Tackling of Renal Carcinogenesis in Wistar Rats by Silybum marianum Total Extract, Silymarin, and Silibinin via Modulation of Oxidative Stress, Apoptosis, Nrf2, PPARγ, NF-κB, and PI3K/Akt Signaling Pathways

The present work was designed to assess the efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally induced renal carcinogenesis in male Wistar rats and their roles in regulating oxidative stress, inflammation, apoptosis, and carcinogenesis. The diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4)-administered rats were orally treated with STE (200 mg/kg b.w.), Sm (150 mg/kg b.w.), and Sb (5 mg/kg b.w.) every other day either from the 1st week or from the 16th week of carcinogen administration to the end of 25th week. The treatments with STE, Sm, and Sb attenuated markers of toxicity in serum, decreased kidney lipid peroxidation (LPO), and significantly reinforced the renal antioxidant armory. The biochemical results were further confirmed by the histopathological alterations. The treatments also led to suppression of proinflammatory mediators such as NF-κβ, p65, Iκβα, and IL-6 in association with inhibition of the PI3K/Akt pathway. Furthermore, they activated the expressions of PPARs, Nrf2, and IL-4 in addition to downregulation of apoptotic proteins p53 and caspase-3 and upregulation of antiapoptotic mediator Bcl-2. The obtained data supply potent proof for the efficacy of STE, Sm, and Sb to counteract renal carcinogenesis via alteration of varied molecular pathways.

Pan-cancer Analysis Combining with Experiments Indicates the Sensitivity of Renal Carcinogenesis to DLGAP5 Expression

Background: Discs large-associated protein 5 (DLGAP5), a kinetochore fibers-binding protein, has been found to function as a oncoprotein in many cancers. However, its expression patterns in normal and cancer tissues across pan-cancer, as well as the cell lines, are far from clear. Methods: Data from genotype-tissue expression (GTEx) and The Cancer Genome Atlas (TCGA) was used to analyze the DLGAP5 expression in normal tissues and cancer cell lines, respectively. The analysis of DLGAP5 expression in cancer tissues and adjacent tissues was based on data from a combined TCGA and GTEx. The associations between the expression, prognosis and cancer immune infiltrates in pan-cancer were also investigated based on TCGA and Tumor Immune Estimation Resource (TIMER), respectively. Furthermore, the analysis results of ccRCC was verified using cell lines via RNAi, western blotting, and the cytological analysis.Results: The low expression levels of DLGAP5 were observed in 31 types of common human tissues, including kidney tissue. However, its expression displayed upregulation in all the 21 tested cancer cell lines, of which kidney cancer cell lines showed a minimal upregulation. As predicted, the significant overexpression of DLGAP5 occurred in at least 26 types of common cancer tissues compared with the adjacent normal tissues. Surprisingly, in three types of kidney cancer (KICH, KIRC/ccRCC, KIRP), DLGAP5 exhibited a statistically significant, but minor, overexpression among 26 types of tested cancers. Furthermore, the survival probability of some tested cancers, including kidney cancer, were significantly related to the upregulated expression of DLGAP5. In addition, among 33 types of tested cancers, KIRC/ccRCC, LGG and LIHC showed a significant positive correlation between DLGAP5 expression and immune infiltration levels. DLGAP5 expression level was also significantly positive correlated with clinical TNM stage of ccRCC patients. Regarding ccRCC tissues and the cell lines, upregulation expression of DLGAP5 was also detected. Its knockdown inhibited the cells viability and proliferation, and compromised the cells migration and invasion. Conclusions: DLGAP5 overexpression occurred in common human cancers, including the kidney cancers. Notably, ccRCC, seemed to be particularly sensitive to the expression. DLGAP5, therefore, may be as a robust independent prognostic biomarker in ccRCC diagnosis.

Targeting Strategies for Renal Cancer Stem Cell Therapy

Renal cell carcinoma (RCC) is an intractable genitourinary malignancy that accounts for approximately 4% of adult malignancies. Currently, there is no approved targeted therapy for RCC that has yielded durable remissions, and they remain palliative in intent. Emerging evidence has indicated that renal tumorigenesis and RCC treatment-resistance may originate from renal cancer stem cells (CSCs) with tumor-initiating capacity (CSC hypothesis). A better understanding of the mechanism underlying renal CSCs will help to dissect RCC heterogeneity and drug treatment efficiency, to promote more personalized and targeted therapies. In this review, we summarized the stem cell characteristics of renal CSCs. We outlined the targeting strategies and challenges associated with developing therapies that target renal CSCs angiogenesis, immunosuppression, signaling pathways, surface biomarkers, microRNAs and nanomedicine. In conclusion, CSCs are an important role in renal carcinogenesis and represent a valid target for treatment of RCC patients.

Morphological findings in frozen non-neoplastic kidney tissues of patients with kidney cancer from large-scale multicentric studies on genomics of renal cancer

Background There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Analysis of non-neoplastic tissues is a way to better understand the carcinogenesis. Methods Having access to a rich, well-annotated collection of “tumor/non-tumor” pairs of kidney cancer patients from Czech Republic, Romania, Serbia, United Kingdom, and Russia for studying genomics of kidney cancer, we aimed to analyze morphology of non-neoplastic renal tissue. By applying digital pathology, we performed microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Renal parenchyma was evaluated and scored for the interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis and arterial wall thickening, globally called chronic renal parenchymal changes. Results Moderate or severe changes was observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07–6.67) and Serbia (OR = 4.37, CI 1.20-15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characterstics and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes were 5.22 times higher for Romania and Serbia compered to Russia. Conclusion Our findings show that the frequency of chronic renal parenchymal changes in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be high. We suggest that these parenchymal changes, possibly linked to environmental exposures, may be relevant to renal carcinogenesis in these countries.

Heading Towards a Possible Rebirth of the Induced Renal Cell Carcinoma Models?

Introduction: Animal models are interesting tools to improve our knowledge of the pathophysiological processes underlying kidney cancer development. Recent advances have been made in the understanding of the genetic founding events underlying clear cell renal carcinoma. The aim of this paper was to review and discuss the characteristics of all the induced animal models of renal carcinogenesis that have been described in the scientific literature to date and to see if and how they could regain some use in the light of the latest discoveries. Methods: The authors reviewed all the papers available in PubMed regarding induced animal models of renal carcinogenesis. From this perspective, the keywords “induced”, “animal model”, and “renal cancer” were used in PubMed’s search engine. Another search was done using the keywords “induced”, “animal model”, and “kidney cancer”. PRISMA recommendations were used to develop the literature review. Results: Seventy-eight studies were included in this review. Results were presented depending on the mechanisms used to induce carcinogenesis in each model: induction by carcinogens, hormones, viral induction, or induction by other agents. Discussion focused on the possibility to rethink these different induced animal models and use them to answer new research questions. Conclusion: Many induced animal models have been developed in the past to study renal cancer. While these models seemed unable to yield new knowledge, the latest advances in the understanding of the genetics behind renal carcinogenesis could well bring the models back to the forefront.

Mechanisms of Rodent Renal Carcinogenesis Revisited

The important renal tumors that can be induced by exposure of rats to chemical carcinogens are renal tubule tumors (RTTs) derived from tubule epithelium; renal pelvic carcinoma derived from the urothelial lining of the pelvis; renal mesenchymal tumors (RMTs) derived from the interstitial connective tissue; and nephroblastoma derived from the metanephric primordia. However, almost all of our knowledge concerning mechanisms of renal carcinogenesis in the rodent pertains to the adenomas and carcinomas originating from renal tubule epithelium. Currently, nine mechanistic pathways can be identified in either the rat or mouse following chemical exposure. These include direct DNA reactivity, indirect DNA reactivity through free radical formation, multiphase bioactivation involving glutathione conjugation, mitotic disruption, sustained cell proliferation from direct cytotoxicity, sustained cell proliferation by disruption of a physiologic process (alpha 2u-globulin nephropathy), exaggerated pharmacologic response, species-dominant metabolic pathway, and chemical exacerbation of chronic progressive nephropathy. Spontaneous occurrence of RTTs in the rat will be included since one example is a confounder for interpreting kidney tumor results in chemical carcinogenicity studies in rats.