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Fructose-1,6-bisphosphatase is shown to be depleted in clear cell renal cell carcinoma (ccRCC) and inhibits ccRCC progression by antagonizing glycolytic flux in renal tubular epithelial cells and by restraining cell proliferation, glycolysis, and the pentose phosphate pathway in von Hippel–Lindau-protein-deficient ccRCC cells by blocking hypoxia-inducible factor function. Carcinoma inhibited by fructose-1,6-bisphosphatase von Hippel–Lindau mutations occur in the vast majority of clear cell renal cell carcinoma (ccRCC) tumours, and these mutations result in stabilization of hypoxia-inducible factors. But this is not sufficient to cause the typical metabolic alterations found in ccRCC, nor sufficient for tumour formation. This paper reports that fructose-1,6-bisphosphatase (FBP1) was uniformly depleted in all of more than six hundred ccRCC tumours examined. FBP1 is shown to inhibit renal carcinoma progression through two different mechanisms. First, the enzyme antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, and this inhibits any potential 'Warburg effect'. Second, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in ccRCC cells deficient in the von Hippel–Lindau protein (pVHL) by blocking nuclear hypoxia-inducible factor function. Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer 1 , is characterized by elevated glycogen levels and fat deposition 2 . These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) 3 secondary to von Hippel–Lindau ( VHL ) mutations that occur in over 90% of ccRCC tumours 4 . However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation 5 , suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others) 6 , 7 , 8 , 9 , indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) 10 is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients 11 . Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin 12 , thereby inhibiting a potential Warburg effect 13 , 14 . Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours 6 , 7 , 15 .

Renal cell carcinoma accounts for a significant number of kidney malignancy-related fatalities globally. Perirenal Fat Thickness (PRFT) may indicate a state of nutritional excess in patients, which is potentially directly linked to both the incidence and prognosis of kidney cancer. This study investigated the association between perirenal fat thickness (PRFT) and overall survival (OS), as well as the predictive value of PRFT for postoperative estimated glomerular filtration rate (eGFR) in patients with renal cell carcinoma (RCC). A retrospective cohort of 1647 RCC patients from 2014 to 2021 was analyzed, divided into radical nephrectomy (RN) and partial nephrectomy (PN) groups. Preoperative measurements included visceral fat area, PRFT, and subcutaneous fat area. Kaplan-Meier curves compared OS between high and low PRFT groups, while Cox regression analyses identified prognostic factors for OS, and linear regression analyses assessed predictors of postoperative eGFR. PRFT significantly influenced OS in RN patients in univariate analysis (HR: 0.32; 95% CI: 0.19–0.52; P  < 0.001), but not in PN patients. After adjusting for covariates such as age, sex, sarcomatoid features, necrosis, T stage, Fuhrman grade, smoking status, subcutaneous adipose tissue, and BMI, PRFT remained an independent risk factor for OS (HR: 0.56; 95% CI: 0.33–0.96; P  < 0.001). Kaplan-Meier analysis showed that higher PRFT was associated with improved OS in RN patients. Univariate linear regression revealed that high PRFT correlated with reduced postoperative eGFR in both RN (β = -0.2, P  = 0.002) and PN (β = -0.34, P  < 0.001) groups; however, this correlation was not significant after multivariate adjustment. In conclusion, Low PRFT is independently associated with higher mortality in RCC patients undergoing RN. High PRFT is associated with reduced postoperative eGFR in initial analyses, but this association was not significant in multivariate analysis.

Background Stereotactic ablative body radiotherapy (SABR) is a non-invasive alternative to surgery to control primary renal cell cancer (RCC) in patients that are medically inoperable or at high-risk of post-surgical dialysis. The objective of the FASTRACK II clinical trial is to investigate the efficacy of SABR for primary RCC. Methods FASTRACK II is a single arm, multi-institutional phase II study. Seventy patients will be recruited over 3 years and followed for a total of 5 years. Eligible patients must have a biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, have ECOG performance ≤2 and be medically inoperable, high risk or decline surgery. Radiotherapy treatment planning is undertaken using four dimensional CT scanning to incorporate the impact of respiratory motion. Treatment must be delivered using a conformal or intensity modulated technique including IMRT, VMAT, Cyberknife or Tomotherapy. The trial includes two alternate fractionation schedules based on tumour size: for tumours ≤4 cm in maximum diameter a single fraction of 26Gy is delivered; and for tumours > 4 cm in maximum diameter 42Gy in three fractions is delivered. The primary outcome of the study is to estimate the efficacy of SABR for primary RCC. Secondary objectives include estimating tolerability, characterising overall survival and cancer specific survival, estimating the distant failure rate, describing toxicity and renal function changes after SABR, and assessment of cost-effectiveness of SABR compared with current therapies. Discussion The present study design allows for multicentre prospective validation of the efficacy of SABR for primary RCC that has been observed from prior single institutional and retrospective series. The study also allows assessment of treatment related toxicity, overall survival, cancer specific survival, freedom from distant failure and renal function post therapy. Trial registration Clinicaltrials.gov NCT02613819 , registered Nov 25th 2015.

Background: Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. Methods: Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. Results: Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m −2 . Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m −2 experienced more DLTs ( P =0.01; odds ratio=4.1; 95% CI: (1.3–13.3)), more cumulative grade 2 or 3 toxicities ( P =0.008), more grade 3 toxicities ( P =0.04) and more acute vascular toxicities ( P =0.009). Conclusion: Patients with sarcopenia and a BMI<25 kg m −2 experienced significantly more DLTs during the first cycle of treatment.

PurposeTo compare the outcomes of PN to those of RN in very elderly patients treated for clinically localized renal tumor.Patients and methodsA purpose-built multi-institutional international database (RESURGE project) was used for this retrospective analysis. Patients over 75 years old and surgically treated for a suspicious of localized renal with either PN or RN were included in this database. Surgical, renal function and oncological outcomes were analyzed. Propensity scores for the predicted probability to receive PN in each patient were estimated by logistic regression models. Cox proportional hazard models were estimated to determine the relative change in hazard associated with PN vs RN on overall mortality (OM), cancer-specific mortality (CSM) and other-cause mortality (OCM).ResultsA total of 613 patients who underwent RN were successfully matched with 613 controls who underwent PN. Higher overall complication rate was recorded in the PN group (33% vs 25%; p = 0.01). Median follow-up for the entire cohort was 35 months (interquartile range [IQR] 13–63 months). There was a significant difference between RN and PN in median decline of eGFR (39% vs 17%; p < 0.01). PN was not correlated with OM (HR = 0.71; p = 0.56), OCM (HR = 0.74; p = 0.5), and showed a protective trend for CSM (HR = 0.19; p = 0.05). PN was found to be a protective factor for surgical CKD (HR = 0.28; p < 0.01) and worsening of eGFR in patients with baseline CKD. Retrospective design represents a limitation of this analysis.ConclusionsAdoption of PN in very elderly patients with localized renal tumor does not compromise oncological outcomes, and it allows better functional preservation at mid-term (3-year) follow-up, relative to RN. Whether this functional benefit translates into a survival benefit remains to be determined.

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.

The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

Background Tumor immune-escape has been related to the ability of cancer cells to inhibit T cell activation and dendritic cell (DC) differentiation. We previously identified a tumor initiating population, expressing the mesenchymal marker CD105, which fulfills the criteria for definition as cancer stem cells (CD105 + CSCs) able to release extracellular vesicles (EVs) that favor tumor progression and metastases. The aim of the present study was to compare the ability of renal CSCs and derived EVs to modulate the behavior of monocyte-derived DCs with a non-tumor initiating renal cancer cell population (CD105 - TCs) and their EVs. Methods Maturation of monocyte-derived DCs was studied in presence of CD105 + CSCs and CD105 - TCs and their derived EVs. DC differentiation experiments were evaluated by cytofluorimetric analysis. T cell proliferation and ELISA assays were performed. Monocytes and T cells were purified from peripheral blood mononuclear cells obtained from healthy donors. Results The results obtained demonstrate that both CD105 + CSCs and CD105 - TCs impaired the differentiation process of DCs from monocytes. However, the immune-modulatory effect of CD105 + CSCs was significantly greater than that of CD105 - TCs. EVs derived from CD105 + CSCs and in less extent, those derived from CD105 - TCs retained the ability to impair monocyte maturation and T cell activation. The mechanism has been mainly related to the expression of HLA-G by tumor cells and to its release in a form associated to EVs. HLA-G blockade significantly reduced the inhibitory effect of EVs on DC differentiation. Conclusions In conclusion, the results of the present study indicate that renal cancer cells and in particular CSCs and derived EVs impair maturation of DCs and T cell immune response by a mechanism involving HLA-G.

Despite recent advances in the understanding of the biology of renal cell carcinoma (RCC), successful surgical treatment and implementation of novel-targeted therapies, the prognosis for RCC patients remains poor. Late presentation, tumor heterogeneity and in particular the lack of molecular biomarkers for early detection, classification and the surveillance of RCC treatments are major obstacles. The increasing knowledge regarding the functional role of microRNAs (miRNAs) in pathophysiological processes may provide an important link to the identification of suitable therapeutic targets and diagnostic/prognostic biomarkers for RCC. The aim of this review was to provide new insight into the function of miRNAs in the pathogenesis of RCC and to emphasize their potential as diagnostic and prognostic markers, as well as therapeutic targets.

Emerging evidence has shown that the PIM serine/threonine kinase family, including PIM1, PIM2 and PIM3, is associated with tumour progression towards metastasis. PIM1, an attractive molecular target, has been identified as a potential prognostic biomarker for haematological and epithelial malignancies. However, to date, the potential regulatory roles and molecular mechanisms by which PIM1 affects the development and progression of cancers, including clear-cell renal-cell carcinoma (ccRCC), remain largely unknown. Herein, we present the first evidence that PIM1 is aberrantly overexpressed in human ccRCC tissues and cell lines and positively correlated with human ccRCC progression. In our study, depletion of PIM1 attenuated ccRCC cell proliferation, colony formation, migration, invasion and angiogenesis, suggesting that PIM1 expression may be a cancer-promoting event in ccRCC. Mechanistically, we observed that PIM1 could interact with Smad2 or Smad3 in the nucleus and subsequently phosphorylate Smad2 and Smad3 to induce the expression of transcription factors, including ZEB1, ZEB2, Snail1, Snail2 and Twist, to promote epithelial-mesenchymal transition (EMT). In addition, PIM1-mediated phosphorylation of c-Myc activates the expression of the above transcription factors to synergistically promote EMT but does not activate Smads. Collectively, our results demonstrate that aberrant expression of PIM1 contributes to ccRCC development and progression. Moreover, our data reveal a potential molecular mechanism in which PIM1 mediates crosstalk between signalling pathways, including different Smad proteins and c-Myc, which target downstream transcription factors (ZEB1, ZEB2, Snail1, Snail2 and Twist) to trigger EMT. Together, our data suggest that PIM1 may be a potential therapeutic target for ccRCC patients.