Targeting HSP47 for cancer treatment.

Heat shock protein 47 (HSP47) serves as an endoplasmic reticulum residing collagen-specific chaperone and plays an important role in collagen biosynthesis and structural assembly. HSP47 is encoded by the SERPINH1 gene, which is located on chromosome 11q13.5, one of the most frequently amplified regions in human cancers. The expression of HSP47 is regulated by multiple cellular factors, including cytokines, transcription factors, microRNAs, and circular RNAs. HSP47 is frequently upregulated in a variety of cancers and plays an important role in tumor progression. HSP47 promotes tumor stemness, angiogenesis, growth, epithelial-mesenchymal transition, and metastatic capacity. HSP47 also regulates the efficacy of tumor therapies, such as chemotherapy, radiotherapy, and immunotherapy. Inhibition of HSP47 expression has antitumor effects, suggesting that targeting HSP47 is a feasible strategy for cancer treatment. In this review, we highlight the function and expression of regulatory mechanisms of HSP47 in cancer progression and point out the potential development of therapeutic strategies in targeting HSP47 in the future.

Unraveling the critical role of iron-enriched sludge hydrochar in mediating the Fenton-like oxidation of triclosan.

The traditional Fenton system is subject to the low efficiency of the Fe(III)/Fe(II) conversion cycle, with significant attempts made to improve the oxidation efficiency by overcoming this hurdle. In support of this goal, iron-enriched sludge-derived hydrochar was prepared as a high-efficiency catalyst by one-step hydrothermal carbonization and its performance and mechanisms in mediating the oxidation of triclosan were explored in the present study. The hydrochar prepared at 240 °C for 4 h (HC240-4) had the highest removal of triclosan (97.0%). The removal of triclosan in the HC240-4/H2O2 system was greater than 90% in both acidic and near-neutral environments and remained as high as 83.5% after three cycles, indicating the broad pH applicability and great recycling stability of sludge-derived hydrochar in Fenton-like systems. H2O2 was activated by both persistent free radicals (PFRs; 19.7%) and iron (80.3%). The binding of Fe(III) to carboxyl decreased the electron transfer energy from H2O2 to Fe(III), making its degradation efficiency 2.6 times greater than that of the conventional Fenton reaction. The study provides a way for iron-enriched sludge utilization and reveals a role for hydrochar in promoting iron cycling and electron transfer in the Fenton reaction.

Particle size of biochar significantly regulates the chemical speciation, transformation, and ecotoxicity of cadmium in biochar.

The pyrolysis of biomass containing excessive heavy metals is likely to produce heavy metal contaminated biochar (BC). Although multiple lines of evidence indicate that higher charring temperature leads to enhanced immobilization of heavy metals in BC, we find that particle size could also play a critical role in the content of heavy metals in BC and BC ecotoxicity. Here, BC derived from cadmium (Cd) enriched rice straw was prepared at different temperatures (300-600 °C) and divided into macro-, colloidal-, and nano-sized fractions, respectively. The content and chemical forms of Cd in BC fractions as well as related algal toxicity were examined. The results show that for the same temperature BC the content of Cd followed an order of colloidal-BC > macro-BC > nano-BC; and the residual fractions of Cd significantly decreased (3.47-16.08%) while that of acid soluble and reducible fractions significantly increased (4.13-16.51% and 0.24-1.71%, respectively) with decreasing particle size of BC. Consistently, colloidal-BC exhibited the highest ecotoxicity for Scenedesmus obliquus. The acid soluble fractions of Cd in macro- and colloidal-BC played a dominating role in their algal toxicity (p < 0.05). However, the ecotoxicity of nano-BC was more dependent on the total content of Cd than specific fractions probably due to the phagocytosis by algal cells. These results indicate that the chemical forms and ecotoxicity of Cd in BC could be remarkably modified by its particle size, which has profound implications for understanding the behavior and potential risk of heavy metal contaminated BC in the environment.

Pneumomediastinum and subcutaneous emphysema secondary to dental extraction: Two case reports.

BACKGROUND: Dental extraction is a common operation in oral surgery and is usually accompanied by pain, swelling, and local infection. The application of high-speed air turbines increases the comfort of alveolar surgery and makes it more minimally-invasive. However, high-speed gas can enter the subcutaneous tissue of the face and neck or even the chest and mediastinum, which is a serious iatrogenic complication. CASE SUMMARY: We describe two cases of severe subcutaneous and mediastinal emphysema caused by high-speed turbine splitting during dental extraction. The first case involved a 34-year-old man who complained of swelling of the face, mild chest tightness, and chest pain after dental extraction. Computed tomography (CT) scan showed a large amount of gas in the neck, chest wall, and mediastinum. The second case involved a 54-year-old woman who complained of swelling and pain of the neck after dental extraction. CT showed a large amount of gas collected in the neck and mediastinum. Both of them used high-speed turbine splitting during dental extraction. CONCLUSION: High-speed turbine splitting during dental extraction may lead to severe subcutaneous and mediastinal emphysema. Dentists should carefully operate to avoid emphysema. If emphysema occurs, CT can be used to improve the diagnosis. The patient should be informed, and the complications dealt with carefully.

Nanoscale Iron trioxide catalyzes the synthesis of auxins analogs in artificial humic acids to enhance rice growth.

Humic acids (HAs), kinds of valuable active carbon, are critical for improving soil fertility. However, the majority of soils are poor in HAs, arousing the development of artificial HAs. In this study, two iron-based catalysts (nanoscale iron trioxide (nFe2O3) and FeCl3) were used to catalyze the hydrothermal humification of waste corn straw. With the help of ultra-performance liquid chromatography-mass spectrometry, we proposed the specific humification process with the action of catalysis for the first time, which is of great significance for the design, synthesis and application of artificial HAs in the future. Moreover, the growth-promoting effect and mechanisms of the artificial HAs were determined by rice planting in a greenhouse. Results showed that compared to no catalyst treatment, the FeCl3 and nFe2O3 catalysts increased the decomposition rate of macromolecular biomass by 39 and 14 %, respectively, increasing the yield of artificial HAs. During the humification process, nFe2O3 catalysts benefit the formation of many aromatic structure monomers including furfural and hydroxycaproic acids. These monomers were condensed into growth hormone analogs such as vanillin and methionine sulfoxide and were further built in the artificial HAs. Therefore, the artificial HAs from nFe2O3 catalytic treatment promoted the rice growth the best, showing that the resultant germination rate, root activity, and photosynthetic rate of rice increased by 50, 167, and 72 %, respectively; moreover, the uptake and accumulation of water and nutrient by roots as well as the contents of soluble protein and sugar of rice are also significantly increased. This could be ascribed to the upregulated expression of functional genes including OsRHL1, OsZPT5-07, OsSHR2 and OsDCL. Considering both the economic and environmental benefits, we suggested that the artificial HAs, especially that produced with the action of nFe2O3 catalysis, are promising in alleviating environmental stress from waste biomass and sustainably improving agricultural production.

Effect of root exudates on the release, surface property, colloidal stability, and phytotoxicity of dissolved black carbon.

In this study, the release of dissolved black carbon (DBC) from bulk-BC, its surface properties, colloidal stability, and oxidative stress to rice seedlings in the presence and absence of rice root exudates were compared. The bulk-BCs were prepared at 550 °C and derived from wood chips and pig manure, respectively. The release of DBC from bulk-BC was significantly enhanced (20.19-23.63%) by the introduction of root exudates, where low molecular weight organic acids played a dominating role in the dissociation of DBC from carbon skeleton. The surface properties of DBC were greatly modified by root exudates including decreases in the surface area (18.13%) and mineral contents (43.90-69.57%). The O-containing groups and graphitization were also enhanced by 11.46% and 18.65%, respectively. Meanwhile, the presence of root exudates not only reduced the colloidal stability of DBC but also lowered the intensity of free radicals (19.44-22.22%) in DBC. Consequently, the oxidative stress of DBC to rice seedlings was significantly (p < 0.05) alleviated, evidenced by reduced antioxidative enzyme activities (5.67-29.25%) and soluble protein content (15.75-46.79%) in rice plants. These results indicate that the interaction between DBC and root exudates could remarkably modify the surface properties and reactivity of DBC, which has profound implications for understanding the behavior and functions of DBC in the environment.

Early-phase insulin hypersecretion associated with weight loss outcome after LSG: a prospective cohort study in Asian patients with BMI ≥28 kg/m2.

BACKGROUND: Obesity has become a global problem that poses a serious threat to human health. Laparoscopic sleeve gastrectomy (LSG) is an effective long-term treatment. However, the weight loss of some patients after LSG is still insufficient. It is necessary to investigate the factors associated with inadequate weight loss after LSG. OBJECTIVE: The objective of this study was to explore whether preoperative insulin secretion could be associated with weight loss after LSG in patients with obesity. SETTING: This is a single-center prospective cohort study conducted in a university hospital. METHODS: Patients from a prospective database who underwent LSG were analyzed. All 178 participants underwent a 75-g oral glucose tolerance test (OGTT) to assess preoperative insulin and c-peptide secretion before LSG. The areas under the curve (AUCs) for glucose, insulin, and c-peptide were determined in the OGTT. The percentage of excess weight loss (%EWL) and the percentage of total weight loss (%TWL) were used to estimate the effect of weight loss after LSG. Regression models were used to assess the correlation between preoperative insulin and c-peptide secretion with %EWL ≥75% and TWL ≥35% at 12 months after LSG. RESULTS: The AUCs of insulin and c-peptide were significantly lower in the %EWL ≥75% and %TWL ≥35% groups at 0-30 minutes, 0-60 minutes, and 0-120 minutes during the OGTT. At 30, 60, and 120 minutes during the OGTT, c-peptide levels were significantly lower in the %EWL ≥75% group and %TWL ≥35% group. The preoperative c-peptide level at 30 minutes during the OGTT (C30) was significantly negatively correlated with %EWL (ß = -.37, P < .001) and %TWL (ß = -.28, P = .011). Univariate logistic regression analysis showed that preoperative C30 was associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative C30 had an 8-fold higher %TWL ≥35% after LSG than those with a high C30 (odds ratio: 8.41 [95% confidence interval: 1.46-48.58], P = .017). Similarly, patients with a low preoperative C30 had a 7-fold higher EWL% ≥75% after LSG than patients with a high C30 (odds ratio: 7.25 [95% confidence interval: 1.11-47.50], P = .039). CONCLUSIONS: The rate of weight loss after LSG is low among patients with preoperative hyperinsulinemia. The preoperative c-peptide level at 30 minutes during the OGTT is associated with weight loss after LSG.

PAI-1 induction during kidney injury promotes fibrotic epithelial dysfunction via deregulation of klotho, p53, and TGF-ß1-receptor signaling.

Renal fibrosis leads to chronic kidney disease, which affects over 15% of the U.S. population. PAI-1 is highly upregulated in the tubulointerstitial compartment in several common nephropathies and PAI-1 global ablation affords protection from fibrogenesis in mice. The precise contribution of renal tubular PAI-1 induction to disease progression, however, is unknown and surprisingly, appears to be independent of uPA inhibition. Human renal epithelial (HK-2) cells engineered to stably overexpress PAI-1 underwent dedifferentiation (E-cadherin loss, gain of vimentin), G2/M growth arrest (increased p-Histone3, p21), and robust induction of fibronectin, collagen-1, and CCN2. These cells are also susceptible to apoptosis (elevated cleaved caspase-3, annexin-V positivity) compared to vector controls, demonstrating a previously unknown role for PAI-1 in tubular dysfunction. Persistent PAI-1 expression results in a loss of klotho expression, p53 upregulation, and increases in TGF-ßRI/II levels and SMAD3 phosphorylation. Ectopic restoration of klotho in PAI-1-transductants attenuated fibrogenesis and reversed the proliferative defects, implicating PAI-1 in klotho loss in renal disease. Genetic suppression of p53 reversed the PA1-1-driven maladaptive repair, moreover, confirming a pathogenic role for p53 upregulation in this context and uncovering a novel role for PAI-1 in promoting renal p53 signaling. TGF-ßRI inhibition also attenuated PAI-1-initiated epithelial dysfunction, independent of TGF-ß1 ligand synthesis. Thus, PAI-1 promotes tubular dysfunction via klotho reduction, p53 upregulation, and activation of the TGF-ßRI-SMAD3 axis. Since klotho is an upstream regulator of both PAI-1-mediated p53 induction and SMAD3 signaling, targeting tubular PAI-1 expression may provide a novel, multi-level approach to the therapy of CKD.

Photochemical Transformation and Catalytic Activity of Dissolved Black Nitrogen Released from Environmental Black Carbon.

Biomass combustion results in the formation and wide distribution of black carbon (BC) in soils, wherein the dissolved fractions are among the most active components. Although the presence of dissolved black nitrogen (DBN) in BC has been identified, its environmental behavior and implication are not understood. This study investigated the photochemical transformation and catalytic activity of DBN under simulated solar irradiation. DBN is more easily transformed than dissolved BC due to its photoactive heteroaromatic N structure, and the half-life of DBN produced at 500 °C (8.6 h) is two times shorter than that of the dissolved BC counterpart (23 h). Meanwhile, solar irradiation is favorable for the homoaggregation of DBN. During irradiation, DBN generates not only reactive oxygen species (e.g., 1O2, O2-, and •OH) but also reactive nitrogen species (mainly •ON), which account for its higher photocatalytic degradation of bisphenol A than dissolved BC. These findings shed new light on the impact of heteroatoms on the phototransformation and activity of BC as well as cycling of N in terrestrial systems.

A Case of Ewing Sarcoma of the Bladder Presenting in Early Infancy.

A 6-week-old female presented with gross hematuria and was diagnosed with Ewing sarcoma of the bladder through ultrasound and cystoscopic biopsies, along with a negative metastatic workup. She was treated with transurethral resection, chemotherapy consisting of with vincristine, cycolphosphamide, doxorubicin, ifosfamide and etoposide, and partial cystectomy. After completing chemotherapy, the patient has been doing well with no evidence of disease. There have been 14 other cases, 4 pediatric, of Ewing sarcoma of the bladder reported. To our knowledge, our case is the youngest patient reported with this disease.

Nickel-catalyzed electrochemical reductive decarboxylative coupling of N-hydroxyphthalimide esters with quinoxalinones.

Herein the first example of electrochemically enabled, NiCl2-catalyzed reductive decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with quinoxalinones is reported. A range of primary, secondary, tertiary aliphatic carboxylic acids and amino acid-derived esters were tolerated well. This decarboxylative coupling allows access to structurally diverse 3-alkylated quinoxalinones in up to 91% yields.

Variety-dependent responses of rice plants with differential cadmium accumulating capacity to cadmium telluride quantum dots (CdTe QDs): Cadmium uptake, antioxidative enzyme activity, and gene expression.

The excess release of engineered nanomaterials into farmland poses a serious threat to food security. Although rice varieties exhibit substantial variation in cadmium accumulation, their responses to Cd-based nanoparticles are largely unknown. In this work, we investigated the accumulation of cadmium telluride quantum dots (CdTe QDs at 0.5, 1.0, 2.5, 5.0mg-Cd/L) in two rice varieties with different Cd accumulation capacity. It was found that 5.0mg-Cd/L of CdTe QDs had minor growth inhibition to the high-Cd-accumulating variety (T705) relative to the low-Cd-accumulating variety (X24) after 7-day exposure. The two rice varieties had comparable Cd content in roots; however, T705 exhibited higher Cd content in shoots than X24. Transmission electron and confocal laser scanning microscopic observations demonstrated that more CdTe QDs can be transported and accumulated from roots to shoots in T705. The activities and gene expression of antioxidative enzymes in leaves of T705 increased more significantly than those of X24. Our findings for the first time validated that Cd accumulation divergence exists in different rice varieties when they are exposed to Cd-based QDs, the genetic basis for which needs to be further examined.

Rac-GTPase promotes fibrotic TGF-ß1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Rac-GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF-ß1 promoted rapid Rac1-GTP loading in human kidney 2 (HK-2) human renal epithelial cells. A Rac-specific chemical inhibitor, EHT 1864, blocked TGF-ß1-induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK-2 cells, moreover, eliminated TGF-ß1-mediated non-SMAD pathway activation [e.g., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22phox knockdown abrogated free radical generation by TGF-ß1 in HK-2 cells, consistent with the role of Rac1 in NAPD(H). TGF-ß1-induced renal epithelial cytostasis was also completely bypassed by Rac1, p22phox, p47phox, and PAI-1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction-driven EGFR, p53, Rac1b, yes-associated protein/transcriptional coactivator with PDZ-binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle-treated obstructed kidneys. Thus, the Rac1-directed redox response is critical for TGF-ß1-driven epithelial dysfunction orchestrated, in part, via PAI-1 up-regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.-Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac-GTPase promotes fibrotic TGF-ß1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways.

Discovery and mechanisms of host defense to oncogenesis: targeting the ß-defensin-1 peptide as a natural tumor inhibitor.

Human beta-defensin-1 (hBD-1) is one of a number of small cationic host-defense peptides. Besides its well-known broad-spectrum antimicrobial function, hBD-1 has recently been identified as a chromosome 8p tumor-suppressor gene. The role of hBD-1 in modulating the host immune response to oncogenesis, associated with cell signaling and potential therapeutic applications, has become increasingly appreciated over time. In this study, multiple approaches were used to illustrate hBD-1 anti-tumor activities. Results demonstrate that hBD-1 peptide alters human epidermal growth factor receptor 2 (HER2) signal transduction and represses retroviral-mediated transgene expression in cancer cells. Loss of orthologous murine defense-1 (mBD1) in mice enhances nickel sulfate-induced leiomyosarcoma and causes mouse kidney cells to exhibit increased susceptibility to HPV-16 E6/7-induced neoplastic transformation. Furthermore, for the first time, a novel function of the urine-derived hBD-1 peptide was discovered to suppress bladder cancer growth and this may lead to future applications in the treatment of malignancy.

Management of pediatric head and neck rhabdomyosarcoma: A case-series of 36 patients.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric population. In 35% of cases, RMS develops in the head and neck (H&N) region, and only combined therapy is recognized as a curative treatment. However, recent advances in skull base and reconstructive surgery, along with microsurgery and endoscopic surgery, have strengthened the role of surgery as an important part of RMS treatment. In the present study, 36 pediatric RMS cases (24 males and 12 females) were analyzed after surgical treatment. The average age at diagnosis was 7 years. In total, 67% of tumors were localized in the parameningeal region. Alveolar RMS was the most common histopathological type. A total of 16 patients were treated due to disease recurrence or a previous non-radical surgical procedure, while 19 cases had inductive chemotherapy and/or radiotherapy preceding surgical treatment due to locally advanced disease. In 1 case, only diagnostic biopsy was performed. It is recommended that the management of H&N RMS is interdisciplinary from the beginning. Extensive surgical dissection in the H&N region for RMS may result in severe cosmetic defects and functional impairment; thus, these risks should be considered during treatment planning, and the surgical approach should be based on the individual characteristics of each patient.

Current approaches in identification and isolation of human renal cell carcinoma cancer stem cells.

In recent years, cancer stem cells (CSCs)/tumor initiating cells (TICs) have been identified inside different tumors. However, currently used anti-cancer therapies are mostly directed against somatic tumor cells without targeting CSCs/TICs. CSCs/TICs also gain resistance to chemotherapies/radiotherapies. For the development of efficient treatment strategies, choosing the best method for isolation and characterization of CSCs/TICs is still debated among the scientific community. In this review, we summarize recent data concerning isolation techniques for CSCs using magnetic cell sorting and flow cytometry. The review focuses on the strategies for sample preparation during flow cytometric analysis, elaborating biomarkers such as CXCR4, CD105, and CD133. In addition, functional properties characteristic of CSCs/TICs using side population selection through Hoechst 33342 dye, aldehyde dehydrogenase 1, dye-cycle violet, and rhodamine 123 are also discussed. We also include a special focus on enriching CSCs/TICs using three-dimensional cell culture models such as agarose-agarose microbeads and sphere formation.

Feasibility, efficacy and safety of tyrosine kinase inhibitor treatment in hemodialyzed patients with renal cell cancer: 10 years of experience.

AIMS: Sine efficiency of tyrosine kinase inhibitor (TKI) therapy in dialyzed patients is still unclear we aim to analyze the outcome of treatment in such cohort. PATIENTS & METHODS: We analyzed treatment outcomes of patients with clear cell renal cell carcinoma (ccRCC) with special focus on those who were also treated with hemodialysis and described treatment safety and progression-free survival of eight patients treated with TKIs and hemodialysis. DISCUSSION & CONCLUSION: Our report supports statement that TKI treatment of dialyzed patients is safe and effective. ccRCC increases risk of developing renal insufficiency as well as end-stage renal disease that require dialysis. Introduction of multitargeted receptor kinase inhibitors (TKIs), including sunitinib, sorafenib and pazopanib significantly expanded life time expectancy of metastatic renal clear cell carcinoma. The advance also applies to patients with ccRCC and end-stage renal disease who undergo dialyses.

Interleukin-6 as an emerging regulator of renal cell cancer.

BACKGROUND: Our knowledge on the molecular basis of kidney cancer metastasisis still relatively low. About 25-30% of patients suffering from clear cell renal cell carcinoma (ccRCC)present metastatic disease at the time of primary diagnosis. Only 10% of patients diagnosed with stage IV disease survive 5 years and 20-50% of patients diagnosed with localized tumor develop metastases within 3 years. High mortality of patients with this cancer is associated with a large potential for metastasis and resistance to oncologic treatments such as chemo- and radiotherapy. Literature data based on studies conducted on other types of cancers suggest that in metastatic ccRCC, the complex of interleukin-6 (IL-6) and its soluble receptor (sIL-6R; complex IL-6/sIL-6R) and the signal transduction pathway (gp130/STAT3) might play a key role in this process. PURPOSE: Therefore, in this review we focus on the role of IL-6 and its signaling pathways as a factor for development and spread of RCC. Analyzing the molecular basis of cancer spreading will enable the development of prognostic tests, evaluate individual predisposition for metastasis, and produce drugs that target metastases. As the development of effective systemic treatments evolve from advancements in molecular biology, continued studies directed at understanding the genetic and molecular complexities of this disease are critical to improve RCC treatment options.

The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis.

The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.

Future perspectives for mTOR inhibitors in renal cell cancer treatment.

Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.