leptin and Bone-Neoplasms

The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

Topics: Adiponectin; Animals; Bone Neoplasms; Breast Neoplasms; DNA-Binding Proteins; Female; Humans; Leptin; Mitosis; Phosphorylation; RNA-Binding Proteins

Cancer and the use of a comprehensive anti-cancer treatment are unfavorable factors, which have a significant impact on bone mass accumulation, bone mineralization and consequently the occurrence of osteoporosis. Bone turnover is regulated by complex mechanisms, among which an important role play OPG/RANK/RANKL signaling pathway, adipokines, and fetuin-A. The aim of the study was to evaluate bone mineral density and concentrations of leptin and fetuin-A in patients with osteosarcoma after anti-cancer treatment.. The study included 50 children and adolescents aged 10-21 years. The study group consisted of 25 patients with osteosarcoma and 25 healthy counterparts as a control group. The examination was conducted 2 months after the last course of postoperative chemotherapy and included densitometric measurements: bone mineral content (BMC), bone mineral density (BMD), fat mass, lean mass and biochemical measurements: serum concentrations of calcium, magnesium, phosphate, 25-hydroksyvitamin D, alkaline phosphatase, leptin and fetuin-A. Concentrations of leptin and fetuin-A were determined by immunoenzymatic methods.. In patients with osteosarcoma after anti-cancer treatment, we observed significantly reduced bone mineral content, bone mineral density and lean body mass compared with the healthy children (p < 0.05, p < 0.01, p < 0.05, respectively). Mean values of z-score of the whole body BMD and z-score of the lumbar BMD L1-L4 were significantly lower in patients than in the controls (p < 0.001). The serum concentrations of phosphate, magnesium, and alkaline phosphatase in both studied groups were similar, while calcium was significantly lower (p < 0.05) in patients than in the healthy children. The concentration of 25-hydroxyvitamin D was about two-fold lower, while leptin approximately 2.5-fold higher in patients than in the controls. The mean value of fetuin-A was similar in both studied groups. Statistically significant positive correlations between body composition parameters and the values of BMD, as well as between anthropometric parameters and leptin and fetuin-A were observed.. The deficit in bone mass observed in patients with malignant bone tumors after anti-cancer treatment might be the result of decreased serum calcium and vitamin D concentrations. The observed correlation between anthropometric and biochemical parameters may indicate the link between bone and adipose tissue metabolism.

Topics: Adipose Tissue; Adolescent; Adult; Alkaline Phosphatase; alpha-2-HS-Glycoprotein; Anthropometry; Bone and Bones; Bone Density; Bone Neoplasms; Calcium; Child; Female; Humans; Leptin; Magnesium; Male; Osteosarcoma; Vitamin D; Young Adult

Leptin signaling influences osteoblastogenesis and modulates the fate of mesenchymal stem cells (MSCs) during bone and cartilage regeneration. Although MSCs abound in the osteosarcoma (OS) microenvironment, and leptin exhibits pro-tumorigenic properties, leptin's influence on OS progression and chemoresistant signaling in MSCs remains unclear. Using cell viability and apoptosis assays, we showed that medium conditioned by leptin-treated human MSCs promotes cisplatin resistance in cultured human OS cells. Moreover, GFP-LC3 expression and chloroquine treatment experiments showed that this effect is mediated by stimulation of autophagy in OS cells. TGF-β expression in MSCs was upregulated by leptin and suppressed by leptin receptor knockdown. Silencing TGF-β in MSCs also abolished OS cell chemoresistance induced by leptin-conditioned medium. Cisplatin resistance was also induced when leptin-conditioned MSCs were co-injected with MG-63 OS cells to generate subcutaneous xenografts in nude mice. Finally, we observed a significant correlation between autophagy-associated gene expression in OS clinical samples and patient prognosis. We conclude that leptin upregulates TGF-β in MSCs, which promotes autophagy-mediated chemoresistance in OS cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Carcinogenesis; Chloroquine; Cisplatin; Drug Resistance, Neoplasm; Leptin; Mesenchymal Stem Cells; Mice; Osteosarcoma; Transforming Growth Factor beta; Tumor Microenvironment; Up-Regulation; Xenograft Model Antitumor Assays

Topics: Adult; Bone Neoplasms; Breast Neoplasms; Cell Movement; Chemokine CXCL12; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Middle Aged; Neoplasm Invasiveness; Receptors, CXCR4; Receptors, Leptin; Signal Transduction

Sirtuin-1 (SIRT1) is a downstream target of Leptin, and its inhibition promotes p53-mediated apoptosis. This study aimed to evaluate the expression and prognostic significance of Leptin and SIRT1 in osteosarcoma. Leptin and SIRT1 levels in osteosarcoma samples from 89 patients were evaluated by immunohistochemical staining. The correlations between Leptin and SIRT1 expression with clinical parameters were analyzed by Spearman's test and Pearson's chi-squared test. Prognostic factors were identified by Univariate and multivariate Cox regression analysis. We found that Leptin and SIRT1 expression was low in 23.6% and 20.2%; moderate in 25.8% and 24.7%; and high in 50.5% and 55.1% of patients with osteosarcoma, respectively. Both Leptin and SIRT1 expression were significantly associated with the Enneking stage, distant metastasis and neo-adjuvant chemotherapy. Leptin expression and SIRT1 expression were significantly correlated and they were significantly associated with shorter overall survival. Among osteosarcoma patients who received neo-adjuvant chemotherapy, both Leptin and SIRT1 expression were significantly associated with overall survival of osteosarcoma patients in univariate analysis, but only SIRT1 expression was significantly associated with overall survival of osteosarcoma patients in multivariate analysis. In conclusion, Leptin and SIRT1 expressions are significantly associated with shorter overall survival of osteosarcoma patients, and SIRT1 expression is a significant independent prognostic indicator in patients with osteosarcoma.

Topics: Adolescent; Adult; Biomarkers, Tumor; Bone Neoplasms; Child; Disease-Free Survival; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leptin; Male; Osteosarcoma; Prognosis; Proportional Hazards Models; Sirtuin 1; Tissue Array Analysis; Young Adult

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.

Topics: Bone Neoplasms; Cell Line, Tumor; Chondrosarcoma; Humans; Leptin; Lymphangiogenesis; MicroRNAs; Neoplasm Proteins; RNA, Neoplasm; Vascular Endothelial Growth Factor C

Recent data support the concept that adipokines, which are secreted by fat cells, are important modulators of bone metabolism. The aim of this study was to assess the relationships between body composition parameters, adipokines (leptin, adiponectin) and bone mineral density (BMD) in patients with malignant bone tumors after anticancer therapy.. The study included 35 patients (median age 14.8 years) with diagnosed malignant bone tumors treated according to obligatory protocols. Total fat mass, lean mass, bone mineral content (BMC) and BMD measurements were performed after treatment completion by dual energy-ray absorptiometry (DXA). Serum concentrations of leptin, leptin receptor and adiponectin were determined using immunoenzymatic assays. The control group consisted of 28 healthy children (median age 14.3 years).. Patients with bone tumor after chemotherapy had significantly higher fat mass (P < 0.01), increased ratio of fat mass/lean mass (P < 0.001), and a decrease (P < 0.001) in total body and lumbar spine BMD compared with controls. We observed higher serum leptin concentration (P < 0.01) and lower soluble leptin receptor (P < 0.001) and adiponectin (P = 0.01) in patients than in controls. The ratios of leptin/leptin receptor and leptin/adiponectin were about three-fold higher in patients compared with the control group (P = 0.001). We found a significant positive correlation between BMD and body composition and a negative correlation between BMD and adiponectin in the patients group.. Changes in body composition parameters coexisting with disturbed adipokine levels, especially higher levels of leptin and lower levels of adiponectin, might be associated with bone status in patients treated for malignant bone tumors.

Topics: Adipokines; Adolescent; Adult; Body Composition; Body Mass Index; Bone Density; Bone Neoplasms; Child; Female; Humans; Leptin; Male; Sex Characteristics

Leptin, an adipocyte-derived cytokine associated with obesity, has been reported to participate in carcinogenesis. Epithelial-mesenchymal transition (EMT) is also considered as a key event in tumor metastasis. The aim of this study is to investigate the mechanism of leptin in the promotion of EMT leading to metastasis in A549 lung cancer cells. We investigated the effect of leptin on migration of A549 cells using wound healing and transwell assays. The incidence of EMT in A549 cells was examined by real-time PCR and immunofluorescence staining. The expression of TGF-β in A549 cells was detected by real-time PCR, and blocking of TGF-β in A549 cells was achieved by siRNA techniques. Additional work was performed using 100 patient samples, which included samples from 50 patients diagnosed with lung cancer and an additional 50 patients diagnosed with lung cancer with metastatic bone lesions. Leptin expression was measured using immunohistochemistry techniques. We demonstrated that leptin can effectively enhance the metastasis of human lung cancer A549 cell line using both wound healing and transwell assays. We also found the incidence of EMT in A549 cells after leptin exposure. Furthermore, we detected the expression of TGF-β in A549 cells, which had been reported to play an important role in inducing EMT. We showed that leptin can significantly upregulate TGF-β at both the mRNA and protein levels in A549 cells. Using siRNA to block the expression of TGF-β in A549 cells, we confirmed the role of TGF-β in the promotion of metastasis and induction of EMT. Furthermore, we found that in patient samples leptin was present at higher levels in samples associated with diagnosis of lung cancer bone metastases tissue than lung cancer tissue. Our results indicated that leptin promoted the metastasis of A549 human lung cancer cell lines by inducing EMT in a TGF-β-dependent manner.

Topics: Bone Neoplasms; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Leptin; Lung Neoplasms; Neoplasm Metastasis; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta

Our objective was to determine whether serum leptin levels and obesity-related factors could affect outcome for metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs).. Sixty MBC patients treated with first line hormonal therapy were enrolled in this study.. Median age was 51 years (range 28-75). Median leptin level was 19400 pg/ml (1970-91900) and estradiol level 29.6 pg/ml (4.0-181.9). Factors associated with overall survival in univariate analysis were age and waist-to-hip ratio (WHR), whereas only WHR retained significance in the multivariate analysis. However, no factor was associated with progression-free survival. However, WHR was found to be a significant prognostic marker only if the leptin level was ≥19400 pg/ml (HR = 0.38; 95% CI: 0.16-0.91).. This study suggests that serum leptin levels and WHR together may serve as potential prognostic markers in MBC patients treated with AIs.

Topics: Adult; Aged; Aromatase Inhibitors; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Estradiol; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Risk Factors; Soft Tissue Neoplasms; Survival Rate; Waist-Hip Ratio

Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin D receptor (VDR) bound to 1,25(OH)2D3, but cycloheximide sensitivity of this induction suggests that it may occur largely via secondary mechanisms requiring cooperating transcription factors. We therefore sought to identify 1,25(OH)2D3-regulated transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was found to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunted this upregulation. Genomic analyses revealed conserved binding sites for STATs (signal transduction mediators of leptin and IL-6 action) along with transcription factor ETS1 in human and other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, and VDR mRNAs were induced in a dose-dependent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis identified nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of mediating direct transcriptional activation of a heterologous reporter gene when bound by a 1,25(OH)2D3-liganded VDR complex. A model is proposed wherein 1,25(OH)2D3 upregulates FGF23 production directly via multiple VDREs and indirectly via induction of STAT3, ETS1, and VDR transcription factors that are then activated via cell surface and intracellular signaling to cooperate in the induction of FGF23 through DNA looping and generation of euchromatin architecture.

Topics: Animals; Bone and Bones; Bone Neoplasms; Calcitriol; Cell Line; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; HEK293 Cells; Humans; Interleukin-6; Leptin; Models, Animal; Osteosarcoma; Rats; Receptors, Calcitriol; Signal Transduction; STAT Transcription Factors

Bone metastasis is a serious complication of patients with tumor, and most primary tumors can metastasize to bone. And the main threat and the reason for most cancer deaths are not the primary neoplasias, but secondary tumors, the metastases. To minimize the morbidity and economic expenditure associated with bone metastases, it is important to decrease the etiological factors of bone metastasis. Although current evidence suggested that the therapies to the underlying malignancy bone metastasis might result in bone loss leading to osteoporosis, no studies have shown direct evidence the successful seeding of bone metastases of cancer cells is the part played by osteoporosis. In the state of osteoporosis, for the enhancement of the osteolysis, the increased inflammatory factors could make blood vessels leakier, resulting in the easier hematogenous metastasis to bone and bone marrow. Moreover, leptin, which was positive correlation with osteoporosis, has been showed to exert angiogenic effects and could regulate VEGF expression, promoting the proliferation of the cancer blood vessel. In addition, the increased growth factors in osteoporosis could enrich the local microenvironment, promoting the growth of the metastasis mass. Given the above background, we hypothesize that osteoporosis may be a potential contributor to the bone metastases.

Topics: Bone Neoplasms; Humans; Leptin; Neoplasm Metastasis; Neovascularization, Pathologic; Osteoporosis; Vascular Endothelial Growth Factor A

Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. In this study, we found that leptin increased the migration and the expression of alphavbeta3 integrin in human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the long form (OBRl) leptin receptor, which was higher than that in normal cartilage and human primary chondrocyte. Leptin-mediated migration and integrin upregulation were attenuated by OBRl receptor antisense oligonucleotide. Activations of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor-kappaB (NF-kappaB) pathways after leptin treatment were demonstrated, and leptin-induced expression of integrin and migration activity was inhibited by the specific inhibitor, small-interfering RNA and mutant of IRS-1, PI3K, Akt and NF-kappaB cascades. Taken together, our results indicated that leptin enhances the migration of chondrosarcoma cells by increasing alphavbeta3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-kappaB signal transduction pathway.

Topics: Blotting, Western; Bone Neoplasms; Cell Movement; Chondrocytes; Chondrosarcoma; Flow Cytometry; Humans; Insulin Receptor Substrate Proteins; Integrin alphaVbeta3; Leptin; NF-kappa B; Oligonucleotides, Antisense; Phosphatidylinositol 3-Kinases; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Transfection; Tumor Cells, Cultured; Up-Regulation

The number of peripheral blood mesenchymal stem cells (PBMSCs) may increase under pathological conditions. We sought to compare the number of MSC-like cells in the peripheral blood of patients with bone sarcomas with healthy controls and to analyze related cytokines in the peripheral blood plasma.. Peripheral blood mononuclear cells (PBMNs) of patients with bone sarcomas and control subjects were isolated for culture and analyzed by flow cytometry for MSC phenotype. Cytokines in the plasma obtained after cell separation were analyzed using enzyme-linked immunosorbent assay (ELISA). Annexin-V and beta-galactosidase staining were used to investigate whether the cells died from apoptosis or senescence.. Flow cytometric analysis demonstrated an >9-fold increase in the number of cells with MSC-like phenotypes (CD34(-), CD45(-), CD105(+)) in patients with bone sarcomas compared with control subjects (p<0.05). ELISA results showed that concentrations of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in patients with bone sarcomas were statistically higher than those in the control subjects (p<0.05), whereas there was no significant difference in plasma concentrations of leptin and stromal cell-derived factor 1 between the two groups. A significant, positive correlation between the percentages of PBMSC-like cells and concentrations of HGF in all samples (R=0.618; p=0.011). Annexin-V staining of MSC-like cells was positive, whereas beta-galactosidase staining was negative.. Peripheral blood of patients with bone sarcomas has more cells with MSC phenotypes than blood of healthy persons. The increased number is accompanied by increased HGF and VEGF in the plasma.

Topics: Adolescent; Adult; Annexin A5; Apoptosis; beta-Galactosidase; Bone Neoplasms; Cell Count; Chemokine CXCL12; Female; Hepatocyte Growth Factor; Humans; Leptin; Male; Mesenchymal Stem Cells; Middle Aged; Sarcoma; Vascular Endothelial Growth Factor A; Young Adult

Serum contents of leptin and soluble Fas antigen were measured in 28 patients with osteosarcoma, 7 with neuroectodermal bone tumors, and 17 healthy subjects. The incidence and levels of soluble Fas antigen in patients with osteosarcoma and neuroectodermal bone tumors were higher than in healthy subjects and did not depend on sex and age in both healthy subjects and patients. Serum concentration of leptin in women was higher than in men (both in healthy controls and patients) and was lower in healthy subjects compared to patients with osteosarcoma and neuroectodermal bone tumors. A trend to a negative correlation between the concentrations of leptin and soluble Fas antigen in female patients with osteosarcoma and male patients with neuroectodermal bone tumors was revealed. The role of leptin and soluble Fas antigen in the pathogenesis of primary bone tumors is discussed.

Topics: Adolescent; Adult; Apoptosis; Bone Neoplasms; fas Receptor; Female; Humans; Leptin; Male; Neuroectodermal Tumors; Osteosarcoma; Receptors, Leptin