VHL gene.…”

Section: Discussionmentioning

confidence: 99%

Overweight and obesity during adolescence increases the risk of renal cell carcinoma

Landberg

Fält

Montgomery

et al. 2019

Intl Journal of Cancer

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While overweight among adults has been linked with renal cell carcinoma (RCC) risk, little is known about the potential influence of overweight and obesity during adolescence. To ascertain if adolescent body mass index is associated with subsequent risk of RCC, we identified a cohort of 238,788 Swedish men who underwent mandatory military conscription assessment between 1969 and 1976 at a mean age of 18.5 years. At the time of conscription assessment, physical and psychological tests were performed including measurements of height and weight. Participants were followed through linkage to the Swedish Cancer Registry to identify incident diagnoses of RCC. The association between body mass index (BMI, kg/m2) at conscription assessment and subsequent RCC was evaluated using multivariable Cox regression. During a follow‐up of up to 37 years, 266 men were diagnosed with RCC. We observed a trend for higher RCC risk with increasing BMI during adolescence, where one‐unit increase in BMI conferred a 6% increased risk of RCC (95% CI 1.01–1.10). compared to normal weight men (BMI 18.5‐ < 25), men with overweight (BMI 25‐ < 30) or obesity (BMI ≥30) had hazard ratios for RCC of 1.76 (95% CI 1.16–2.67) and 2.87 (95% CI 1.26–6.25), respectively. The link between overweight/obesity and RCC appear to be already established during late adolescence. Prevention of unhealthy weight gain during childhood and adolescence may thus be a target in efforts to decrease the burden of RCC in the adult population.

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Renal cell carcinoma: a review of biology and pathophysiology

Cited by 113 publications

References 50 publications

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications

CREB1 is affected by the microRNAs miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p and correlates with adverse clinicopathological features in renal cell carcinoma

Overweight and obesity during adolescence increases the risk of renal cell carcinoma

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