leptin and Carcinoma

Obesity is highly complicated by hypertension and hyperglycemia. In particular, it has been proposed that obesity-related hypertension is caused by adipocyte-derived factors that are recognized as undetermined proteins secreted from adipocytes. Adipocyte-derived factors have been known to be related to aldosterone secretion in the adrenal gland. So far, Wnt proteins, CTRP-1, VLDL, LDL, HDL and leptin have been demonstrated to stimulate aldosterone secretion. In contrast, it has not yet been clarified whether adipocyte-derived factors also affect adrenal cortisol secretion.. In the present study, we investigated the effect of adipocyte-derived factors on cortisol synthase gene CYP11B1 mRNA expression in vitro study using adrenocortical carcinoma H295R cells and mouse fibroblast 3T3-L1cells. Interestingly, adipocyte-derived factors were demonstrated to have the ability to stimulate CYP11B1 mRNA expression.. Since CYP11B1 is well known as a limiting enzyme of cortisol synthesis, our study suggests that adipocyte-derived factors may stimulate cortisol secretion, as well as aldosterone secretion. Taken together, adipocyte-derived factors may be the cause of metabolic syndrome due to their stimulating effects on aldosterone/cortisol secretion. Therefore, the innovation of novel drugs against them may possibly be a new approach against metabolic syndrome.

Topics: Adipocytes; Adrenal Cortex; Adrenal Cortex Neoplasms; Animals; Carcinoma; Cell Line; Cell Line, Tumor; Cytochrome P-450 CYP11B2; Fibroblasts; Gene Expression Regulation; Humans; Hydrocortisone; Leptin; Lipoproteins, LDL; Mice; Proteins; RNA, Messenger; Steroid 11-beta-Hydroxylase; Wnt Proteins; Zona Fasciculata

The incidence of thyroid carcinoma is increasing all over the world. Some studies have suggested that the change of adipokines expression can induce thyroid carcinoma. However, other studies have come to the opposite conclusion. Therefore, we studied the relationship between adipokines and thyroid carcinoma.. Databases-PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries were searched. A meta-analysis was then performed through a fixed or random-effects model to calculate I values for heterogeneity analysis.. Adipokines (TNF-α, IL-6 and leptin) show a strong relationship between elevated concentrations (in serum and/or tissue) and thyroid carcinoma. However, the association between adiponectin and thyroid carcinoma needs further research.

Topics: Adipocytes; Adiponectin; Carcinoma; Case-Control Studies; Humans; Incidence; Interleukin-6; Leptin; Risk Factors; Thyroid Gland; Thyroid Neoplasms; Tumor Necrosis Factor-alpha

Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary.. To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC.. Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan-Meier curve was generated to test survival time.. The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival (all P > 0.05).. High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival.

Topics: Biomarkers; Breast Neoplasms; Carcinoma; Female; Humans; Leptin; Polymorphism, Single Nucleotide; Receptors, Leptin; Retrospective Studies

Employing targeting ligands on the surface of liposomes has the great potential to improve therapeutic efficacy and decreases off-target effects of liposomal formulations. In the present study, a leptin-derived peptide (Lp31) was evaluated to optimize the therapeutic efficacy of PEGylated liposomal Doxorubicin (PLD, Caelyx®). Leptin is an appetite regulatory hormone that is secreted into the blood circulation by the adipose tissue and it functions via its over expressed receptors (Ob-R) in a wide variety of cancers. Lp31, as targeting ligand, was conjugated to Maleimide-PEG2000-DSPE and then post-inserted into Caelyx. The anti-tumor activity and therapeutic efficacy of leptin modified Caelyx were evaluated and compared with Caelyx. The in vitro experiments demonstrated enhanced cytotoxicity and cellular uptake of Lp31-targeted Caelyx in C26 cell line compared to Caelyx. In BALB/c mice bearing C-26 murine carcinoma, Lp31 modified Caelyx groups exhibited significantly higher doxorubicin concentration at tumor tissue. Furthermore, Lp31 modified Caelyx at the dose of 10 mg/kg resulted in significant tumor growth inhibition and enhanced survival time compared to Caelyx. According to these results, the novel Lp31-liposomal doxorubicin offers great promise for the treatment of colon cancer and merits further investigation.

Topics: Animals; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Doxorubicin; Leptin; Liposomes; Mice; Mice, Inbred BALB C; Peptides; Polyethylene Glycols; Tissue Distribution

This study examined leptin expression in cases of bladder cancer and its diagnostic and prognostic usefulness in bladder malignancies.A set of 128 urinary bladder cancer cases and 24 normal specimens of bladders were employed for an immunohistochemical investigation of leptin expression in tissue microarrays.Leptin was up-regulated during transformation and was identified as brown cytoplasmic granules in the malignant urothelium of 123 (96%) bladder neoplasms, of which 68 (53.1%) cases showed high levels (moderate to strong) of staining. Strong staining was found to be associated with high stages (P = 0.001), muscularis propria infiltration (P < 0.001), vascular invasion (P < 0.03), lymph node involvement (P < 0.02), metastases (P < 0.05), and mortality (P < 0.03). Furthermore, various important survival distributions were detected with leptin expression in the malignant urothelium (P < 0.03).These pilot results suggest that leptin might be a valid marker for predicting the stage and bad prognoses in bladder carcinoma.

Topics: Carcinoma; Humans; Leptin; Prognosis; Urinary Bladder Neoplasms

Triple-Negative breast cancer (TNBC), accounts for a large percentage of breast cancer cases in India including Northeast India. TNBC has an unclear molecular aetiology and hence limited targeted therapies. Human breast is comprised of glandular, ductal, connective, and adipose tissues. Adipose tissue is composed of adipocytes. The adipocytes apart from being energy storage depots, are also active sources of adipocytokines and/or adipokines. The role of adipokines in breast cancer including TNBC has been sporadically documented. Two adipokines in particular, leptin and adiponectin, have come to be recognized for their influence on breast cancer risk and tumour biology. Therefore, the aim of this study was to understand the association of differential expression of critical adipokines and associated cellular mechanism in the susceptibility and severity of TNBC in northeast Indian population.. We collected 68 TNBC and 63 controls cases and examined for serum leptin and adiponectin levels using enzyme linked immunosorbent assay (ELISA). Leptin Receptor (Ob-R) mRNA expression was determined by real-time polymerase chain reaction (RT-PCR) assay. Differential Ob-R mRNA expression and correlation with cancer stem cell (CSC) markers was evaluated, and correlated with severity.. The serum leptin levels were significantly associated with TNBC severity, while the adiponectin levels were comparative. The serum leptin levels correlated inversely with the adiponetin levels. Serum leptin levels were unaffected with difference in parity. The difference in leptin levels in pre and post menopausal cases were found to be statistically non-significant. Higher leptin levels were also found to be associated obesity, mortality and recurrence. Obesity was found to be a factor for TNBC pathogenesis and severity. Increased Ob-R mRNA expression was associated with TNBC, significantly with TNBC severity, and was significantly higher in obese patients with higher grade TNBC cases. The Ob-R gene mRNA expression was significantly higher in the obese TNBC cases showing recurrence or mortality. The higher Ob-R gene mRNA expression correlated significantly with higher serum leptin levels and lower serum adiponectin levels in TNBC cases. The Ob-R mRNA expression with associated with modulation of CSC oct4 and nanog.. In conclusion, the present study is first of its kind on TNBC from northeast India, indicates that adipocytokines does play a role in TNBC pathogenesis. Thus, the understanding of molecular mechanisms of both leptin and adiponectin and their interplay in TNBC offer the prospects for new therapeutic approaches targeting similar signalling pathways.

Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Carcinoma; Case-Control Studies; Female; Humans; India; Leptin; Middle Aged; Nanog Homeobox Protein; Neoplastic Stem Cells; Obesity; Octamer Transcription Factor-3; Receptors, Leptin; Triple Negative Breast Neoplasms

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

Topics: Carcinoma; Female; Humans; Leptin; Male; Thyroid Neoplasms

Topics: Carcinoma; Humans; Leptin; Thyroid Neoplasms

There is a proven relationship between obesity and several cancers including breast, endometrium, colorectal, and esophagus. With the increasing incidence of both obesity and thyroid cancer, we designed the present study to investigate a causal relationship between leptin, which is one of the well known adipokines, and well-differentiated thyroid cancer (WDTC).. Serum leptin levels were measured in 30 patients with WDTC and compared to 30 healthy control subjects before and 1 month after surgery. Other parameters studied included age, sex, body mass index, menopausal status in women, lymph node status, tumor size, and disease multifocality.. There were no differences between the two groups regarding age and sex. Preoperative leptin levels were higher in the WDTC patients when compared to the control patients [19.25 (1.50-109.60) vs 0.90 (0.50-11.80) ng/ml, p < 0.001, group 1 vs group 2, respectively]. A significant drop in leptin levels 1 month after surgery occurred in the WDTC group, falling from 19.25 (1.50-109.60) to 0.90 (0.60-8.90) ng/ml (p < 0.001). This did not occur in the control group (p = 0.274). Lymph node involvement, tumor size, and multifocality had no effect on leptin levels, although trends were observed (p = 0.48, 0.079, and 0.064), respectively.. Serum leptin levels were significantly higher in WDTC patients when compared to control group patients, with a significant drop after surgery. Leptin may play a role in diagnosis of WDTC; however, its prognostic value is still undetermined.

Topics: Adolescent; Adult; Aged; Body Mass Index; Carcinoma; Case-Control Studies; Cell Differentiation; Female; Humans; Leptin; Lymph Node Excision; Male; Middle Aged; Postoperative Period; Preoperative Period; Prognosis; Thyroid Neoplasms; Thyroidectomy; Young Adult

Leptin (LEP), an adipocyte-derived cytokine, has been reported to participate in carcinogenesis. Elevated levels of systemic and pulmonary LEP are associated with diseases related to lung injury and lung cancer. The purpose of the present study was to investigate if the LEP and leptin receptor (LEPR) gene polymorphisms are associated with lung cancer in a cohort of Turkish population. One hundred and sixty-two lung cancer patients and 130 healthy controls were included in the study. The genotypes of LEP gene -2548G > A and LEPR gene Q223R polymorphisms were determined using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) analysis. The genotype frequencies of LEP -2548G > A polymorphism showed statistically significant differences between lung cancer patients and controls (p = 0.007). GA + AA genotypes and A allele of LEP -2548G > A polymorphism was found to be susceptibility factors for lung cancer (p = 0.003, odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.32-4.10; p = 0.003, OR 1.65, 95 % CI 1.18-2.29, respectively). The genotype and allele frequencies of LEPR Q223R polymorphism did not show any statistically significant differences between lung cancer patients and controls (p = 0.782 and p = 0.762, respectively). Although AA-QQ and AA-QR combined genotypes of LEP -2548G > A-LEPR Q223R loci were significantly higher in lung cancer patients (p = 0.020 and p = 0.047, respectively), GG-QQ, GG-QR, and AA-RR combined genotypes were significantly higher in control group. As a result, susceptibility effects of LEP -2548G > A polymorphism alone or in combination with LEPR Q223R polymorphism on lung cancer were observed. Further studies are necessary to prove the association of LEP and LEPR gene polymorphisms with lung cancer.

Topics: Aged; Carcinoma; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Lung Neoplasms; Male; Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Receptors, Leptin

Leptin, a multifunctional peptide hormone encoded by the obese (ob) gene, plays an important role in modulating lipid metabolism and energy equilibrium. Leptin reportedly acts as a cell growth factor and enhances the proliferation of various tumors. We investigated the effect of leptin on aromatase (P450arom) expression and estradiol (E2) formation in a model of endometrial carcinoma.. We established a co-culture model of endometrial fibroblasts and the Ishikawa endometrial carcinoma cell line. P450arom mRNA and protein expression were measured with RT-PCR and immunoblotting, respectively, before and after leptin treatment. The effect of leptin on estradiol formation in endometrial carcinoma cells was also detected with a radioimmunological method.. P450arom mRNA expression was increased in co-cultures treated with 100 ng/ml leptin (P<0.01). Estradiol synthesis was induced when androstenedione was added to the culture medium, and significantly higher estradiol concentration was observed in co-cultures treated with 100 ng/ml leptin,. Leptin is an important component of the microenvironment and stimulates endometrial carcinoma cell proliferation via enhancing P450arom expression and estradiol synthesis.

Topics: Aromatase; Carcinoma; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Endometrial Neoplasms; Estradiol; Female; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Leptin

Metabolic syndrome (MetS) describes a clustering of factors including central obesity, hypertension and raised plasma glucose, triglycerides and high-density lipoprotein (HDL) cholesterol. Central obesity is associated with a risk for colorectal cancer, but the impact of MetS on colorectal cancer biology and outcomes is unclear.. A prospective observational study of colorectal cancer patients was carried out in an Irish population. Patients underwent metabolic and anthropometric assessment before treatment, including measurement of serum hormones and adipokines and CT measurement of visceral fat. MetS was defined according to the International Diabetes Federation definition(3) .. One-hundred and thirty consecutive colorectal cancer patients (66 men and 64 women) were recruited. MetS was diagnosed in 38% patients compared with the population norms reported at 21%(21) . Male patients had a significantly greater visceral fat area compared with female patients. MetS was associated with node-positive disease (P = 0.026), percentage nodal involvement (P = 0.033) and extramural vascular invasion (P = 0.049) in male patients but no significant association was observed in female patients. HDL cholesterol was also significantly associated with a more advanced pathological stage (P = 0.014) and node-positive disease (P = 0.028). Leptin was associated with nodal status (P = 0.036), microvascular invasion (P = 0.054), advanced pathological stage (P = 0.046) and more advanced Dukes stage (P = 0.042).. We report a high prevalence of MetS and visceral obesity in a colorectal cancer population. MetS and plasma leptin are associated with a more aggressive tumour phenotype in male patients only.

Topics: Aged; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Carcinoma; Cholesterol, HDL; Cholesterol, LDL; Colorectal Neoplasms; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lymphatic Metastasis; Male; Metabolic Syndrome; Neoplasm Invasiveness; Prospective Studies; Radiography; Sex Factors; Triglycerides; Waist Circumference

Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr(-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-)Fxr(-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr(-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr(-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-)Fxr(-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-)Fxr(-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (<11 months old) Ob(-/-)Fxr(-/-) mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Carcinoma; Cell Transformation, Neoplastic; Diet, High-Fat; Dietary Fats; Energy Metabolism; Female; Gene Knockout Techniques; Glucose Intolerance; Intestinal Absorption; Leptin; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Obese; Muscle, Skeletal; Obesity; Receptors, Cytoplasmic and Nuclear; Sex Factors; Weight Gain

Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and "educated" CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer-stromal cell communication may represent an effective strategy for targeted therapy of breast cancer.

Topics: Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epidermal Growth Factor; Estrogen Receptor alpha; Female; Fibroblasts; Gene Expression Profiling; Humans; Leptin; Neoplasm Invasiveness; Receptors, Leptin; Signal Transduction; Stromal Cells

To investigate the expression and biological significance of Leptin, Leptin receptor, Vascular Endothelial Growth Factor (VEGF), and CD34 protein in colorectal carcinoma tissues. The expression of Leptin, Leptin receptor, VEGF, and CD34 was detected in 68 cases of colorectal carcinoma tissues, paired para-carcinoma tissues and normal colorectal tissues by Immunohistochemical SP Method. The results and related clinicopathological data were analyzed. The positive rate of Leptin, Leptin receptor, and VEGF was significantly higher in colorectal carcinoma tissues than that in paired para-carcinoma tissues and normal colorectal tissues. The expression of Leptin, Leptin receptor, and VEGF was correlated with grade of tumor differentiation, depth of bowel wall invasion, lymph node metastasis, Dukes stage, distant metastasis, and lympho/vascular tumor embolization. Microvessel density (MVD) value in colorectal carcinoma was significantly higher than that in para-carcinoma tissues and normal colorectal tissues, and the density in para-carcinoma tissues was higher than that in normal colorectal tissues. The expression of Leptin, Leptin receptor, VEGF, and MVD value in colorectal carcinoma was positively correlated. In conclusion, microvessel density value is an important index of the growth, invasion, and metastasis of colorectal carcinoma. The binding of Leptin and Leptin receptor promotes the proliferation of colorectal carcinoma cells. The synergy between Leptin and VEGF accelerates the angiogenesis in colorectal carcinoma and accelerates the invasion and metastasis of the tumor cells.

Topics: Adult; Aged; Antigens, CD34; Carcinoma; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Receptors, Leptin; Vascular Endothelial Growth Factor A

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice. In vivo limiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheres in vitro and leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

Topics: Animals; Carcinoma; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Down-Regulation; Female; Leptin; Mammary Neoplasms, Animal; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Neoplastic Stem Cells; Obesity; Receptors, Leptin; Wnt1 Protein

There is growing evidence that obesity is a risk factor of cancer incidence and mortality. Hence, the identification of the mechanistic links between obesity and cancer progression is emerging as a topic of widespread interest. Recently, several groups have addressed the functional roles of leptin, an adipocyte-derived adipokine, for mammary tumor progression. In this issue of Endocrine-Related Cancer, Zheng et al. study the role of leptin on tumor growth in a xenograft model of MMTV-Wnt1-derived cancer cells. They study growth of these cancer cells in the context of obese animals, such as ob/ob mice (lacking leptin) and db/db mice (lacking functional leptin receptors (LEPR)) and find that leptin triggers LEPR-positive cancer stem cell differentiation, thereby promoting tumor cell survival. These findings highlight the therapeutic potential for leptin and leptin signaling in the context of mammary tumor growth.

Topics: Animals; Carcinoma; Cell Proliferation; Female; Leptin; Mammary Neoplasms, Animal; Mammary Tumor Virus, Mouse; Neoplastic Stem Cells; Wnt1 Protein

The incidence of thyroid cancer has remarkably increased in recent years. Epidemiologic data suggest that obesity is associated with an increased incidence of several types of malignancies, including thyroid cancer. Leptin, an adipocyte-derived cytokine, has been shown to be involved in cancer development and progression. We previously demonstrated that papillary thyroid cancer expressing leptin receptor and/or leptin has a higher incidence of lymph node metastasis. In this study, we investigated the effects of leptin on cell migration in K1 and B-CPAP papillary thyroid cancer cells. Expression of leptin receptor was observed in both cell lines. Leptin enhanced the migratory activity significantly in a dose-dependent manner. We showed that leptin induced AKT and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of phosphatidylinositol 3-kinase and ERK activation using pharmacological inhibitors effectively blocked leptin-induced migration of K1 and B-CPAP cells. Taken together, this study provides new mechanistic evidence for a role of leptin in the regulation of papillary thyroid cancer progression by stimulating tumor cell migration.

Topics: Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Extracellular Signal-Regulated MAP Kinases; Humans; Immunohistochemistry; Leptin; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms

Active migration of tumor cells is a prerequisite for the development of metastasis and tumor progression, and is regulated by a variety of extracellular ligands. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5- to 2-fold with obesity-associated colon cancer accounting for 14-35% of total incidence. In obese individuals, serum levels of leptin are markedly increased, and therefore, we have investigated the impact of this adipocytokine on the migration of various human colon carcinoma cell lines such as SW480, SW620, and HCT116. Leptin significantly enhanced the migratory activity of all three cell lines, and the strongest effect was observed in SW480 cells, which increased their locomotor activity from 28% spontaneously locomoting cells to 50%. The intracellular signal transduction regulating this pro-migratory effect involves the activation of the transcription factor signal transducer and activator of transcription-3 via Janus kinases, but also the activity of src tyrosine kinases, focal adhesion kinase, exclusively protein kinase Cdelta, and the phosphatidyl-inositol-3-kinase, as proven by the use of particular inhibitors and target-specific small interfering RNAs. Herein, we deliver new evidence for a modulatory role of leptin in the regulation of colon cancer progression by stimulating tumor cell migration. Thus, our findings have potential clinical implications, because understanding the impact of leptin on tumor cell migration and the underlying signal transduction mechanisms is mandatory for future development of novel therapeutics to treat obesity-associated colorectal cancer.

Topics: Carcinoma; Cell Movement; Colonic Neoplasms; Disease Progression; HCT116 Cells; Humans; Janus Kinases; Leptin; Phosphatidylinositol 3-Kinases; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Transcription Factors; Tumor Cells, Cultured

Excess body weight is associated with a moderately increased risk of thyroid cancer. Adipocyte-derived hormone, leptin, has been shown to enhance cell growth and migration in many cancer types. Limited evidence suggests that leptin has direct actions on the thyroid gland, but there are no data available on the effect of leptin on thyroid cancer cells. We evaluated the action of leptin on gene expression, cell growth, cell cycle, and cell migration in anaplastic (ARO), follicular (WRO) and papillary (CGTH-W3) thyroid carcinoma cell lines. Expression of long-form leptin receptors was observed in all thyroid cancer cell lines. Leptin stimulation did not alter the expression levels of leptin, leptin receptor and sodium-iodide symporter. Cell growth and cell cycle were not changed after leptin treatment. However, leptin was able to promote cell migration of papillary thyroid cancer cells, but inhibited migration of anaplastic and follicular cancer cells. In summary, our study suggests that leptin modulates cell migration of thyroid cancer cells in a cell type-specific manner.

Topics: Adenocarcinoma, Follicular; Apoptosis; Blotting, Western; Carcinoma; Carcinoma, Papillary; Cell Cycle; Cell Movement; Cell Proliferation; Humans; Leptin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Neoplasms

Obesity results in increased circulating levels of specific adipokines, which are associated with colon cancer risk. The disease state is associated with increased leptin, insulin, IGF-1, and IL-6. Conversely, adiponectin levels are decreased in obese individuals. Previously, we demonstrated adipokine-enhanced cell proliferation in preneoplastic, but not normal, colon epithelial cells, demonstrating a differential effect of adipokines on colon cancer progression in vitro. Using a model of late stage carcinoma cancer cell, namely murine MC-38 colon carcinoma cells, we compared the effect of obesity-associated adipokines (leptin, insulin, IGF-1, and IL-6) on MC-38 cell proliferation and determined whether adiponectin (full length or globular) could modulate adipokine-induced cell proliferation. We show that insulin and IL-6, but not leptin and IGF-1, induce proliferation in MC-38 cells. Adiponectin treatment of MC-38 cells did not inhibit insulin-induced cell proliferation but did inhibit IL-6-induced cell proliferation by decreasing STAT-3 phosphorylation and activation. Nitric oxide (NO) production was increased in MC-38 cells treated with IL-6; co-treatment with adiponectin blocked IL-6-induced iNOS and subsequent NO production. These data are compared to previously reported findings from our laboratory using the YAMC (model normal colon epithelial cells) and IMCE (model preneoplastic) cells. The cell lines are utilized to construct a model summarizing the hormonal consequences of obesity and the impact on the differential regulation of colon epithelial cells along the continuum to carcinoma. These data, taken together, highlight mechanisms involved in obesity-associated cancers and may lead to potential-targeted therapies.

Topics: Adipokines; Adiponectin; Animals; Carcinoma; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; Humans; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Obesity; STAT3 Transcription Factor

Topics: Adult; Body Mass Index; Carcinoma; Child, Preschool; Fasting; Humans; Hypothyroidism; Insulin; Leptin; Obesity; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triglycerides; Triiodothyronine; Weight Loss

Leptin and adiponectin are cytokines produced by adipose tissue with opposite effects on tumor growth: the former stimulate whereas the latter inhibit it. The objective was to analyze the association of LEP A19G and ADIPOQ+45 T/G and +276 G/T polymorphisms in Mexican patients with colorectal cancer (CRC). 68 unrelated patients with CRC (study group) and 102 blood donors (control group); all subjects were Mestizos from western Mexico. The polymorphisms were established by PCR-RFLP on DNA samples obtained from peripheral blood. The LEP A19G polymorphism showed significant differences between CRC patients and control group (p= 0.01 for G/A genotype and p= 0.02 for the recessive model G/G +G/A); yet, in the analysis stratified by gender, this difference remained significant only in males. The ADIPOQ polymorphisms did not shown any significant differences. Our results suggest that the A19G LEP polymorphism is associated with CRC in Mexican patients.

Topics: Adiponectin; Carcinoma; Colorectal Neoplasms; Female; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Leptin; Male; Mexico; Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide

Aberrations of circulating nucleic acid integrity have been observed in cancer patients. However, the clinical significance of such changes has not been completely elucidated. In this study, we investigated the plasma DNA integrity in nasopharyngeal carcinoma (NPC) patients and its association with patients' survival after radiotherapy.. Plasma DNA integrity was analyzed for 105 NPC patients before and after curative-intent radiotherapy and for 40 healthy controls. The plasma DNA concentration of each sample was measured by two real-time PCRs targeting the leptin gene. The amplicon sizes of the two assays were 105 and 201 bp. The integrity index was calculated as the ratio of the two concentrations (201 bp/105 bp). More intact circulating DNA would give a higher integrity index.. The plasma DNA integrity index of the NPC patients was significantly higher than that of the healthy controls (median, 0.356 versus 0.238; P < 0.001). After radiotherapy, a reduction in plasma DNA integrity index was observed in 70% NPC patients. Patients with persistent aberrations of plasma DNA integrity had significantly poorer survival probability than those with reduced DNA integrity after treatment (P < 0.001, Kaplan-Meier).. NPC is associated with disturbances in the integrity of circulating cell-free DNA. The persistence of DNA integrity aberrations after radiotherapy is associated with reduced probability of disease-free survival. Therefore, the measurement of plasma DNA integrity may serve as a useful marker for the detection and monitoring of malignant diseases.

Topics: Adult; Carcinoma; Case-Control Studies; Disease-Free Survival; DNA; DNA Damage; Female; Humans; Leptin; Middle Aged; Nasopharyngeal Neoplasms; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Treatment Outcome

Some extra-thyroid effects of TSH have been described in vitro and in vivo. TSH has recently been suggested to induce interleukin-6 secretion by adipocytes. Leptin is the main protein secreted by adipose tissue.. The aim of our study was to evaluate the acute effect of the recombinant human TSH (rhTSH)-induced TSH surge on serum leptin levels in thyroidectomized patients undergoing levothyroxine (L-T4) suppressive therapy for differentiated thyroid carcinoma (DTC).. A cohort of 15 female DTC patients was evaluated. Standard rhTSH testing was performed. Leptin, TSH, thyroid hormones, and thyroglobulin were measured before and 3, 6, and 9 days after rhTSH testing. Some metabolic parameters were also evaluated at the baseline.. Baseline leptin levels were 12.2+/-3.2 microg/l. Only body mass index (BMI) correlated significantly (p<0.05) with leptin levels. After rhTSH administration, TSH levels increased significantly (p<0.001), while thyroid hormones remained unchanged. Twenty hours after the last rhTSH administration, leptin (11.8+/-3.0 microg/l) levels were unchanged. The maximal TSH level was negatively related with BMI (p<0.05), but no correlation between maximal TSH and leptin levels after rhTSH was noted.. Our in vivo experimental model suggests that an acute TSH increase after rhTSH testing is ineffective in changing circulating leptin levels.

Topics: Adult; Aged; Carcinoma; Female; Humans; Leptin; Middle Aged; Recombinant Proteins; Thyroid Neoplasms; Thyroidectomy; Thyrotropin; Thyroxine

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.

Topics: Animals; Anticarcinogenic Agents; Azoxymethane; Carcinoma; Catechin; Cholesterol; Colonic Neoplasms; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Insulin; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred C57BL; Precancerous Conditions; Receptor, IGF Type 1; Triglycerides

Microvascular transplantation of subcutaneous adipose tissue is an essential step in reconstructive surgery after breast carcinoma. Serum levels of adipose tissue products may serve as indicators for transplant function. This study aimed to determine serum leptin and tumor necrosis factor (TNF)-alpha plasma levels pre-, intra-, and postoperatively in 20 patients undergoing reconstructive breast surgery and in 7 women undergoing abdominoplasty operation. In the patients undergoing reconstructive breast surgery, the serum leptin levels decreased intraoperatively from 14.5 +/- 13.1 to 9.1 +/- 7.3 ng/ml, a decrease of 63%. An increase in serum leptin levels to 13.5 +/- 12.7 ng/ml (93% of the initial value) was found on postoperative day 1. This was paralleled by similar changes in the plasma levels of TNF-alpha (preoperatively, 20 +/- 7.3 pg/ml; intraoperatively, 17 +/- 11.4 pg/ml; postoperatively, 21 +/- 10.8 pg/ml). In the patients undergoing abdominoplasty, plasma leptin and TNF-alpha levels decreased intraoperatively (20% and 27%, respectively) and postoperatively (44% and 27%, respectively). The results of our pilot study indicate that a postoperative increase in the level of serum leptin after reconstructive breast surgery may be related to successful transplant function.

Topics: Abdomen; Adipocytes; Adipose Tissue; Adult; Breast Neoplasms; Carcinoma; Female; Humans; Leptin; Mammaplasty; Microcirculation; Microsurgery; Pilot Projects; Plastic Surgery Procedures; Postoperative Care; Tumor Necrosis Factor-alpha

The relationship between the expression of leptin in the tissue of gastric cancer and the clinicopathological features as well as patients' outcome were investigated.. Sixty-one gastric cancer specimens were investigated by immunohistochemical studies with anti-leptin and anti-vascular endothelial growth factor (VEGF) antibodies and by monitoring patients for at least 3 years after surgery.. A positive rate of leptin expression was significantly associated with Borrmann classification (Borrmann type 1 and type 2 68.2% vs Borrmann type 3 and type 4 or unclassified 35.3%), tumor histology (well differentiated tumors 87.5% vs poorly differentiated tumors 48.9%), lymph node metastasis (with 69.0% vs without 36.8%) and stage (stage III + IV 69.0% vs stage I + II 36.8%). There was a significant association between leptin expression and VEGF expression. In the poorly differentiated group, the overall survival rate for patients with a weak expression of leptin (histochemistry score <0.5) was significantly higher than that in patients with a strong expression (histochemistry score =0.5). The Cox proportional hazards model identified serosal involvement, tumor size, metastasis, tumor histology, leptin expression, lymph node metastasis, age and postoperative chemotherapy as significant prognostic factors.. The expression of leptin in the tissue of gastric cancer was significantly associated with tumor histology, Borrmann classification, lymph node metastasis and stage of gastric cancer. In patients with poorly differentiated gastric cancer, a poor prognosis was found in those with a strong expression of leptin.

Topics: Carcinoma; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Stomach Neoplasms; Survival Rate; Vascular Endothelial Growth Factor A

Leptin (LEP) has been consistently associated with angiogenesis and tumor growth. Leptin exerts its physiological action through its specific receptor (LEPR). We have investigated whether genetic variations in LEP and LEPR have implications for susceptibility to and prognosis in breast carcinoma.. We used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the LEP and LEPR genes in 308 unrelated Tunisian patients with breast carcinoma and 222 healthy control subjects. Associations of the clinicopathologic parameters and these genetic markers with the rates of the breast carcinoma-specific overall survival (OVS) and the disease free survival (DFS) were assessed using univariate and multivariate analyses.. A significantly increased risk of breast carcinoma was associated with heterozygous LEP (-2548) GA (OR = 1.45; P = 0.04) and homozygous LEP (-2548) AA (OR = 3.17; P = 0.001) variants. A highly significant association was found between the heterozygous LEPR 223QR genotype (OR = 1.68; P = 0.007) or homozygous LEPR 223RR genotype (OR = 2.26; P = 0.001) and breast carcinoma. Moreover, the presence of the LEP (-2548) A allele showed a significant association with decreased disease-free survival in breast carcinoma patients, and the presence of the LEPR 223R allele showed a significant association with decreased overall survival.. Our results indicated that the polymorphisms in LEP and LEPR genes are associated with increased breast cancer risk as well as disease progress, supporting our hypothesis for leptin involvement in cancer pathogenesis.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Case-Control Studies; Disease Progression; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Neovascularization, Pathologic; Polymorphism, Genetic; Prognosis; Receptors, Cell Surface; Receptors, Leptin; Risk Assessment; Tunisia