leptin and Cell-Transformation--Neoplastic

Topics: Adiponectin; Adipose Tissue; Breast Neoplasms; Cell Transformation, Neoplastic; Estrogens; Exosome Multienzyme Ribonuclease Complex; Female; Humans; Inflammation; Leptin; Menopause; MicroRNAs; Obesity, Abdominal; Signal Transduction; Tumor Microenvironment

Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

Topics: Adipokines; Adiponectin; Animals; Carrier Proteins; Cell Transformation, Neoplastic; Colorectal Neoplasms; Cytokines; GPI-Linked Proteins; Humans; Lectins; Leptin; Membrane Proteins; Obesity; Overweight; Receptors, Adipokine

Obesity is rapidly becoming pandemic and is associated with increased carcinogenesis, especially hepatocellular carcinoma (HCC). Adipose tissue is considered as an endocrine organ because of its capacity to secrete a variety of adipokines, such as leptin, adiponectin and resistin. Recently, adipokines have been demonstrated to be associated with kinds of chronic liver diseases including fibrosis, cirrhosis and carcinogenesis. Direct evidence is accumulating rapidly supporting the inhibitory and/or activating role of adipokines in the process of carcinogenesis and progression of human HCC. This review aims to provide important insight into the potential mechanisms of adipokines in the development of HCC.

Topics: Adiponectin; Adipose Tissue; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Disease Progression; Humans; Leptin; Liver Cirrhosis; Liver Neoplasms; Obesity; Resistin

More than one million new cases of breast cancer are diagnosed each year worldwide and more than 400,000 deaths occur due to this pathology. Obesity is a risk factor for postmenopausal breast cancer and the place held by the adipose tissue and secretions (i.e. adipokines) begins to be recognized. Indeed, firstly, plasma adipokine levels, modulated in obesity situation, could have effects "remotely" on mammary carcinogenesis and, secondly, breast cancer cells are surrounded by adipocyte microenvironment, which is probably more important in the case of obesity, and may be locally influenced by it. In this context, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the angiogenesis process and local pro-inflammatory mechanisms, especially in obese patients for whom increased metastatic potential and risk of mortality are described.

Topics: Adipocytes; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Female; Humans; Leptin; Obesity

In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Mice; Obesity; Receptors, Estrogen

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Obesity

Leptin, also called the satiation hormone plays a key role in regulating body weight, energy intake, and expenditure. Leptin interacts with its receptors, mainly located in the hypothalamus. Moreover, there has been an increasing evidence that leptin exerts pleiotropic effects. Multiple peripheral effects of leptin have been recently described including synthesis of the various hormones, e.g., sexual hormones, thyroid hormones, and growth hormone, as well as regulation of blood pressure, reproduction, osteogenesis, hematopoesis, angiogenesis. Leptin also plays a regulatory function in immunity.and in the process of tumorigenesis. Despite intensive investigations since leptin discovery in 1994 we have much to learn about the leptin mechanism of actions and effects.

Topics: Animals; Body Weight; Cell Transformation, Neoplastic; Energy Metabolism; Hematopoiesis; Hormones; Humans; Leptin; Neoplasms; Neovascularization, Physiologic; Receptors, Leptin

Obesity is currently reaching epidemic levels worldwide and is a major predisposing factor for a variety of life-threatening diseases including diabetes, hypertension and cardiovascular diseases. Recently, it has also been suggested to be linked with cancer. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-2 fold with obesity-associated colon cancer accounting for 14-35% of total incidence. Several factors, altered in obesity, may be important in cancer development including increased levels of blood insulin, insulin-like growth factor I, leptin, TNF-alpha, IL-6 as well as decreased adiponectin. A unifying characteristic of all these factors is that they increase the activity of the PI3K/Akt signal pathway. The PI3K/Akt signal pathway in turn activates signals for cell survival, cell growth and cell cycle leading to carcinogenesis. Here we review the evidence that PI3K/Akt and its downstream targets are important in obesity-associated colon cancer and thus, that targeted inhibition of this pathway could be employed for the prevention of obesity-associated colon cancer and incorporated into the therapy regime for those with irremovable colon cancers.

Topics: Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Colonic Neoplasms; Comorbidity; Enzyme Inhibitors; Humans; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Obesity; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer.

Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Humans; Leptin; Neovascularization, Pathologic; Signal Transduction

Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic.

Topics: Animals; Breast Neoplasms; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Estrogen Receptor Modulators; Estrogens; Humans; Leptin; Lipid Metabolism; Obesity

Leptin's relation with obesity has been clearly demonstrated while its role in oncobiology is still largely unknown. Epidemiological studies on serum leptin provide valuable though controversial data, while in vitro studies consistently show leptin's angiogenic and proliferative potential in cancer. Leptin's activity is mediated by tissue-specific receptors, differentially expressed in organs such as the prostate. The molecular cascades triggered by leptin result in prostatic cell proliferation and angiogenic activity, thus linking the hormone mainly to prostate cancer prognosis. This review also addresses leptin's metabolic interactions with cytokines, growth factors or hormones, establishing perceptive pathways leading to carcinogenesis or prostate cancer progression and metastasis. Better understanding of these mechanisms may help in the development of new and more effective treatments for prostate cancer. The consolidation of leptin molecular genetics profile in prostate cancer patients may help to create susceptibility groups in normal individuals, facilitating a preventive dietary intervention or strategies for chemoprevention. We hypothesize that the balance between androgen and leptin levels may facilitate the increase in the ratio of androgen-independent prostate cancer cells to androgen-dependent cells in the tumour.

Topics: Cell Transformation, Neoplastic; Chemoprevention; Diet; Genetic Predisposition to Disease; Humans; Leptin; Male; Obesity; Prostatic Neoplasms; Risk Factors; Signal Transduction

There is a need for "anabolic" drugs that can directly stimulate bone growth, improve bone microarchitecture, accelerate fracture healing, and, thus, restore bone strength to osteoporosis patients and, hopefully, regenerate eroded bone in arthritis patients. The anabolic agents currently leading the way to the clinic are the parathyroid hormone (PTH) and some of its adenylyl cyclase-stimulating fragments. This article is a summary of what is known about how PTHs stimulate bone growth. The controversial bone anabolic activities of the cholesterol-lowering lipophilic statins are also described, and mechanisms by which they may stimulate bone growth are presented. Finally, evidence is presented for the body's "fat-o-stat" cytokine--leptin--indirectly restraining bone growth via a hypothalamic factor, while at the same time serving as a local PTH-like autocrine/paracrine stimulator of osteoblast activity, as well as an inhibitor of osteoclast generation.

Topics: Animals; Bone and Bones; Bone Regeneration; Cell Transformation, Neoplastic; Fractures, Bone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Models, Animal; Osteogenesis; Osteoporosis; Parathyroid Hormone

Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Dogs; Exons; Humans; Leptin; Lymphoma; Mice; Obesity; Prostatic Neoplasms; Tumor Protein p73

Breast cancer is the second leading cause of cancer deaths in the USA. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with high rates of metastasis, tumor recurrence, and resistance to therapeutics. Obesity, defined by a high body mass index (BMI), is an established risk factor for breast cancer. Women with a high BMI have increased incidence and mortality of breast cancer; however, the mechanisms(s) by which obesity promotes tumor progression are not well understood.. In this study, obesity-altered adipose stem cells (obASCs) were used to evaluate obesity-mediated effects of TNBC. Both in vitro and in vivo analyses of TNBC cell lines were co-cultured with six pooled donors of obASCs (BMI > 30) or ASCs isolated from lean women (lnASCs) (BMI < 25).. We found that obASCs promote a pro-metastatic phenotype by upregulating genes associated with epithelial-to-mesenchymal transition and promoting migration in vitro. We confirmed our findings using a TNBC patient-derived xenograft (PDX) model. PDX tumors grown in the presence of obASCS in SCID/beige mice had increased circulating HLA1. Leptin signaling is a potential mechanism through which obASCs promote metastasis of TNBC in both in vitro and in vivo analyses.

Topics: Adipose Tissue; Animals; Biopsy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Coculture Techniques; Disease Models, Animal; Female; Gene Expression Profiling; Gene Knockout Techniques; Humans; Leptin; Mice; Obesity; Stem Cells; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

To investigate the inhibitory effect of Liuwei Dihuang Pill (LDP) on gastric tumorigenesis induced by N-methyl-N-nitrosourea (MNU) in diabetic mice.. Four-week-old mice were divided into four groups: A, 12 db/m mice treated with MNU and saline, as the non-diabetic control; B, 12 db/db mice treated with MNU and saline, as the diabetic control; C, 12 db/db mice treated with MNU and metformin, as the positive control; and D, 12 db/db mice treated with MNU and LDP. MNU was administrated for 20 wk to induce gastric carcinogenesis. LDP was administrated for 10 wk for improvement of insulin resistance. Body weight and food intake were measured every week. Blood samples were collected for assays of fasting blood glucose, insulin, insulin-like growth factor (IGF)-1, adiponectin and leptin. Stomach tissues were collected for histopathological analysis, immunohistochemical staining of Ki67, quantitative reverse transcription-polymerase chain reaction and western blotting.. The incidence of MNU-induced gastric dysplasia was significantly elevated in diabetic (db/db) mice relative to the control (db/m) mice. The incidence of gastric dysplasia was significantly reduced by LDP with suppression of cell proliferation, as demonstrated by a decrease in Ki67 staining. Hyperglycemia, hyperinsulinemia and serum IGF-1 were inhibited by LDP. Expression of IGF-1 and insulin receptor mRNAs was decreased, phosphorylation of IGF-1 receptor and AKT protein was reduced in the stomach tissues by LDP. In addition, adiponectin was increased and leptin was decreased in the serum by LDP.. LDP decreased risk of gastric dysplasia in type 2 diabetic mice by down-regulation of IGF and insulin activity and correction of adipokines disorders.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Carcinogenesis; Cell Transformation, Neoplastic; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Immunohistochemistry; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Ki-67 Antigen; Leptin; Male; Methylnitrosourea; Mice; Stomach Neoplasms

In the central nervous system injury induces cellular reprogramming and progenitor proliferation, but the molecular mechanisms that limit regeneration and prevent tumorigenesis are not completely understood. We previously described a zebrafish optic pathway tumor model in which transgenic Tg(flk1:RFP)is18/+ adults develop nonmalignant retinal tumors. Key pathways driving injury-induced glial reprogramming and regeneration contributed to tumor formation. In this study, we examine a time course of proliferation and present new analyses of the Tg(flk1:RFP)is18/+ dysplastic retina and tumor transcriptomes. Retinal dysplasia was first detected in 3-month-old adults, but was not limited to a specific stem cell or progenitor niche. Pathway analyses suggested a decrease in cellular respiration and increased expression of components of Hif1-α, VEGF, mTOR, NFκβ, and multiple interleukin pathways are associated with early retinal dysplasia. Hif-α targets VEGFA (vegfab) and Leptin (lepb) were both highly upregulated in dysplastic retina; however, each showed distinct expression patterns in neurons and glia, respectively. Phospho-S6 immunolabeling indicated that mTOR signaling is activated in multiple cell populations in wild-type retina and in the dysplastic retina and advanced tumor. Our results suggest that multiple pathways may contribute to the continuous proliferation of retinal progenitors and tumor growth in this optic pathway tumor model. Further investigation of these signaling pathways may yield insight into potential mechanisms to control the proliferative response during regeneration in the nervous system.

Topics: Animals; Animals, Genetically Modified; Cell Proliferation; Cell Transformation, Neoplastic; Eye Neoplasms; Gene Expression Regulation, Neoplastic; Leptin; Retinal Dysplasia; Signal Transduction; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins

There is an established link between obesity related metabolic derangement and colorectal cancer development. Recently, we developed a metabolic-colorectal cancer risk score. In this follow-up study, we studied its association with colorectal neoplasm by measuring two major metabolic syndrome biomarkers, leptin and adiponectin.. To evaluate the serum levels of leptin and adiponectin in patients with colorectal polyps and colorectal cancer and to determine any correlation with metabolic risk score.. In total, 130 individuals were studied: 30 controls without colonic pathology, 18 with colonic adenoma (CAP), and 82 with colorectal adenocarcinoma (CRC, 17 cases of T1-2 and 65 cases of T3-4). The metabolic risk scores in CAP and T1-2 CRC were higher than those in the controls and T3-4 CRC cases. There were no statistically significant differences in leptin levels among CAPs, CRCs, and controls. Both leptin and adiponectin levels reflected differences in body mass index and metabolic risk scores. Cases in the CAP group and early T-stage CRC groups had lower adiponectin levels (14.03 and 13.01 mg/ml, respectively) than the no polyps group (19.5mg/ml, p = 0.03). The average serum adiponectin level in the invasive cancer group (18.5 ng/ml) was comparable with that of the control group.. The level of serum adiponectin was positively correlated with the metabolic risk score. Decreased serum adiponectin was significantly associated with the development of colorectal adenoma and early stage colorectal carcinoma.

Topics: Adenocarcinoma; Adenoma; Adiponectin; Biomarkers, Tumor; Case-Control Studies; Cell Transformation, Neoplastic; Colonic Polyps; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Risk Factors

Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor-xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling-network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-β-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK-mediated inhibition of Wnt1-MTA1-β-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1-β-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-β-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-β-catenin axis.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Biphenyl Compounds; Breast Neoplasms; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin D1; Drugs, Chinese Herbal; Female; Histone Deacetylases; Humans; Leptin; Lignans; Magnolia; MCF-7 Cells; Mice; Mice, Nude; Mice, Obese; MicroRNAs; Neoplasm Invasiveness; Obesity; Phosphorylation; Plant Extracts; Promoter Regions, Genetic; Repressor Proteins; RNA Interference; RNA, Small Interfering; Signal Transduction; Spheroids, Cellular; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Wnt1 Protein; Xenograft Model Antitumor Assays

Previously we reported that intermittent calorie restriction (ICR) provided greater prevention of mammary tumors (MTs) than chronic calorie restriction (CCR). Here the impact of increased fat intake during refeeding in an ICR protocol was evaluated. MMTV-TGF-α female mice were assigned to one of three groups: ad libitum (AL) fed (n = 45) with free access to a moderately high fat diet (22 % fat calories); ICR (n = 45) 50 % calorie restricted for 3-week intervals followed by 3 weeks of 100 % of AL intake; and CCR (n = 45) fed 75 % of AL mice, matching each 6-week cycle of ICR mice. ICR mice were further designated as ICR-Restricted or ICR-Refed for data obtained during these intervals. All mice consumed the same absolute amount of dietary fat. Mice were followed to assess MT incidence, body weight and serum IGF-1, IGFBP3, leptin and adiponectin levels until 79 (end of final 3-week restriction) or 82 (end of final 3-weeks refeeding) weeks of age. Age of MT detection was significantly extended for CCR (74 weeks) and ICR (82 weeks) mice, compared to 57.5 weeks for AL mice. MT incidence for AL, ICR and CCR mice was 66.7, 4.4, and 52.3 %, respectively. Mammary and fat pad weights were reduced significantly following 50 % calorie restriction in ICR-Restricted mice compared to AL, CCR and ICR-Refed mice. IGF-1 and leptin levels also tended to be reduced in ICR-Restricted mice over the course of the study while adiponectin was not compared to AL, CCR, and ICR-Refed mice. The adiponectin:leptin ratio was consistently higher following 50 % restriction in ICR-Restricted mice. There was no relationship of IGF-1, leptin, or adiponectin with the presence of MTs in any groups. Thus the manner in which calories are restricted impacts the protective effect of calorie restriction independently of high fat intake.

Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Caloric Restriction; Cell Transformation, Neoplastic; Diet, High-Fat; Eating; Female; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Transforming Growth Factor alpha

Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 μg of 17β-estradiol, 15 μg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P < 0.001), and the majority (93%) of tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor-monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P < 0.001). The mammary glands of the exposed parous rats contained significantly more proliferating cells (P < 0.001). In addition, the E2- or leptin-treated parous rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Biomarkers, Tumor; Carcinogens; Cell Proliferation; Cell Transformation, Neoplastic; Estradiol; Estrogens; Female; Gene Expression Profiling; Genomics; Immunoenzyme Techniques; Leptin; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Oligonucleotide Array Sequence Analysis; Parity; Pregnancy; Pregnancy Complications, Neoplastic; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger

Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.. Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.. ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.. ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.

Topics: Adipocytes; Animals; Aromatase; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Coculture Techniques; Cyclin-Dependent Kinase Inhibitor p16; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Profiling; Glutathione S-Transferase pi; Humans; Intercellular Signaling Peptides and Proteins; Leptin; MCF-7 Cells; Membrane Proteins; Mice; Obesity; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Stem Cells; Tumor Burden

The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.

Topics: Adiponectin; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Leptin; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Invasiveness; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Rosiglitazone; Signal Transduction; Thiazolidinediones

The association between obesity and cancer is controversial: whereas several epidemiological, clinical and research studies using cancer cell lines have supported that high levels of insulin and leptin could favor prostate cancer development and dissemination, other studies have demonstrated opposite effects or even absence of association. The main goal of this study was to evaluate the in vitro proliferation of murine androgen insensitive prostate carcinoma cells RM1 in the presence of leptin and insulin. After assessing and confirming the presence of leptin and insulin receptors in RM1 cells by immunocytochemistry, cells were cultured in the presence of different concentrations of leptin (0, 25, 50, 100 and 200 ng/mL), insulin (0, 50, 100, 150 and 200 nM) or leptin plus insulin ( 25 ng/ml + 50 nM; 50 ng/ml + 100 nM; 100 ng/ml + 150 nM; 200 ng/ml + 200 nM; 25 ng/ml + 150 nM; 100 ng/ml + 50 nM of leptin plus insulin, respectively). Cell proliferation was evaluated by assessing the percentage of resazurin reduction, a surrogate marker of cell metabolic rate. Leptin significantly decreased the percentage of resazurin reduction in all studied concentrations while there was only a slight or non significant difference in RM1cell proliferation in the presence of insulin or insulin combined with leptin when compared with control. These results show that leptin decreases RM1 prostate cancer cell proliferation at the studied concentrations, while insulin is able to antagonize the leptin inhibition of RM1 prostate cancer cell growth in vitro. The difference in cell growth that is modulated by the various hormonal environments may explain the heterogeneous behavior of prostate cancer in the obese human population.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Mice; Prostatic Neoplasms

Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr(db/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC-signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.

Topics: AC133 Antigen; Animals; Antigens, CD; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Glycoproteins; Humans; Leptin; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Obesity; Octamer Transcription Factor-3; Peptides; Pluripotent Stem Cells; Receptors, Leptin; SOXB1 Transcription Factors

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 has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters.. Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD).. Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients.. The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cell Transformation, Neoplastic; Chemokine CCL2; Colorectal Neoplasms; Female; Humans; Inflammation; Interleukin-1alpha; Leptin; Male; Middle Aged; Obesity, Morbid; Plasminogen Activator Inhibitor 1; Resistin; Tumor Necrosis Factor-alpha; Young Adult

Molecular effects of obesity, a well-established risk factor for breast cancer progression, are mediated by adipocytokine leptin. Given the important role of leptin in breast cancer growth and metastasis, novel strategies to antagonize biological effects of this adipocytokine are much desired. We showed previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g. garden cress), confers significant protection against mammary carcinogenesis in a transgenic mouse model. The present study provides first evidence for the efficacy of BITC against oncogenic effects of leptin. The BITC treatment circumvented leptin-induced clonogenicity and anchorage-independent growth of MDA-MB-231 and MCF-7 human breast cancer cells. Leptin-stimulated migration and invasion of these cells was also inhibited in the presence of BITC. Analysis of the underlying molecular mechanisms revealed that BITC treatment suppressed leptin-induced Stat3 phosphorylation and cyclin D1 transactivation. The BITC-mediated inhibition of MDA-MB-231 xenograft growth correlated with a modest yet significant decrease in levels of Tyr705 phosphorylated Stat3. The BITC treatment efficiently inhibited Stat3 and SRC1 recruitment to cyclin D1 promoter in a chromatin immunoprecipitation analysis. Furthermore, overexpression of constitutively active Stat3 imparted significant protection against BITC-mediated inhibition of cyclin D1 transactivation, whereas RNA interference of Stat3 resulted in a significant increase in BITC-mediated inhibition of cyclin D1 transactivation in the presence of leptin. These results indicate that Stat3 plays an important role in BITC-mediated inhibition of leptin-induced cyclin D1 transactivation. In conclusion, BITC could potentially be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Chromatin Immunoprecipitation; Cyclin D1; Humans; Immunoenzyme Techniques; Isothiocyanates; Leptin; Luciferases; Oncogenes; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Wound Healing

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

The risk of developing breast cancer and fatty liver is increased by alcohol consumption. The objective of the present study was to determine if obesity and exogenous estrogen supplementation alter the effects of alcohol on mammary tumorigenesis and fatty liver. Ovariectomized female mice were (1) fed diets to induce overweight and obese phenotypes, (2) provided water or 20% alcohol, (3) implanted with placebo, low- or high-dose estrogen pellets and (4) injected with Met-1 mouse mammary cancer cells. Alcohol-consuming mice were more insulin sensitive and developed larger tumors than water consuming mice. Obese mice developed slightly larger tumors than control mice. Alcohol consumption and obesity increased growth factors, hepatic steatosis, activation of Akt, and inhibited the caspase-3 cascade. Estrogen treatment triggered the loss of body fat, induced insulin sensitivity, suppressed tumor growth, reduced growth factors and improved hepatic steatosis. Results show that the effects of alcohol on mammary tumor and fatty liver are modified by obesity and estrogen supplementation.

Topics: Adipose Tissue; Animals; Cell Transformation, Neoplastic; Diet; Estrogens; Ethanol; Fatty Liver; Female; Insulin Resistance; Leptin; Liver; Mammary Neoplasms, Experimental; Mice; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Obesity is considered to be a risk factor for prostate cancer. Mitogenic actions of leptin, an adipocyte-derived hormone in a variety of cancer cell types have been identified. We have investigated the proliferative effects of leptin on human prostate cancer cells and assessed the role of tyrosine kinase signalling in mediating these actions.. Two human androgen-resistant prostate cancer cell lines and one androgen-sensitive human prostate adenocarcinoma cell line were treated with leptin (5-100 ng / mL) for up to 48 hours. Under serum-free conditions, cell proliferation was measured using an enzyme-linked colorimetric assay. Furthermore, phosphorylation of a downstream component of MAPK (ERK1 / 2) was detected by Western blotting and a specific inhibitor of MAPK (PD98059; 40 microM) was used to evaluate the role of this signalling pathway.. Leptin dose-dependently increased the cell number in both androgen-resistant cell lines after 24 h and 48 h of incubation (percent of control: DU145 = 194.6 +/- 5.9 %, PC-3 = 177.9 +/- 6.8 %; 100 ng / mL leptin; 48 h; p < 0.001). Conversely, leptin's proliferative effect on the androgen-sensitive cell line was less pronounced (percent of control: LNCaP = 112.3 +/- 6.1 %; 100 ng / mL leptin; 48 h). Leptin also caused dose-dependent ERK1 / 2 phosphorylation in both androgen-resistant cell lines. In addition, pre-treatment with PD98059 inhibited these responses and attenuated leptin's mitogenic action.. Data from this in vitro study suggest an association between obesity-associated hyperleptinemia and an increased risk for prostate cancer. Further investigations are necessary to clarify whether these data have clinical relevance regarding the use as a prognostic marker for predicting the timing of the occurrence of androgen resistency.

Topics: Adenocarcinoma; Adipokines; Blotting, Western; Cell Division; Cell Line, Tumor; Cell Transformation, Neoplastic; Humans; In Vitro Techniques; Leptin; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Neoplasms, Hormone-Dependent; Obesity; Phosphorylation; Prostatic Neoplasms; Protein-Tyrosine Kinases; Risk Factors; Signal Transduction

The molecular links between breast cancer and obesity have been studied for many years. Obesity significantly increases the incidence rate and chance of morbidity of breast cancer. Leptin, mainly secreted by adipocytes, plays an important role in breast cancer development. Leptin expression is up-regulated in obesity and it can promote breast cancer cell growth. Zeranol is used as an anabolic growth promoter to stimulate cattle growth in the U.S. beef industry. (-)-Gossypol, a natural polyphenolic compound extracted from cottonseed, is an anticancer chemopreventive agent.. Zeranol, leptin and (-)-gossypol were used to investigate MCF-7 Adr cell growth.. Leptin enhanced the sensitivity of MCF-7 Adr cells to zeranol and increased cell growth. Exposure to zeranol may lead to initiation of transformation of normal breast cells to breast preneoplastic cells.. It is suggested that obese individuals may be at greater risk of developing zeranol-induced breast cancer.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Drug Synergism; Gossypol; Humans; Leptin; Recombinant Proteins; RNA, Messenger; Tumor Suppressor Protein p53; Zeranol

Both normal and malignant mammary tissues have been shown to produce leptin and express leptin receptors. This study compared the expression of leptin and leptin receptor mRNA in a variety of normal and malignant mammary epithelial cell lines and observed that in general the malignant lines expressed higher levels of leptin and leptin receptor mRNA than nonmalignant lines. Furthermore, oncogenic transformation of nonmalignant cell lines increased expression of leptin and leptin receptor, with expression of ErbB2 giving particularly high levels of expression of long-form leptin receptor. In addition, nonmalignant cells exhibited little or no increase in DNA synthesis following leptin treatment, whereas oncogene-transformed cells had increased DNA synthesis in response to leptin. These effects varied among oncogenes, with ErbB2-transformed cells showing particularly high expression of leptin receptor mRNA and high response to leptin.

Topics: Animals; Cell Line; Cell Line, Transformed; Cell Transformation, Neoplastic; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mammary Glands, Animal; Mammary Glands, Human; Mice; Receptors, Leptin

To explore the expression patterns and possible involvement of leptin and its receptor in the pathogenesis of urinary bladder cancer, with a focus on transitional cell carcinoma.. Using reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemistry techniques, we correlated the expression patterns of leptin and its receptor with the occurrence of transitional cell carcinoma. We also applied transient transfection followed by BrdU labeling and immunofluorescent staining to address the effect of the leptin receptor on bladder cancer cell growth.. Although leptin was not detected in the bladder tissue specimens, a decreased expression of the leptin receptor was observed in most cancer tissue specimens we analyzed. Furthermore, the forced expression of the leptin receptor in T24 bladder cancer cells prevented them from entering the S phase.. Our data demonstrated for the first time that the leptin receptor is aberrantly expressed in bladder cancer tissue and is possibly involved in the carcinogenesis of bladder cancer.

Topics: Aged; Aged, 80 and over; Carcinoma, Transitional Cell; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Middle Aged; Neoplasm Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; S Phase; Transfection; Urinary Bladder Neoplasms

Topics: Animals; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Colonic Neoplasms; Intestinal Mucosa; Leptin; Obesity; Precancerous Conditions; Rats; Rats, Zucker

Several studies have shown a positive association of dietary fat with prostate cancer. Leptin, a peptide hormone that has a role in the regulation of body weight, currently serves as a more accurate biomarker for total body fat. We designed a study to determine whether leptin influences cellular differentiation and the progression of prostate cancer.. In this study we investigated serum leptin in 21 patients with prostate cancer, 50 with benign prostatic obstruction and 50 healthy individuals matched for sex, body mass index and age. Patients with cancer were stratified into 2 groups by the disease spread, including groups 1--organ confined and 2--advanced disease, and into 3 groups by the differentiation degree, including groups 3--Gleason sum 2 to 4 or well differentiated, 4--Gleason sum 5 to 7 or moderately differentiated and 5--Gleason sum 8 to 10 or poorly differentiated.. We noted significant differences in serum leptin in the cancer versus control and cancer versus benign prostatic obstruction groups. In addition, in the prostate cancer group serum leptin correlated with prostate specific antigen and biopsy Gleason score. We also observed significant differences in serum leptin in groups 1 versus 2, 3 versus 5 and 4 versus 5.. Leptin may have roles in the development of prostate cancer through testosterone and factors related to obesity. It influences cellular differentiation and the progression of prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; Body Weight; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Risk Factors; Testosterone; Urinary Bladder Neck Obstruction

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes.

Topics: Adipocytes; Aged; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diabetes Mellitus; Diabetes Mellitus, Type 1; Energy Intake; Fatty Acids; Fatty Acids, Nonesterified; Homeostasis; Humans; Islets of Langerhans; Leptin; Liver Diseases; Models, Biological; Obesity; Proteins; Rats; Rats, Zucker; Risk Factors; Triglycerides