leptin and Kidney-Neoplasms

Renal cell carcinoma (RCC) is the commonest from of renal neoplasm. Although surgery is a successful curative treatment for localized RCC, most patients are diagnosed with advanced or metastatic RCC, which has poor prognosis. RCC is classified by stage and grade using tissue samples. Whilst these provide good prognostic information, they are not very useful for early detection. Proteins that are dysregulated in patient's serum can be a valuable alternative and less invasive biomarker for early detection of the disease. For this reason, a hypothesis was formed that leptin is a possible biomarker for early detection and prognostication of RCC. The literature has disparate results on the usefulness of leptin as a biomarker for the early detection of RCC. Hence, a systematic review and a meta-analysis was carried out to investigate whether serum leptin could be a reliable diagnostic and prognostic factor in RCC patients. Literature on the available cohort and case-control studies on serum leptin in RCC was searched in electronic databases and included to evaluate this adipokine in the progression of RCC. The relevant studies were evaluated for the diagnostic and prognostic value of leptin in RCC patients. Overall, only 6 original research studies matched selection criteria and were included for meta-analysis. This study was hypothesised that; leptin might be a useful biomarker for early detection and prognostication of RCC. However, the data were presented in this study did not support our hypothesis. Serum leptin levels in RCC patients do not strongly associate with the development or progression of RCC, thus cannot act as a biomarker for early detection in RCC in patients. Extending our hypothesis further to include levels of obesity and RCC development may be worthwhile, but studies are currently limited.

Topics: Adipokines; Adipose Tissue; Biomarkers, Tumor; Carcinoma, Renal Cell; Early Detection of Cancer; Humans; Kidney Neoplasms; Leptin; Models, Theoretical; Obesity; Prognosis

It is well-documented that obesity participated in the development of renal cell carcinoma (RCC). Leptin is closely associated with obesity. This study is aimed to investigate the relationship between leptin level and RCC susceptibility and progression.. A meta-analysis was conducted to explore the association between leptin level and RCC susceptibility and progression. The studies were retrieved from electronic databases during January 1990-September 2017 with keywords. The qualified studies were screened with inclusion and exclusion criteria. A random effects model was applied to calculate the pooled standard mean differences and the corresponding confidence intervals.. Ten studies were finally included in this meta-analysis. The serum leptin level in male RCC was significantly lower than that of in female RCC in overall populations, Asians, and Caucasians while no marked difference was noted between genders in the plasma samples. Plasma leptin level in Stage I-II RCC was significantly higher than that in the Stage III-IV. In addition, no significant difference was observed between following parameters, including RCC and non-RCC, clear and non-clear RCC, Grade I-II and Grade III-IV RCC, M0 and M1 RCC, N0 and N1 RCC, and size <4 cm and size >4 cm RCC. No evidence of publication bias was observed.. Our findings indicated that serum leptin level was lower in men with RCC than in women with RCC. Leptin level may not be related to the risk and progression of RCC. However, more studies should be performed in the future.

Topics: Biomarkers; Carcinoma, Renal Cell; Disease Progression; Disease Susceptibility; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasm Grading; Neoplasm Staging; Publication Bias; Risk; Sex Factors; Tumor Burden

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Colorectal Neoplasms; Endometrial Neoplasms; Esophageal Neoplasms; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasms; Obesity; Pancreatic Neoplasms; Prostatic Neoplasms; Thyroid Neoplasms

Multiple epidemiologic studies have linked the development of renal cancer to obesity. In this chapter, we begin with a review of selected population studies, followed by recent mechanistic discoveries that further link lipid deregulation to the RCC development. The upregulation of leptin and downregulation of adiponectin pathways in obesity fit well with our molecular understanding of RCC pathogenesis. In addition, two forms of hereditary RCC involve proteins, Folliculin and TRC8, that are positioned to coordinately regulate lipid and protein biosynthesis. Both of these biosynthetic pathways have important downstream consequences on HIF-1/2alpha levels and angiogenesis, key aspects in the disease pathogenesis. The role of lipid biology and its interface with protein translation regulation represents a new dimension in RCC research with potential therapeutic implications.

Topics: Adiponectin; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Carrier Proteins; Cholesterol; Cytoskeletal Proteins; Estrone; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Leptin; Lipids; Molecular Chaperones; Neoplastic Syndromes, Hereditary; Obesity; Receptors, Cell Surface; Sterol Regulatory Element Binding Proteins

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients' clinical information have revealed leptin's prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Polarity; Cluster Analysis; Cohort Studies; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Leptin; MAP Kinase Signaling System; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Regression Analysis; Signal Transduction; Transcriptome; Treatment Outcome

The mechanisms that link obesity and cancer development are not well-defined. Investigation of leptin and leptin receptor expressions may help define some of the mechanisms. These proteins are known for associating with the immune response, angiogenesis and, signalling pathways such as JAK2/STAT3, PI3K, and AKT pathways. Tissue proteins can be easily detected with immunohistochemistry (IHC), a technique widely used both in diagnostic and research laboratories. The identification of altered levels of leptin and leptin receptor proteins in tumour tissues may lead to targeted treatment for cancer.. The objective of this study was to use IHC to compare leptin and leptin receptor expressions in clear cell renal cell carcinomas (ccRCC) in non-obese and obese patients to determine the association between these proteins with the clinicopathological features and prognosis of ccRCC.. There was neither significant difference in the overall cellular and nuclear expressions of leptin and leptin receptor between non-cancerous kidney and ccRCC tissues nor in non-obese and obese individuals with ccRCC.. In this present study, it was revealed that leptin and leptin receptor were not associated with tumour characteristics and progression of ccRCC patients. Interestingly, nuclear expression of leptin was significantly associated with overall survival. However, the significance of these proteins as biomarkers in other RCC histotypes is still unclear.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Humans; Immunohistochemistry; Kidney Neoplasms; Leptin; Male; Middle Aged; Obesity; Prognosis; Receptors, Leptin; Survival Rate

One of the challenges in differentiating chromophobe renal cell carcinoma (chRCC) from benign renal oncocytoma (RO) is overlapping morphology between the two subtypes. The aim of this study was to investigate the usefulness of expression of leptin (Ob) and its receptor (ObR) in discriminating chRCC from RO. Sections from paraffin-embedded, formalin-fixed tumour nephrectomy specimens of 45 patients, made up of 30 chRCC (15 eosinophilic variant and 15 non-eosinophilic variant) and 15 RO, were used in this study. Samples (30) of clear cell RCC (ccRCC), the most common histological subtype, were used to verify staining patterns found by others in our cohort of Australasian patients. Matched morphologically normal non-cancer kidney tissues were included for each specimen. Sections were batch-immunostained using antibodies against Ob and ObR. Stained sections were digitally scanned using Aperio ImageScope, and the expression pattern of Ob and ObR was studied. In this cohort, male to female ratio was 2:1; median age was 64 (45-88 years); and median tumour size was 3.8 cm (range 1.2-18 cm). There were 47 (62.7%) T1, seven T2, 20 T3 and one T4 stage RCC. Two patients with ccRCC presented with metastases. Nuclear expression of Ob was significantly higher in RO compared with chRCC. The increased nuclear expression of Ob in RO compared with chRCC may be a useful aid in the difficult histological differentiation of RO from chRCC, especially eosinophilic variants of chRCC.

Topics: Adenoma, Oxyphilic; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Renal Cell; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Kidney; Kidney Neoplasms; Leptin; Male; Middle Aged

Topics: Adenocarcinoma; Adenoviridae; Aging; Animals; Antibodies, Monoclonal; Cell Line, Tumor; CTLA-4 Antigen; Diet; Disease Models, Animal; Female; Humans; Immunity; Immunotherapy; Kidney Neoplasms; Leptin; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Obesity; Oligodeoxyribonucleotides; Receptors, Fc; Receptors, Leptin; Recombinant Fusion Proteins; TNF-Related Apoptosis-Inducing Ligand

Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence.. Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis.. Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P = .02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10. Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27. © 2017 American Cancer Society.

Topics: Aged; Carcinoma, Renal Cell; Cohort Studies; CpG Islands; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Neuropeptide Y; Obesity; Prognosis; Promoter Regions, Genetic; Proportional Hazards Models; Prospective Studies; Receptors, Leptin; Risk Assessment; Survival Analysis

Obesity is considered one of the risk factors for many cancers. Serum leptin levels are often elevated in obese people. Leptin has been reported to act as a mitogenic agent and promote renal cancer cell proliferation, whereas the detailed mechanisms still remain to be elucidated. The purpose of this study is to investigate the proliferation and mobility effects in leptin-treated Caki-2 renal cell carcinoma and analyze the alterations of leptin-inducible STAT3 pathways and mitogenic signaling ERK pathways. Our results indicate the constitutive expression of leptin receptor could not be upregulated upon the stimulation of leptin in Caki-2 cells. Leptin increases the proliferation and mobility capabilities of Caki-2 cells via upregulating the expression of both phosphor-ERK and phosphor-STAT3 and these two pathways could be partially abolished by inhibition of the activation of JAK-STAT3 and completely abrogated by inhibition of ERK1/2 pathways. Our results also suggest that mitogenic actions of leptin are not the consequence of altered its receptor expression; whereas the cellular proliferation appears to be working through the cross-talking of JAK-STAT3 and ERK1/2 pathways in renal cell carcinoma caki-2 cells.

Topics: Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Flow Cytometry; Gene Expression Regulation; Humans; Janus Kinase 1; Kidney Neoplasms; Leptin; MAP Kinase Signaling System; Obesity; Protein Kinase C; Signal Transduction; STAT3 Transcription Factor

Leptin, an adipocyte derived cytokine that is closely associated with obesity, was recently shown to be involved in carcinogenesis and cancer progression. Because obesity is a significant risk factor for renal cell carcinoma, we investigated the link between leptin and the development of renal cell carcinoma.. Associations between preoperative serum leptin levels and leptin receptor expression in tumor specimens and various clinicopathological parameters were analyzed in 57 patients with renal cell carcinoma.. Serum leptin levels were 1.2 to 16.2 ng/ml (mean 4.5). Of 57 tumors 22 (38.6%) demonstrated high leptin receptor expression. Serum leptin levels were significantly higher in patients with vs without tumor specimen venous invasion (p = 0.030) and higher in patients with high vs low leptin receptor expression (p = 0.019). There were significant associations between high leptin receptor expression and the presence of venous invasion (p = 0.013), histological type (p = 0.0076) and regional lymph node metastasis (p = 0.047). Of 42 patients with N0M0 disease those with serum leptin 5.0 ng/ml or more had significantly shorter progression-free survival than patients with lower levels (p = 0.0043). Multivariate Cox proportional hazards model analysis demonstrated that higher serum leptin was an independent predictor of progression-free survival (p = 0.0406).. Leptin and leptin receptor could have a key role in the invasion of renal cell carcinoma and they could be valuable predictors of progression.

Topics: Adult; Aged; Body Mass Index; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Kidney Neoplasms; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Receptors, Cell Surface; Receptors, Leptin; Treatment Outcome

Obesity is a significant risk factor for renal cell carcinoma. The adipocyte derived cytokine leptin, which controls body weight homeostasis through food intake and energy expenditure, recently provided a potential link between obesity and cancer development. We examined whether leptin promotes the invasiveness of renal cancer cells and we investigated its underlying signaling pathway.. Leptin receptor expression in the 6 human renal cancer cell lines Caki-1, ACHN, 769P, A498, SKRC44 and SKRC49, and in the murine renal cancer cell line Renca was examined by reverse transcriptase-polymerase chain reaction and Western blotting. The effect of leptin on renal cancer cell invasiveness was assessed by the invasion of cells through Matrigel coated Transwell inserts. Leptin induced intracellular signaling was examined by Western blotting.. Leptin receptor was detected in all renal cancer cells examined at the mRNA and protein levels. Leptin increased Renca cell invasiveness at 1 ng/ml (p < 0.05). There was up to 3-fold invasiveness compared to untreated cells at 100 ng/ml with the activation of extracellular signal-regulated kinases and rho guanosine triphosphatase (p < 0.01). Leptin induced activation of rho guanosine triphosphatase was inhibited not only by the rho kinase inhibitor Y27632, but also by the MEK1 inhibitor PD98059, of which each inhibited leptin induced invasion of Renca cells (p < 0.01).. Leptin promoted the invasiveness of murine renal cancer cells via extracellular signal-regulated kinases and rho guanosine triphosphatase dependent pathways. Rho guanosine triphosphatase was a downstream effector of extracellular signal-regulated kinases in leptin induced invasion. Leptin signaling could have a key role in renal cell carcinoma invasion.

Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Leptin; MAP Kinase Signaling System; Mice; Neoplasm Invasiveness; Protein Serine-Threonine Kinases; Receptors, Cell Surface; Receptors, Leptin; rho GTP-Binding Proteins; rho-Associated Kinases; RNA, Messenger

Advances in diagnosis and improved methods of treatment have resulted in increasing number of long-term survivors in children with Wilms tumor. Growth and puberty are important for accumulation of bone mass; chemotherapy nad radiotherapy used in treatment for Wilms tumor can influence bone structure and physical development. Leptin plays an important role in metabolism of adipose tissue and bone mineralization. Considering that neoplasm and its treatment can affect normal development in childhood, we analysed the influence of antineoplastic treatment on bone mineralization and the correlations between serum leptin levels, body composition and bone mineral density in survivors of Wilms tumor. Twenty subjects (12 boys) treated for Wilms tumor at the mean age of 10.9 (range 3-20 years) participated in this study. Mean follow up period after discontinuation of therapy was 5.6 years (range 2 months - 13.5 years). Mean age of diagnosis was 3.9 years (range 1 month - 12.6 years). 18 patients received chemotherapy, 7 - additionally radiotherapy and 2 infants had only surgery treatment. We measured fat mass - FM, fat free mass - FFM, bone mineral density - BMD total and BMD spine using dual energy x-ray absorptiometry (DXA) and compared to the results obtained for healthy references (SD score). Leptin levels were measured with RIA method.. 1. No difference was found in leptin levels, body mass index, FM, FFM, BMD total and spine in relation to sex. 2. Means of SDS BMI, FM, FFM, BMD and leptin were in the normal range for the age and sex matched controls. 3. We found the correlation between leptin level and BMI, FM, FFM and BMD total and spine, no correlation was found between SDS values. 4. We observed a positive correlation between SDS BMD and SDS BMI, FM, FFM, BMD spine. 5. BMI, FM and leptin levels were higher in children treated with radiotherapy and chemotherapy than in children treated with only chemotherapy. However, the SDS values were comparable with the healthy controls. 6. SDS BMD total was decreased in 5/20 subjects (25% of all studied patients) compared with healthy controls.. The results demonstrated the risk of osteopenia in the group of children treated for Wilms tumor and the necessity for long-term monitoring of bone mineralization.

Topics: Absorptiometry, Photon; Adolescent; Antineoplastic Agents; Body Composition; Body Mass Index; Bone Diseases, Metabolic; Calcification, Physiologic; Case-Control Studies; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Kidney Neoplasms; Leptin; Male; Radiotherapy, Adjuvant; Wilms Tumor

Several lines of evidence from in vivo animal experiments and human studies suggest that leptin, a peptide secreted from adipose tissue, plays a role in regulating food intake and energy expenditure. However, the signal transduction mechanism of leptin in its target cells remains unknown thus far since leptin-responsive cell lines have not been available yet. We found that leptin caused the tyrosine phosphorylation of several proteins in human renal cell carcinoma cells, ACHN cells, in which STAT-1, but neither STAT-3 nor STAT-5, was involved. An ACHN cell line would serve as a useful tool for analyzing the signal transduction mechanism of leptin.

Topics: Adenocarcinoma; Blotting, Western; DNA-Binding Proteins; Humans; Kidney Neoplasms; Leptin; Obesity; Phosphorylation; Proteins; Recombinant Proteins; STAT1 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tyrosine