leptin and Neoplasm-Metastasis

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.

Topics: Adipose Tissue; Animals; Carcinogenesis; Humans; Immunotherapy; Inflammation Mediators; Leptin; Macrophages; Myeloid-Derived Suppressor Cells; Neoplasm Metastasis; Neoplasms; Obesity; Risk Factors; Tumor Microenvironment

The association of adiponectin with metabolism and cancer is well established. Since its discovery in 1990, adiponectin, as one of the adipose tissue-secreted adipokines, has been very widely studied in biomedical research. Low levels of circulatory adiponectin have been reported in obesity, inflammatory diseases and various types of cancers including colorectal cancer (CRC), which is highly linked with obesity and gut inflammation. However, the function and underlying mechanisms of adiponectin in CRC is not well understood. In addition, there are contradictory reports on the role of adiponectin in cancer. Therefore, further investigation is needed. In this review, we explore the information available on the relationship between adiponectin and CRC with respect to proliferation, cell survival, angiogenesis and inflammation. We also highlighted the knowledge gaps, filling in which could help us better understand the function and mechanisms of adiponectin in CRC.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Leptin; Mice; Neoplasm Metastasis; Neovascularization, Pathologic; Obesity; Tumor Microenvironment

The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.

Topics: Biomarkers; Breast Neoplasms; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic; Obesity

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

Topics: Animals; Cell Movement; Humans; Leptin; Neoplasm Metastasis; Neoplasms; Obesity; Signal Transduction

Obesity has a complicated connection to both breast cancer risk and the clinical behaviour of the established disease. The obese setting provides a unique adipose tissue microenvironment that, in association with systemic endocrine modifications, promotes tumor initiation, primary growth, invasion, and metastatic progression. This review presents an overview of the clinical and experimental evidences highlighting the adipokine leptin as the most important molecular mediator of obesity-breast cancer axis. The research of leptin network operating in this context could launch a new field not only in the knowledge of risk factors for breast cancer but also in the development of leptin targeting drugs as promising anticancer agents.

Topics: Adipose Tissue; Animals; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Design; Female; Humans; Leptin; Neoplasm Invasiveness; Neoplasm Metastasis; Obesity; Risk Factors

The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Cachexia; Cytokines; Ghrelin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Interleukin-6; Leptin; Myostatin; Neoplasm Metastasis; Neoplasms; Prognosis; Syndrome; Tumor Microenvironment; Tumor Necrosis Factor-alpha

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

Type-II Endometrial Cancer (EMC) is one of the most common types of gynaecological cancer affecting more than 2.7 million people worldwide. Clinical evidence shows that adipokines levels are abnormally altered in Type-II EMC and reported to be one of the major responsible factor for uncontrolled proliferation and metastasis in Type-II EMC. Reversing the altered adipokine levels, therefore, help to control Type-II EMC proliferation and metastasis. In the present hypothesis we focus on the possible role of Thiazolidinediones in favourably altering the adipokine levels to benefit in the management of Type-II EMC.

Topics: Adipokines; Adiponectin; Animals; Cell Proliferation; Endometrial Neoplasms; Female; Gene Expression Regulation; Humans; Leptin; Mice; Models, Biological; Neoplasm Metastasis; Resistin; Thiazolidinediones

Leptin phenotype has been suggested to be a possible biomarker for the diagnosis and prognosis of different neoplasms. Nonetheless, there are conflicts among the outcomes found in several tumors, and little is proven concerning the correlation between the phenotype of leptin and its clinical significance in colorectal carcinomas. This study will describe the phenotype of leptin in colorectal adenocarcinomas, and investigate its correlation with clinicopathological factors.Two hundred and twenty eight tissue samples include 155 colorectal carcinomas, 40 adenomas, and 33 noncancerous cases were utilized in constructing tissue microarrays which have been used in the revealing of leptin expression using leptin monoclonal antibody and immunohistochemistry staining protocol.Immunoexpression of leptin was recognized in 145 (93.5%) of colorectal tumors and 56 (76.7%) cases of control group. Histotype was considerably associated with leptin phenotype (P = .000), there is up regulation in leptin expression in colorectal carcinoma cases. Significantly higher proportion of negative leptin immunostaining cases were observed in tumors which have size more than 5 cm (P = .045). Whereas, significant different survival patterns were observed in positive cases regarding tumor size, lymphovascular invasion, distant metastasis, local recurrence and relapse of disease (P-values .046, .011, .000, .013, and .001, respectively). On the other hand, positive leptin staining colorectal tumors with size <5 cm, and with no distant metastases, local recurrence, or disease relapse had significantly better survival estimates. However, leptin immunostaining did not show noteworthy associations with age, gender, differentiation, tumor location, stage, margins involvement, lymphovascular invasion, and lymph node metastasis.The current study shows up regulation in leptin expression in colorectal adenocarcinoma compared with noncancerous control cases. Thus, immunohistochemical staining of leptin in colorectal cancer could be a helpful tool in the prediction of prognosis and survival pattern of colorectal cancer with certain clinicopathological factors (tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease).

Topics: Adenocarcinoma; Adenoma; Adult; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenotype; Prognosis; Saudi Arabia; Survival Analysis; Tumor Burden

Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.. Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.. Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.. Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Gene Knockdown Techniques; Humans; Interleukin-6; Janus Kinases; Leptin; Mice; Neoplasm Metastasis; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Prognosis; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; Tumor Microenvironment; Up-Regulation

Bone morphogenetic protein 9 (BMP9) possesses multiple functions, but its effects on breast cancer cells in adipose microenvironment are still unclear. This study aimed to investigate whether BMP9 is able to modulate the interaction between pre-adipocytes/adipocytes and breast cancer cells. An in vitro co-culture system was established by using pre-adipocytes/adipocytes and MDA-MB-231 breast cancer cells with BMP9 over-expression. The leptin expression and leptin-induced signaling pathway were evaluated in this co-culture system. MTT assay, EdU assay and flow cytometry were used to assess the proliferation of MDA-MB-231 cells. Wound-healing assay and Transwell migration assay were used to assess the migration of MDA-MB-231 cells. Immunofluorescence staining was used to detect the expression of leptin recepter (ObR) in MDA-MB-231 cells. The expression of key molecules in leptin signaling pathway in co-culture system were detected by Western blotting. MDA-MB-231 cells and pre-adipocytes/adipocytes were inoculated into nude mice, the tumor volume was measured, and the protein expression of key molecules in leptin signaling pathway was detected. Results showed BMP9 inhibited breast tumor growth in vitro and in vivo and reduced the migration of breast cancer cells in vitro. MDA-MB-231 cells with BMP9 over-expression decreased leptin expression in pre-adipocytes/adipocytes and had reduced phosphorylation of STAT3, ERK1/2 and AKT. Taken together, our study indicates that BMP9 can inhibit the growth and metastasis of breast cancer cells, which may be related to interaction between pre-adipocytes/adipocytes and MDA-MB-231 cells via leptin signaling pathway.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Apoptosis; Breast Neoplasms; Cell Communication; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Female; Gene Expression; Growth Differentiation Factor 2; Heterografts; Humans; Leptin; Mice; Neoplasm Metastasis; Signal Transduction

Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.

Topics: Acetyl-CoA Carboxylase; Acetylation; Animals; Breast Neoplasms; Disease Models, Animal; Female; HEK293 Cells; Humans; Leptin; Lung Neoplasms; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Recurrence, Local; Tissue Array Analysis

Emerging evidence has shown that leptin, an adipocyte-derived cytokine that is closely associated with obesity, play a significant role in carcinogenesis and tumorigenesis. However, its impact on gallbladder cancer (GBC) remains unclear. In this study, we firstly found that leptin and its functional receptor OB-Rb were significantly co-expressed in human GBC tissues and cell lines, the content of which were higher than those in normal human gallbladder tissues. Treatment with leptin promoted the proliferation, migration and invasion of GBC cells, which were attenuated by OB-Rb shRNA. Blocking in the G2/M period of cell cycle, increasing of MMP3 and MMP9, increasing of VEGF-C/D, activation of SOCS3/JAK2/p-STAT3 pathway was demonstrated after treatment with leptin. All of these positive responses were attenuated by OB-Rb receptor shRNA. Taken together, our findings suggest that leptin promoted the proliferation, migration and invasion of GBC cells by increasing OB-Rb expression through the SOCS3/JAK2/p-STAT3 signal pathway. Targeting the leptin/OB-Rb axis could be an attractive therapeutic strategy for treatment of GBC.

Topics: Cell Movement; Cell Proliferation; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Leptin; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Leptin; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D

Obesity prevalence is increasing worldwide and is accompanied by low-grade inflammation with macrophage infiltration, which is linked with a poorer breast cancer prognosis. Lunasin is a natural seed peptide with chemopreventive properties and multiple bioactivities. This is the first study to explore the chemopreventive effects of lunasin in the obesity-related breast cancer condition using 4T1 breast cancer cells, 3T3-L1 adipocytes, and conditioned media. An obesity-related environment, such as leptin-treatment or adipocyte-conditioned medium (Ad-CM), promoted 4T1 cell proliferation and metastasis. Lunasin treatment inhibited metastasis of breast cancer cells, partially through modestly inhibiting production of the angiogenesis-mediator vascular endothelial growth factor (VEGF) and significantly by inhibiting secretion in the Ad-CM condition. Subsequently, two adipocytes inflammation models, 3T3-L1 adipocytes were stimulated by tumor necrosis factor (TNF)-α, and RAW 264.7 cell-conditioned medium (RAW-CM) was used to mimic the obese microenvironment. Lunasin significantly inhibited interleukin (IL)-6 and macrophage chemoattractant protein (MCP)-1 secretion by TNF-α stimulation, and MCP-1 secretion in the RAW-CM model. This study highlights that lunasin suppressed 3T3-L1 adipocyte inflammation and inhibited 4T1 breast cancer cell migration. Interestingly, lunasin exerted more effective anti-metastasis activity in the obesity-related condition models, indicating that it possesses anti-inflammatory properties and blocks adipocyte-cancer cell cross-talk.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Inflammatory Agents; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Culture Media, Conditioned; Cytokines; Female; Inflammation; Inflammation Mediators; Leptin; Lipid Metabolism; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Models, Biological; Neoplasm Metastasis; Obesity; Peptides; RAW 264.7 Cells; Vascular Endothelial Growth Factor A

To investigate the potential prognostic significance of leptin and its receptor (Ob-R) in thyroid carcinoma.. The study cohort consisted of 173 patients including 93 cases with papillary thyroid carcinoma (PTC), 41 cases with follicular thyroid carcinoma (FTC), 25 cases with medullary thyroid carcinoma (MTC) and 14 cases with anaplastic thyroid carcinoma (ATC). We investigated the correlation between clinicopathological features and leptin or Ob-R. The Kaplan-Meier method was used to analyse the survival rate.. There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. For PTC, leptin expression was strongly correlated with older age, larger tumour size, nodal metastasis and advanced stage. Ob-R was significantly correlated with larger tumour size, nodal metastasis and advanced stage. The 5-year disease-free survival (DFS) rate in patients with positive leptin or its receptor expression was lower than that in patients without expression (with statistical difference). For FTC, patients with positive leptin or Ob-R expression developed no recurrence or metastasis during the follow-up. For MTC, Ob-R was significantly correlated with nodal metastasis and advanced stage (P < 0·05). For ATC, patients with positive Ob-R expression had longer median DFS than those with negative expression (436 ± 185 vs 57 ± 71 days), and the difference in the survival rate was statistically significant (P < 0·05).. There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. Leptin and Ob-R had negative prognostic significance in PTC, while Ob-R may play a protective role in ATC.

Topics: Adenocarcinoma, Follicular; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Cohort Studies; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leptin; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Receptors, Leptin; Recurrence; Survival Rate; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tissue Array Analysis

The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women.

Topics: Aged; Ascites; Cell Line, Tumor; Cell Movement; Cohort Studies; Disease Progression; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Leptin; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Obesity; Ovarian Neoplasms; Overweight; Prognosis; Recombinant Proteins; Recurrence; Treatment Outcome

The steady increase in the incidence of obesity among adults has been paralleled with higher levels of obesity-associated breast cancer. While recent studies have suggested that adipose stromal/stem cells (ASCs) isolated from obese women enhance tumorigenicity, the mechanism(s) by which this occurs remains undefined. Evidence suggests that increased adiposity results in increased leptin secretion from adipose tissue, which has been shown to increased cancer cell proliferation. Previously, our group demonstrated that ASCs isolated from obese women (obASCs) also express higher levels of leptin relative to ASCs isolated from lean women (lnASCs) and that this obASC-derived leptin may account for enhanced breast cancer cell growth. The current study investigates the impact of inhibiting leptin expression in lnASCs and obASCs on breast cancer cell (BCC) growth and progression.. Estrogen receptor positive (ER+) BCCs were co-cultured with leptin shRNA lnASCs or leptin shRNA obASCs and changes in the proliferation, migration, invasion, and gene expression of BCCs were investigated. To assess the direct impact of leptin inhibition in obASCs on BCC proliferation, MCF7 cells were injected alone or mixed with control shRNA obASCs or leptin shRNA obASCs into SCID/beige mice.. ER+ BCCs were responsive to obASCs during direct co-culture, whereas lnASCs were unable to increase ER(+) BCC growth. shRNA silencing of leptin in obASCs negated the enhanced proliferative effects of obASC on BCCs following direct co-culture. BCCs co-cultured with obASCs demonstrated enhanced expression of epithelial-to-mesenchymal transition (EMT) and metastasis genes (SERPINE1, MMP-2, and IL-6), while BCCs co-cultured with leptin shRNA obASCs did not display similar levels of gene induction. Knockdown of leptin significantly reduced tumor volume and decreased the number of metastatic lesions to the lung and liver. These results correlated with reduced expression of both SERPINE1 and MMP-2 in tumors formed with MCF7 cells mixed with leptin shRNA obASCs, when compared to tumors formed with MCF7 cells mixed with control shRNA obASCs.. This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women.

Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Breast; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Leptin; Matrix Metalloproteinase 2; MCF-7 Cells; Mice; Mice, SCID; Neoplasm Metastasis; Obesity; Plasminogen Activator Inhibitor 1; Receptors, Estrogen; RNA, Small Interfering; Stem Cells; Stromal Cells

Several mechanisms have been proposed to explain the adverse effect of obesity on quality of life among women with breast cancer, including alteration in some inflammatory markers. The aim of this study was to determine the status of serum levels of leptin, IL-6 and CRP in obese, overweight and normal weight breast cancer survivors in order to determine the relationship between inflammatory markers' levels and obesity.. This cross-sectional study was done on 75 women with breast cancer, 30 obese, 15 overweight and 30 normal weight patients. Serum leptin, IL-6, CRP, total protein, albumin and lipid profile as well as anthropometric parameters were measured in three groups.. Serum leptin levels of obese patients were significantly higher than those of overweight and normal weight patients (P<0.05). Higher serum CRP and lower albumin levels were observed in obese patients in comparison with normal weight patients (P<0.05). HDL-C level was significantly different between overweight and normal weight patients (P<0.05). Significant differences in serum IL-6 levels were not observed between the study groups (P>0.05). Moreover, multiple regression analysis showed that leptin was significantly associated with BMI (P<0.001), while albumin was negatively correlated with BMI (P<0.05). CRP levels were significantly correlated with BMI and waist-to-hip ratio (WHR) (P<0.05).. In conclusion, high leptin levels and alteration in acute phase proteins in obese patients may exaggerate the inflammation status. As inflammation has the potential to increase the susceptibility of the patients to metastasis development, it is necessary to decline its rate.

Topics: Adult; Biomarkers; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Inflammation Mediators; Interleukin-6; Leptin; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Obesity; Risk Factors; Survivors

Insulin-like growth factor (IGF) and adipokines have been implicated in prostate cancer carcinogenesis.. Data from 122 men with serum samples drawn within 3 months of starting ADT for metastatic prostate cancer was accessed retrospectively. IGF-1, IGF binding protein (BP)-1, leptin, and adiponectin levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to castration resistant prostate cancer (CRPC) and overall survival by the protein levels, adjusted for clinical variables, age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, extent of metastases and were reported as hazard ratio (HR) with 95% confidence interval (CI).. Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥ 1 vs. 0) was negatively associated with overall survival [H  = 2.8 (1.1-7.0), P = 0.03], and PSA nadir <0.2 was predictive of longer time to CRPC [HR = 0.3 (0.2-0.5), P < 0.0001]. The median time to CRPC by low, middle, and top IGFBP-1 tertile distribution was 20.7, 18.1, and 12.4 months, respectively, with HR for middle versus low tertile levels 3.1 (1.7-5), P = 0.0003, and for top versus low tertile levels was 2.4 (1.3-4.2), P = 0.003. The median overall survival by low, middle and top tertile IGFBP-1 level was 48.5, 46.4, and 32.8 months, respectively, with HR for top versus low tertile 2.5 (1.2-5.1), P = 0.01. There was no association with IGF-1, adiponectin and leptin.. Elevated IGFBP-1 appears to be associated with shorter time to CRPC and lower overall survival in men with metastatic prostate cancer.

Topics: Adiponectin; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Time Factors

Cachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated.. 140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months.. Ghrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 - 1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 - 0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease.. Ghrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

Topics: Aged; Area Under Curve; Biomarkers; Cachexia; Case-Control Studies; Cholesterol; Diabetes Mellitus; Female; Follow-Up Studies; Ghrelin; Heart Failure; Humans; Kaplan-Meier Estimate; Leptin; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Predictive Value of Tests; Proportional Hazards Models; ROC Curve; Serum Albumin; Survival Rate

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

Obesity is a well-established risk factor for endometrial cancer, due in part to the adipokines generated by adipose tissue, such as adiponectin (also known as Acrp30) and leptin, which are associated with many endocrine-related cancers. Recent reports suggested that Acrp30 inhibits leptin-stimulated cell proliferation in HEC-1A and RL95-2 endometrial cancer cell lines, and that the serum leptin/Acrp30 ratio plays an important role in endometrial cancer development. We explored whether Acrp30 could reverse the leptin-induced metastasis phenotype in the SPEC-2 endometrial cancer cell line. Transcripts for Acrp30 receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rb) were detected by quantitative real-time RT-PCR (qRT-PCR) in six endometrial cancer cell lines. Leptin (1 µg/ml) treatment stimulated SPEC-2 cell proliferation by inducing cell cycle arrest and apoptosis, while Acrp30 (10 µg/ml) treatment inhibited the growth of SPEC-2 cells. Importantly, Acrp30 was able to inhibit leptin-induced SPEC-2 cell proliferation. Leptin promoted SPEC-2 cell invasion in a Matrigel transwell assay, while Acrp30 partly suppressed the invasion stimulated by leptin. To investigate the molecular mechanism underlying this phenomenon, we monitored the AMPK and JAK/STAT3 signaling pathways by western blotting and cell immunofluorescence. Acrp30 reduced leptin-induced STAT3 phosphorylation and nuclear translocation via activation of the MAPK pathway. AG490 (JAK/STAT3 inhibitor) reduced MMP-2 and MMP-9 protein levels in cells treated with leptin, while IL-6 (JAK/STAT3 stimulator) and Compound C (AMPK inhibitor) elevated MMP-2 and MMP-9 protein levels in cells treated with Acrp30. In conclusion, we demonstrated that Acrp30 effectively reversed the invasion stimulated by leptin, and AMPK and JAK/STAT3 pathways mediated the invasive phenotype of SPEC-2 cells.

Topics: Adiponectin; AMP-Activated Protein Kinases; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Down-Regulation; Endometrial Neoplasms; Enzyme Activation; Female; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinases; Leptin; Membrane Proteins; Neoplasm Metastasis; Protein Transport; Receptors, Adiponectin; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade.. Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype.. Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and β-catenin from the plasma membrane.. We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Interleukin-6; Leptin; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Obese; Neoplasm Invasiveness; Neoplasm Metastasis; Obesity; Plasminogen Activator Inhibitor 1; Prostate; Prostatic Neoplasms; Testosterone; Vascular Endothelial Growth Factor A

Epidemiological studies have indicated that obesity is associated with colorectal cancer. The obesity hormone leptin is considered as a key mediator for cancer development and progression. The present study aims to investigate regulatory effects of leptin on colorectal carcinoma. The expression of leptin and its receptor Ob-R was examined by immunohistochemistry in 108 Chinese patients with colorectal carcinoma. The results showed that leptin/Ob-R expression was significantly associated with T stage, TNM stage, lymph node metastasis, distant metastasis, differentiation and expression of p-mTOR, p-70S6 kinase, and p-Akt. Furthermore, the effects of leptin on proliferation and apoptosis of HCT-116 colon carcinoma cells were determined. The results showed that leptin could stimulate the proliferation and inhibit the apoptosis of HCT-116 colon cells through the PI3K/Akt/mTOR pathway. Ly294002 (a PI3K inhibitor) and rapamycin (an mTOR inhibitor) could prevent the regulatory effects of leptin on the proliferation and apoptosis of HCT-116 cells via abrogating leptin-mediated PI3K/Akt/mTOR pathway. All these results indicated that leptin could regulate proliferation and apoptosis of colorectal carcinoma through the PI3K/Akt/ mTOR signalling pathway.

Topics: Apoptosis; Asian People; Cell Proliferation; Chromones; Colorectal Neoplasms; Humans; Immunohistochemistry; Leptin; Morpholines; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To investigate the relationship between the expression of leptin, p-mTOR protein and the pathogenesis, development and clinicopathological features in colon carcinoma.. The expression of leptin and p-mTOR protein was evaluated by immunohistochemical methods in 40 normal colon mucosas, 40 colon adenomatous polyps and 108 cases of colon carcinomas. The relationship between the staining pattern and clinicopathogical features was examined.. The positive rates of detection of leptin in normal colon mucosa, adenomatous polyps and colon carcinomas were 10% (4/40), 27.5% (11/40), and 71.3% (77/108), respectively; with significant differences among the three groups (P<0.05). The positive rates of p-mTOR protein in the normal colon mucosa, the adenomatous polyps, and the colon carcinomas were 2.5% (1/40), 20% (8/40), and 61.1% (66/108), respectively; with significant differences among the three groups (P<0.05). The expression of leptin and p-mTOR proteins were related to invasive depth, TNM stages, lymph node metastasis, distant metastasis and tumor differentiation (P<0.05), but not to age, sex, or site (P>0.05). In colon carcinoma tissues, leptin expression was positively correlated with p-mTOR expression (P<0.01).. Leptin and p-mTOR proteins may play important roles in the occurrence and development of colon carcinoma. The detection of leptin and p-mTOR may be helpful for evaluation of the prognosis of the patient with colon carcinoma.

Topics: Adenocarcinoma; Adenomatous Polyps; Aged; Colon; Colonic Neoplasms; Female; Humans; Intestinal Mucosa; Leptin; Male; Middle Aged; Neoplasm Metastasis; Phosphorylation; Prognosis; TOR Serine-Threonine Kinases

The present study investigated the effects of non-motorized voluntary running on experimental metastasis of B16BL/6 melanoma and spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice. After 9 weeks of running, mice (n=30 per group) received an intravenous injection of B16BL/6 cells or a subcutaneous injection of LLC cells, and then they were continued with their running activities. Experiments were terminated 2 weeks after the intravenous injection of B16BL/6 cells or 2 weeks after surgical removal of the primary tumor from mice subcutaneously injected with LLC cells. Mice in the running group ran an average of 4-6 km/day for the duration of the experiment. Voluntary running reduced body weight compared with the sedentary controls, but there were no differences in the number and size of lung metastases between groups with either model. Voluntary running significantly reduced plasma insulin and leptin levels and increased adiponectin level in mice with and without LLC compared with the sedentary controls. Having LLC significantly increased plasma concentrations of vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), PDGF-AB and monocyte chemotactic protein-1 (MCP-1) in mice. Voluntary running significantly increased plasma PDGF-BB and PDGFAB, but not VEGF and MCP-1, in mice with LLC compared to their sedentary counterparts. In conclusion, non-motorized voluntary running was favorable to body weight and the expression of related adipokines, but at 4-6 km/day it did not affect either experimental or spontaneous metastasis in mice.

Topics: Adiponectin; Animals; Becaplermin; Body Weight; Chemokine CCL2; Insulin; Leptin; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Physical Conditioning, Animal; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Regression Analysis; Vascular Endothelial Growth Factor A

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

Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development. TRAMP mice were assigned to ad libitum (AL), ICR (2 wk 50% AL consumption followed by 2 wk pair feeding to AL consumption), and CCR (25% AL consumption) groups at 7 wk of age and followed until disease burden necessitated euthanasia or mice reached terminal endpoints (48 or 50 wk of age). Body weights fluctuated in response to calorie intake (P < 0.0001). ICR mice were older at tumor detection than AL (P = 0.0066) and CCR (P = 0.0416) mice. There was no difference for age of tumor detection between AL and CCR mice (P = 0.3960). Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups. These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.

Topics: Adiponectin; Aging; Animals; Body Composition; Caloric Restriction; Diet; Genotype; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Transgenic; Neoplasm Metastasis; Prostatic Neoplasms; Survival Rate; Time Factors

Obesity is an independent risk factor for pancreatic cancer development and progression, although the mechanisms underlying this association are completely unknown. The aim of the current study was to investigate the influence of obesity on pancreatic cancer growth using a novel in vivo model.. Lean (C57BL/6 J) and obese (Lep(Db) and Lep(Ob)) mice were inoculated with murine pancreatic cancer cells (PAN02), and studied after 5 weeks of tumor growth. Tumor histology was evaluated by hematoxylin and eosin staining, cellular proliferation was assessed by 5-bromodeoxyuridine, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Serum adiponectin, leptin, and insulin levels were assayed.. Obese mice developed larger tumors, and a significantly greater number of mice developed metastases; mortality was also greater in obese mice. Tumor apoptosis did not differ among strains, but tumors from both obese strains had greater proliferation relative to those growing in lean animals. Serum adiponectin concentration correlated negatively and serum insulin concentration correlated positively with tumor proliferation. Intratumoral adipocyte mass in tumors from both obese strains was significantly greater than that in tumors of lean mice.. Data from this novel in vivo model suggest that the altered adipokine milieu and insulin resistance observed in obesity may lead directly to changes in tumor microenvironment, thereby promoting pancreatic cancer growth and dissemination.

Topics: Adipocytes; Adiponectin; Animals; Apoptosis; Blood Glucose; Cell Line, Tumor; Cell Proliferation; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neoplasm Metastasis; Neoplasm Transplantation; Obesity; Pancreatic Neoplasms

To evaluate the expression of leptin and leptin receptor in benign prostatic hyperplasia (BPH) and prostate cancer (PCa), and to investigate whether they are associated with the development and progression of PCa.. Immunohistochemical staining was performed to examine the expression of leptin and leptin receptor in BPH and PCa. PCa was divided into three groups: localized PCa, locally advanced PCa and metastatic PCa. The positive staining was identified and the percentage of the positive staining was graded. We also assessed the relationship between both the Gleason score and body mass index (BMI) and PCa.. The percentage of the leptin expression in PCa was significantly higher than that in BPH (P < 0.01). For the PCa group, the expressed levels of leptin showed a considerable correlation with localized PCa and metastatic PCa (P < 0.05). Leptin receptor, however, did not reveal a definite difference between BPH and PCa. The expression of leptin indicated a significant difference between well-differentiated PCa (Gleason score =or< 6) and poorly differentiated PCa (Gleason score 8?0) (P < 0.05). The relation between the leptin expression level in PCa and the BMI was not remarkable (P = 0.447).. Our results suggest that leptin might have a promoting effect on the carcinogenesis and progression of PCa.

Topics: Aged; Biomarkers; Body Mass Index; Disease Progression; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Neoplasm Metastasis; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Leptin

Identification of regional node metastasis is important for accurate staging and optimal treatment of early melanoma. We hypothesize that the nodal profile of immunoregulatory cytokines can confirm the identity of the first tumor-draining regional node, i.e., the sentinel node (SN) and indicate its tumor status.. RNA was extracted from freshly dissected and preserved nodal tissue of 13 tumor-negative SNs, 10 tumor-positive SNs (micrometastases <2 mm), and 11 tumor-negative non-SNs (NSN). RNA was converted into cDNA and then amplified by PCR. Expression of 96 cytokines and chemokines was assessed using cDNA microarray and compared by using hierarchical clustering.. Fifty-seven genes were expressed at significantly (P < 0.05) different levels in SNs and NSNs (4 genes had higher expression, and 53 genes had lower expression in SNs). Expression levels of interleukin-13 (IL-13), leptin, lymphotoxin beta receptor (LTbR), and macrophage inflammatory protein 1b (MIP1b) were significantly higher (P < 0.04, P < 0.01, P < 0.05, and P < 0.01, respectively), and expression level of IL-11Ra was lower (P < 0.03) for tumor-positive as compared with tumor-negative SN. Receiver-operator characteristics curve analyses showed that the area under the curve (AUC) for IL-13, leptin, LTbR, MIP1b, and IL-11Ra was 0.79, 0.83, 0.75, 0.81, and 0.77, respectively. The AUC for the five genes in combination was 0.973, suggesting high concordance of gene-expression profiles with SN staging.. SNs have a different immunoregulatory cytokine profile than NSNs. The cytokine profile of tumor-positive SNs; increased expression of IL-13, leptin, LTbR, and MIP1b and decreased expression of IL-11Ra, may provide clues to the local tumor lymph node interaction seen in the earliest steps of melanoma metastasis.

Topics: CD3 Complex; Cell Line, Tumor; Chemokines; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-13; Leptin; Lymph Nodes; Melanoma; Neoplasm Metastasis; Receptors, Interleukin-11; Sentinel Lymph Node Biopsy; Skin Neoplasms

Epidemiological studies indicate that the risk factors for the development of various cancers are closely associated with metabolic symptoms such as obesity, hyperlipidemia, and insulin resistance caused by the excess consumption of high-calorie diets. However, the mechanisms of tumor growth and metastasis caused by feeding a high-calorie diet have not been clarified yet in tumor-bearing mice. In this study, we examined the effects of a high-fat (HF), a high-sucrose (HS), a high-cholesterol (HC) or a low-fat/low-sucrose (LF/LS) diet on tumor growth and metastasis in tumor-bearing mice. Angiogenic factors such as plasma leptin and monocyte chemoattractant protein-1 (MCP-1) were increased after the implantation of tumors, whereas conversely, an antiangiogenic factor, adiponectin, was reduced after the implantation of tumors in mice fed the HF, the HS, or the HC diet compared to LF/LS diet. Furthermore, we found that vascular endothelial growth factor, hypoxia inducible factor-1alpha and MCP-1 expression levels in tumors of mice fed the HF, the HS, or the HC diet were increased compared to those of mice fed the LF/LS diet. These findings suggest that the acceleration of tumor growth and metastasis by feeding the 3 diets may be due to the increase of angiogenic factors and the reduction of antiangiogenic factors.

Topics: Adiponectin; Animals; Body Weight; Carcinoma, Lewis Lung; Chemokine CCL2; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Sucrose; Disease Progression; Dose-Response Relationship, Drug; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Hyperlipidemias; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Obesity; Random Allocation

To evaluate leptin and leptin receptor (OB-R) expression in human breast cancer and determine whether it could be effective for the prevention and treatment of breast cancer.. Immunohistochemical staining using specific antibodies was used to evaluate the protein expression of leptin and OB-R in 76 invasive ductal carcinomas and 32 samples of corresponding normal mammary gland, and the relationship between the expression of OB-R and leptin and clinicopathological features was analyzed.. Normal mammary epithelial cells did not express a significant level of Ob-R, whereas carcinoma cells showed positive staining for OB-R in 63 (83%) cases. Both normal epithelial cells and carcinoma cells expressed a significant level of leptin. However, overexpression of leptin, as determined by staining intensity, was observed in 70 cancers (92%) but in no normal epithelium. The expression of OB-R showed a significant correlation with the level of leptin expression. Interestingly, distant metastasis was detected in 21 (34%) of 61 OB-R-positive tumors with leptin overexpression, but in none of the 15 tumors that lacked OB-R expression or leptin overexpression (P < 0.05). Consequently, patients with the former tumors showed significantly lower survival than those with the latter.. Leptin may have a promoting effect on the carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Functional inhibition of leptin may be effective for the prevention and treatment of breast cancer.

Topics: Adipose Tissue; Adult; Aged; Breast; Breast Neoplasms; Carcinoma, Ductal; Cells, Cultured; Epithelium; Female; Humans; Immunohistochemistry; Leptin; Male; Mammary Glands, Human; Middle Aged; Neoplasm Metastasis; Receptors, Cell Surface; Receptors, Leptin; Risk; Time Factors

Angiogenesis plays an important role in tumor growth and metastasis in solid tumors. VEGF is an important regulator of tumor angiogenesis. Both leptin and prolactin have also been suggested to have roles in the regulation of angiogenic process. In our study, we measured serum leptin, prolactin and VEGF levels in 30 metastatic, 55 non-metastatic breast cancer patients and 25 control subjects. Serum leptin levels were found to be similar in non-metastatic (38.1+/-19.5 ng/ml), metastatic patients (39.6+/-16.3 ng/ml) and control subjects (35.6+/-13.9 ng/ml) (p>0.05). There was no statistically significant difference between patients with visceral metastasis (44.0+/-16.8 ng/ml) and patients with bone metastasis (35.2+/-15.0 ng/ml) (p>0.05). Serum prolactin levels were found to be similar in non-metastatic (12.2+/-10.7 ng/ml), metastatic patients (11.6+/-8.2 ng/ml) and control subjects (12.3+/-8.1 ng/ml), (p>0.05). Moreover, serum prolactin levels were not different in patients with visceral (11.4+/-8.8 ng/ml) and bone metastasis (11.8+/-8.0 ng/ml), (p>0.05). Metastatic patients had higher serum VEGF levels (249.8+/-154.9 pg/ml), when compared to the non-metastatic patients (138.7+/-59.3 pg/ml) and control subjects (108.4+/-47.7 pg/ml), (p<0.05). There was no difference in serum VEGF levels in non-metastatic patients and control subjects (p>0.05). Patients with visceral metastasis (337.0+/-168.0 pg/ml) had higher serum VEGF levels, when compared to patients with bone metastasis (162.6+71.8 pg/ml), (p<0.05). Serum VEGF activity may be used to evaluate angiogenic and metastatic activity in breast cancer patients. However, serum leptin and prolactin levels does not seem to be related with angiogenic activity and metastasis in breast cancer patients.

Topics: Adult; Breast Neoplasms; Carcinoembryonic Antigen; Endothelial Growth Factors; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Lymphokines; Mucin-1; Neoplasm Metastasis; Neovascularization, Pathologic; Prolactin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors