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2.
Am J Surg Pathol ; 44(8): 1031-1039, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32271189

RESUMO

Acquired cystic disease of kidney-associated renal cell carcinoma (ACD-RCC) is a distinct subtype of renal cell carcinoma with unique morphologic and clinicopathologic features. Generally, ACD-RCC is regarded as an indolent tumor; however, prognostic and outcomes data have been conflicted by the limited and relatively low number of cases with patient follow-up or adverse events. In this study, we focused on the histology of metastatic lesions and identifying prognostic factors associated with metastatic progression. From 32 cases in the cohort, 9 patients had metastasis [ACD-RCC (M+)] and 23 patients were without metastasis [ACD-RCC (M-)]. The median age of patients was 52 years; right side, n=10; left side, n=18; bilateral, n=4; median tumor size=2.6 cm; median hemodialysis duration=17 y; and the median duration of follow-up was 50 mo. Immunohistochemistry showed ACD-RCC to be racemase positive and CK7 negative to focally positive within tumor cells, with consistent positivity for renal histogenesis-associated markers (PAX8 and RCC antigen); S100A1 was a less reliable marker at metastatic sites. All metastatic ACD-RCC except 2 cases involved lymph nodes (para-aortic, renal hilar, subclavicular). Overall, 6/9 (67%) had visceral metastasis to sites including lung (n=3), liver (n=3), bone (n=5), stomach (n=1), and brain (n=1). In total, 5/9 (56%) metastatic tumors had distinctive cystic growth pattern at the metastatic site; intriguingly metastatic tumors had intrametastatic oxalate crystal deposition, a pathognomonic feature associated with primary tumors. Four of nine (44%) patients with ACD-RCC (M+) had fatal outcomes due to metastatic disease. Clinically significant adverse prognostic features associated with metastasis [median follow-up 47 mo, ACD-RCC (M+) vs. ACD-RCC (M-), 50 mo] included: duration of hemodialysis (≥20 vs. <20 y, P=0.0085) and tumor necrosis (P=0.049). Because of sufficient overlap between these parameters, the study was not able to identify parameters that would be reliable in further management strategies, in clinical settings. Our data indicate that ACD-RCC is a tumor which has distinct metastatic potential with nodal and visceral tropism and proclivity for cystic morphology at metastatic sites; this is the first report of the presence of oxalate crystals in metastatic tumors. Our data suggest that ACD-RCC patients with prolonged hemodialysis and tumoral coagulative necrosis require additional surveillance in view of the association of these parameters with metastatic progression.


Assuntos
Carcinoma de Células Renais/secundário , Doenças Renais Císticas/complicações , Falência Renal Crônica/etiologia , Neoplasias Renais/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/química , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/terapia , Cristalização , Feminino , Humanos , Japão , Doenças Renais Císticas/diagnóstico , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Neoplasias Renais/química , Neoplasias Renais/etiologia , Neoplasias Renais/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Ácido Oxálico/análise , Prognóstico , Diálise Renal , Fatores de Risco
3.
Nat Commun ; 11(1): 739, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029730

RESUMO

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease with features that vary by ethnicity. A systematic characterization of the genomic landscape of Chinese ccRCC is lacking, and features of ccRCC associated with tumor thrombus (ccRCC-TT) remain poorly understood. Here, we applied whole-exome sequencing on 110 normal-tumor pairs and 42 normal-tumor-thrombus triples, and transcriptome sequencing on 61 tumor-normal pairs and 30 primary-thrombus pairs from 152 Chinese patients with ccRCC. Our analysis reveals that a mutational signature associated with aristolochic acid (AA) exposure is widespread in Chinese ccRCC. Tumors from patients with ccRCC-TT show a higher mutational burden and genomic instability; in addition, mutations in BAP1 and SETD2 are highly enriched in patients with ccRCC-TT. Moreover, patients with/without TT show distinct molecular characteristics. We reported the integrative genomic sequencing of Chinese ccRCC and identified the features associated with tumor thrombus, which may facilitate ccRCC diagnosis, prognosis and treatment.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Trombose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aristolóquicos/toxicidade , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/etiologia , China , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Instabilidade Genômica , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Trombose/complicações , Trombose/etiologia , Sequenciamento Completo do Exoma
4.
Nutrients ; 12(1)2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31906594

RESUMO

BACKGROUND: Conclusive evidence on foods, nutrients, or dietary patterns and the risk of renal cell carcinoma (RCC) is lacking in the literature. METHODS: We considered data from an Italian hospital-based case-control study (1992-2004) on 767 incident RCC cases and 1534 controls. A posteriori dietary patterns were identified by applying principal component factor analysis on 28 nutrients derived from a 78-item food-frequency questionnaire. We estimated the odds ratios (ORs) of RCC and corresponding 95% confidence intervals (CIs) for each quartile category (compared to the lowest one) using conditional multiple logistic regression models providing adjustment for major confounding factors. RESULTS: We identified four dietary patterns, named "Animal products", "Starch-rich", "Vitamins and fiber", and "Cooking oils and dressings". Higher intakes of the "Starch-rich" pattern were positively associated with RCC risk (OR = 1.38, 95% CI: 1.04-1.82 for the highest quartile, p = 0.018). The association was inverse with the "Cooking oils and dressings" pattern (OR = 0.61, 95% CI: 0.47-0.80, p < 0.001), whereas no association was found with "Animal products" and "Vitamins and fiber" patterns. CONCLUSIONS: Higher intakes of starch-related foods may increase RCC risk, whereas consumption of olive and seed oils may favorably influence RCC risk.


Assuntos
Carcinoma de Células Renais/etiologia , Dieta/estatística & dados numéricos , Comportamento Alimentar , Neoplasias Renais/etiologia , Adulto , Idoso , Carcinoma de Células Renais/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Componente Principal , Reprodutibilidade dos Testes , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
5.
Eur J Epidemiol ; 35(3): 251-258, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31993884

RESUMO

Adult obesity increases risks of renal cell carcinoma (RCC). This study investigated if birth weight, child body mass index (BMI) and height are associated with adult RCC. The study included 301,418 children (152,569 boys) from the Copenhagen School Health Records Register born 1930-1985 with measured weights and heights at ages 7 to 13 years. Birth weight was obtained by parental report. BMI and height were transformed to z-scores, and BMI was categorized as normal BMI or overweight. RCC was identified by linkage to the Danish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression. During follow-up, 1010 individuals (680 men) were diagnosed with RCC. BMI and height were positively associated with RCC with no significant sex-differences (age 13: HR = 1.14, 95% CI 1.06-1.23 per BMI z-score, HR = 1.12, 95% CI 1.05-1.20 per height z-score). Compared to children with normal BMI at ages 7 and 13 years, children with overweight only at age 13 had higher risks of RCC (HR = 1.67, 95% CI 1.24-2.26). Compared to children with average growth in height, persistently taller-than-average children (HR = 1.06, 95% CI 1.03-1.10) and children who changed from average to above-average height (HR = 1.08, 95% CI 1.01-1.15) had increased risks of RCC. Birth weight was positively associated with RCC (HR = 1.12, 95% CI 1.05-1.20 per 500 grams). Birth weight, childhood BMI and height were positively associated with RCC risk in men and women.


Assuntos
Tamanho Corporal , Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Adolescente , Adulto , Idoso , Estatura , Índice de Massa Corporal , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Criança , Pré-Escolar , Dinamarca , Feminino , Seguimentos , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco
6.
Technol Cancer Res Treat ; 19: 1533033819901114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994979

RESUMO

Increasing studies have suggested that circular RNAs play an important function in the process of numerous cancers. We aimed to investigate the possible role of cir-CCDC66 in renal carcinoma cancer. As cancer stem cells are responsible for the renal carcinoma cancer tumor growth and resistance to conventional therapy, we focus on the cir-CCDC66 influence on renal carcinoma cancer stem cells. In this study, we performed experiments in human renal tubular epithelial cell HK2 cells and several renal carcinoma cancer cancer cell lines. The results showed that cir-CCDC66 was upregulated not only in renal carcinoma cancer cancer cell lines but also in cancer stem cell spheres. What's more, the results showed that cir-CCDC66 enhanced the cancer stem cell enrichment. Further mechanistic studies showed that hepatocyte growth factor/c-Met pathway was activated in cancer stem cell enrichment and responsible for the cir-CCDC66 upregulation. Inhibition of hepatocyte growth factor/c-Met could block cir-CCDC66-induced cancer stem cell enrichment. In conclusion, our research revealed a novel mechanism between hepatocyte growth factor/c-Met/cir-CCDC66 and cancer stem cell enrichment. We verified that cir-CCDC66 could be a promising biomarker and therapy target for renal carcinoma cancer treatment.


Assuntos
Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Proteínas do Olho/genética , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Circular , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Suscetibilidade a Doenças , Fator de Crescimento de Hepatócito/genética , Humanos , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-met/genética
7.
EBioMedicine ; 51: 102596, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31911271

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive. METHODS: The clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection. FINDINGS: SH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain- and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region. INTERPRETATION: Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.


Assuntos
Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias Renais/etiologia , Neoplasias Renais/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Adulto , Idoso , Animais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Am J Clin Pathol ; 153(3): 303-314, 2020 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-31628837

RESUMO

OBJECTIVES: To review rare cases of BK polyomavirus (BKPyV) associated urologic carcinomas in kidney transplant recipients at one institution and in the literature. METHODS: We describe the clinicopathologic features of BKPyV-associated urologic carcinomas in a single-institution cohort. RESULTS: Among 4,772 kidney recipients during 1994 to 2014, 26 (0.5%) and 26 (0.5%) developed posttransplantation urothelial carcinomas (UCs) and renal cell carcinomas (RCCs), respectively, as of 2017. Six (27%) UCs but none of the RCCs expressed large T antigen (TAg). TAg-expressing UCs were high grade with p16 and p53 overexpression (P < .05 compared to TAg-negative UCs). Tumor genome sequencing revealed BKPyV integration and a lack of pathogenic mutations in 50 cancer-relevant genes. Compared to TAg-negative UCs, TAg-expressing UCs more frequently presented at advanced stages (50% T3-T4) with lymph node involvement (50%) and higher UC-specific mortality (50%). CONCLUSIONS: Post-renal transplantation BKPyV-associated UCs are aggressive and genetically distinct from most non-BKPyV-related UCs.


Assuntos
Carcinoma de Células Renais/patologia , Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/patologia , Infecções Tumorais por Vírus/patologia , Adulto , Idoso , Vírus BK , Carcinoma de Células Renais/etiologia , Carcinoma de Células de Transição/etiologia , Feminino , Humanos , Rim/patologia , Neoplasias Renais/etiologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/etiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Infecções Tumorais por Vírus/etiologia
9.
J Immunother Cancer ; 7(1): 354, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31856918

RESUMO

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/etiologia , Gerenciamento Clínico , Humanos , Imunoterapia , Neoplasias Renais/etiologia , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto
10.
Sci Rep ; 9(1): 16719, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723229

RESUMO

Low vitamin D status is associated with an increased risk of renal cell carcinoma (RCC). This study investigated the association of vitamin D status with serum C-reactive protein (CRP) and adhesion molecules among RCC patients. Fifty newly diagnosed RCC patients and 100 age- and sex-matched controls were recruited. As expected, serum 25(OH)D level was lower in RCC patients than in controls. By contrast, serum levels of CRP, an inflammatory molecule, and ICAM, LAMA4 and EpCAM, three adhesion molecules, were higher in RCC patients than in controls. All RCC patients were divided into two groups: H-VitD (>20 ng/ml) or L-VitD (<20 ng/ml). Interestingly, the levels of serum CRP and all adhesion molecules were higher in RCC patients with L-VitD than those with H-VitD. Nuclear vitamin D receptor (VDR) was downregulated and nuclear factor kappa B (NF-κB) was activated in cancerous tissues. The in vitro experiments found that VitD3 suppressed NF-κB activation and adhesion molecules in RCC cells. Moreover, VitD3 suppressed NF-κB through reinforcing physical interaction between VDR and NF-κB p65 subunit in RCC cells. These results provide a mechanistic explanation for the association among low vitamin D status, local inflammation and increased expression of adhesion molecules among RCC patients.


Assuntos
Proteína C-Reativa/metabolismo , Carcinoma de Células Renais/etiologia , Moléculas de Adesão Celular/metabolismo , Neoplasias Renais/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/sangue , Adulto , Idoso , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais , Vitaminas/sangue
11.
Aging (Albany NY) ; 11(21): 9597-9615, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727869

RESUMO

Kidney cancer ranked in the top 10 for both men and women in the estimated numbers of new cancer cases in the United States in 2018. Targeted therapies have recently been administered to patients with clear cell renal cell carcinoma (ccRCC), but the overall survival of patients at the terminal stage of the disease has not been as good as expected. It is therefore necessary to uncover efficient biomarkers for early diagnosis, and to clarify the molecular mechanisms underlying ccRCC progression and metastasis. Increased evidence has shown that long non-coding RNAs (lncRNAs) play important roles during tumor progression. In this study, 10 candidate lncRNAs with diagnostic and prognostic values in ccRCC were identified: IGFL2-AS1, AC023043.1, AP000439.2, AC124854.1, AL355102.4, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1. Enrichment analysis revealed metabolic and functional pathways, which may be closely associated with kidney cancer tumorigenesis. Six representative processes were summarized, namely glycolysis, amino acid metabolism, lipid synthesis, reductive carboxylation, nucleotide metabolism, transmembrane transport and signal transduction. In combination, the present results provided prognostic and diagnostic biomarkers for ccRCC and might pave the way for targeted intervention and molecular therapies in the future.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , RNA Longo não Codificante/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/etiologia , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/etiologia , Prognóstico
12.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575031

RESUMO

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c-met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of "hereditary renal cancer in a dish" model using c-met-mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.


Assuntos
Carcinoma Papilar/etiologia , Carcinoma de Células Renais/etiologia , Corpos Embrioides/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-met/genética , Alelos , Carcinoma Papilar/diagnóstico , Carcinoma de Células Renais/diagnóstico , Corpos Embrioides/metabolismo , Corpos Embrioides/ultraestrutura , Imunofluorescência , Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética/métodos , Reprodutibilidade dos Testes
13.
Cancer Treat Rev ; 79: 101891, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491662

RESUMO

Collecting ducts carcinoma (CDC) is a rare and aggressive histological subtype of renal cancer accounting for only 1% of renal tumors. Usually patients present in bad clinical conditions due to a symptomatic disease with synchronous metastasis. Due to the rarity of CDC, data from prospective trials evaluating the best treatment for these patients are limited. The prognosis is poor with a median overall survival of around 11 months for patients with metastatic disease. The best treatment option today is considered a doublet chemotherapy with platinum salt plus gemcitabine as a result from a prospective phase II trial, but survival outcomes remain unsatisfactory. The interest in the in-depth understanding the biology of this orphan disease is growing, leading to find potential new biological-driven treatment approaches. Here we review the up-to-date literature evidences to address the best management of this rare and unfavorable clinical condition.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/terapia , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Animais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/mortalidade , Terapia Combinada , Gerenciamento Clínico , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/mortalidade , Prognóstico , Resultado do Tratamento
14.
Cancer Discov ; 9(10): 1349-1357, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31527133

RESUMO

Renal cell carcinoma stands out as one of the most immune-infiltrated tumors in pan-cancer comparisons. Features of the tumor microenvironment heavily affect disease biology and may affect responses to systemic therapy. With evolving frontline options in the metastatic setting, several immune checkpoint blockade regimens have emerged as efficacious, and there is growing interest in characterizing features of tumor biology that can reproducibly prognosticate patients and/or predict the likelihood of their deriving therapeutic benefit. Herein, we review pertinent characteristics of the tumor microenvironment with dedicated attention to candidate prognostic and predictive signatures as well as possible targets for future drug development. SIGNIFICANCE: Tumor microenvironment features broadly characterizing angiogenesis and inflammatory signatures have shown striking differences in response to immune checkpoint blockade and antiangiogenic agents. Integration of stromal and immune biomarkers may hence produce predictive and prognostic signatures to guide management with existing regimens as well as future drug development.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Microambiente Tumoral , Animais , Biomarcadores Tumorais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Terapia Combinada , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia
15.
Clin Cancer Res ; 25(22): 6827-6838, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383732

RESUMO

PURPOSE: Despite the FDA approval of mTOR inhibitors (mTORi) for the treatment of renal cell carcinoma (RCC), the benefits are relatively modest and the few responders usually develop resistance. We investigated whether the resistance to mTORi is due to upregulation of PD-L1 and the underlying molecular mechanism. EXPERIMENTAL DESIGN: The effects of transcription factor EB (TFEB) on RCC proliferation, apoptosis, and migration were evaluated. Correlation of TFEB with PD-L1 expression, as well as effects of mTOR inhibition on TFEB and PD-L1 expression, was assessed in human primary clear cell RCCs. The regulation of TFEB on PD-L1 was assessed by chromatin immunoprecipitation and luciferase reporter assay. The therapeutic efficacies of mTORi plus PD-L1 blockade were evaluated in a mouse model. The function of tumor-infiltrating CD8+ T cells was analyzed by flow cytometry. RESULTS: TFEB did not affect tumor cell proliferation, apoptosis, and migration. We found a positive correlation between TFEB and PD-L1 expression in RCC tumor tissues, primary tumor cells, and RCC cells. TFEB bound to PD-L1 promoter in RCCs and inhibition of mTOR led to enhanced TFEB nuclear translocation and PD-L1 expression. Simultaneous inhibition of mTOR and blockade of PD-L1 enhanced CD8+ cytolytic function and tumor suppression in a xenografted mouse model of RCC. CONCLUSIONS: These data revealed that TFEB mediates resistance to mTOR inhibition via induction of PD-L1 in human primary RCC tumors, RCC cells, and murine xenograft model. Our data provide a strong rationale to target mTOR and PD-L1 jointly as a novel immunotherapeutic approach for RCC treatment.


Assuntos
Antígeno B7-H1/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/etiologia , Neoplasias Renais/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Evasão Tumoral , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica , Humanos , Neoplasias Renais/patologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int Urol Nephrol ; 51(11): 1893-1902, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385177

RESUMO

Despite rapid advances in diagnostic and therapeutic medicine, renal cell carcinoma (RCC) continues to cause significant morbidity and mortality in patients. While there has been a shift towards earlier detection, approximately 16% of patients present with metastatic disease at the time of diagnosis. Kidney injury molecule-1 (KIM-1) is a glycoprotein that has been shown to be a robust and reliable biomarker of acute proximal tubular injury. As KIM-1 is mainly expressed in RCC derived from the proximal tubules, it is a reliable marker to differentiate between proximal tubular primary RCC and distal nephron primary RCC. Several studies have investigated urinary KIM-1 (uKIM-1) in RCC and demonstrated that it is a sensitive and specific marker for detecting localized RCC, as patients had markedly reduced uKIM-1 levels following nephrectomy, with uKIM-1 levels correlating with tumor size and grade. In addition, levels of KIM-1 present in plasma have also shown utility as a biomarker of RCC with levels being elevated in RCC cases at least 5 years before diagnosis. This review focuses on a progressive understanding of KIM-1 in the diagnosis of RCC using biopsies, urine, and plasma samples, and it will also provide some insight into potential roles of KIM-1 in the growth and spread of RCC.


Assuntos
Biomarcadores Tumorais/urina , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/urina , Receptor Celular 1 do Vírus da Hepatite A/análise , Neoplasias Renais/diagnóstico , Neoplasias Renais/urina , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/etiologia , Diagnóstico Diferencial , Receptor Celular 1 do Vírus da Hepatite A/sangue , Receptor Celular 1 do Vírus da Hepatite A/fisiologia , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/etiologia
17.
Crit Rev Oncol Hematol ; 142: 86-93, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387065

RESUMO

PURPOSE: We aim to provide the most accurate and updated quantification of the effect of cigarette smoking on kidney cancer risk focusing on dose-response relationships. METHODS: We conducted a meta-analysis, using an innovative approach combining an umbrella review and a traditional literature search. RESULTS: Fifty-six original studies were included, providing pooled relative risks (RR) of kidney cancer of 1.39 (95% confidence interval, CI: 1.28-1.51) for current and 1.20 (95% CI: 1.14-1.27) for former compared with never smokers. Kidney cancer risk increased non-linearly with smoking intensity, the RR compared with never smokers being 1.18 (95% CI: 1.11-1.26) for five and 1.72 (95% CI: 1.52-1.95) for 30 cigarettes/day, and increased linearly with smoking duration, the RR being 1.70 (95% CI: 1.10-2.64) after 25 years. The risk linearly decreased with time-since-quitting. CONCLUSIONS: Even smoking few cigarettes per day significantly increases kidney cancer risk. Quitting smoking reduces the risk, the earlier the better.


Assuntos
Fumar Cigarros/efeitos adversos , Neoplasias Renais/etiologia , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Renais/epidemiologia , Masculino , Fatores de Risco
18.
FASEB J ; 33(11): 12226-12239, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424966

RESUMO

Down-regulation/mutation of AT-rich interactive domain 1A (ARID1A), a novel tumor suppressor gene, has been reported in various cancers. Nevertheless, its role in renal cell carcinoma (RCC) remained unclear and underinvestigated. We thus evaluated carcinogenesis effects of ARID1A knockdown in nonmalignant Madin-Darby canine kidney (MDCK) renal cells using small interfering RNA (siRNA) against ARID1A (siARID1A). The siARID1A-transfected cells had decreased cell death, increased cell proliferation, and cell cycle shift (from G0/G1 to G2/M) compared with those transfected with controlled siRNA (siControl). Additionally, the siARID1A-transfected cells exhibited epithelial-mesenchymal transition (EMT) shown by greater spindle index, increased mesenchymal markers (fibronectin/vimentin), and decreased epithelial markers (E-cadherin/zonula occludens-1). Moreover, the siARID1A-transfected cells had increases in migratory activity, nuclear size, self-aggregated multicellular spheroid size, invasion capability, chemoresistance (to docetaxel), Snail family transcriptional repressor 1 expression, and TGF-ß1 secretion. All of these siARID1A-knockdown effects on the carcinogenic features were reproducible in malignant RCC (786-O) cells, which exhibited a higher degree of carcinogenic phenotypes compared with the nonmalignant MDCK cells. Finally, immunohistochemistry showed obvious decrease in ARID1A protein expression in human RCC tissues (n = 23) compared with adjacent normal renal tissues (n = 23). These data indicate that ARID1A down-regulation triggers EMT and carcinogenesis features of renal cells in vitro, and its role in RCC could be proven in human tissues.-Somsuan, K., Peerapen, P., Boonmark, W., Plumworasawat, S., Samol, R., Sakulsak, N., Thongboonkerd, V. ARID1A knockdown triggers epithelial-mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma.


Assuntos
Carcinogênese , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA/fisiologia , Transição Epitelial-Mesenquimal , Neoplasias Renais/patologia , Fatores de Transcrição/fisiologia , Animais , Carcinoma de Células Renais/etiologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Cães , Humanos , Neoplasias Renais/etiologia , Células Madin Darby de Rim Canino , Fatores de Transcrição da Família Snail/fisiologia , Fatores de Transcrição/antagonistas & inibidores , Fator de Crescimento Transformador beta1/fisiologia
19.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357507

RESUMO

A significantly increased level of the reactive oxygen species (ROS) scavenger glutathione (GSH) has been identified as a hallmark of renal cell carcinoma (RCC). The proposed mechanism for increased GSH levels is to counteract damaging ROS to sustain the viability and growth of the malignancy. Here, we review the current knowledge about the three main RCC subtypes, namely clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC), at the genetic, transcript, protein, and metabolite level and highlight their mutual influence on GSH metabolism. A further discussion addresses the question of how the manipulation of GSH levels can be exploited as a potential treatment strategy for RCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Glutationa/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Animais , Biomarcadores Tumorais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/terapia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/terapia , Redes e Vias Metabólicas , Terapia de Alvo Molecular , Estresse Oxidativo , Espécies Reativas de Oxigênio , Microambiente Tumoral/imunologia
20.
Curr Opin Nephrol Hypertens ; 28(5): 490-497, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31313673

RESUMO

PURPOSE OF REVIEW: Members of the Cullin family act as scaffolds in E3 ubiquitin ligases and play a central role in mediating protein degradation. Interactions with many different substrate-binding adaptors permit Cullin-containing E3 ligases to participate in diverse cellular functions. In the kidney, one well established target of Cullin-mediated degradation is the transcription factor Nrf2, a key player in responses to oxidative stress. The goal of this review is to discuss more recent findings revealing broader roles for Cullins in the kidney. RECENT FINDINGS: Cullin 3 acts as the scaffold in the E3 ligase regulating Nrf2 abundance, but was more recently shown to be mutated in the disease familial hyperkalemic hypertension. Studies seeking to elucidate the molecular mechanisms by which Cullin 3 mutations lead to dysregulation of renal sodium transport will be discussed. Disruption of Cullin 3 in mice unexpectedly causes polyuria and fibrotic injury suggesting it has additional roles in the kidney. We will also review recent transcriptomic data suggesting that other Cullins are also likely to play important roles in renal function. SUMMARY: Cullins form a large and diverse family of E3 ubiquitin ligases that are likely to have many important functions in the kidney.


Assuntos
Proteínas Culina/fisiologia , Nefropatias/etiologia , Rim/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Carcinoma de Células Renais/etiologia , Humanos , Neoplasias Renais/etiologia , Proteínas dos Microfilamentos/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Pseudo-Hipoaldosteronismo/etiologia , Pseudo-Hipoaldosteronismo/fisiopatologia , Simportadores de Cloreto de Sódio/fisiologia
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