leptin and Skin-Neoplasms

Leptin is an adipokine, adipocyte-derived compound, which acts both as a hormone and cytokine. It is mainly synthesized by adipocytes of white adipose tissue. Leptin possesses pleiotropic functions including, among others, stimulation of angiogenesis and production of proinflammatory cytokines. The various types of leptin activity are related to the wide distribution of leptin receptors. This adipokine acts by activating intracellular signaling cascades such as JAKs (Janus kinases), STATs (signal transducers and activators of transcription), and others.In a course of obesity, an increased serum level of leptin coexists with tissue receptor resistance. It has been reported that enhanced leptin levels, leptin receptor impairment, and dysfunction of leptin signaling can influence skin and hair. The previous studies revealed the role of leptin in wound healing, hair cycle, and pathogenesis of skin diseases like psoriasis, lupus erythematosus, and skin cancers. However, the exact mechanism of leptin's impact on the skin is still under investigation. Herein, we present the current knowledge concerning the role of leptin in psoriasis and selected skin diseases.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Humans; Janus Kinases; Leptin; Lupus Erythematosus, Cutaneous; Psoriasis; Receptors, Leptin; Signal Transduction; Skin Diseases; Skin Neoplasms; STAT Transcription Factors

Here, we examine the currently available information which supports that the adipokine, leptin, is a major player in the biology and pathology of mammalian skin and its appendages. Specifically, the potent metabolic effects of leptin and its mimetics may be utilized to improve, preserve and restore skin regeneration and hair cycle progression, and may halt or even partially reverse some aspects of skin ageing. Since leptin can enhance mitochondrial activity and biogenesis, this may contribute to the wound healing-promoting and hair growth-modulatory effects of leptin. Leptin dependent intracellular signalling by the Janus kinase 2 dependent signal transducer and activator of transcription 3, adenosine monophosphate kinase, and peroxisome proliferator-activated receptor (PPAR) gamma coactivator/PPAR converges to mediate mitochondrial metabolic activation and enhanced cell proliferation which may orchestrate the potent developmental, trophic and protective effects of leptin. Since leptin and leptin mimetics have already been clinically tested, investigative dermatology is well-advised to place greater emphasis on the systematic exploration of the cutaneous dimensions and dermatological potential of this pleiotropic hormone.

Topics: Animals; Hair; Humans; Leptin; Signal Transduction; Skin; Skin Neoplasms; Wound Healing

Topics: Humans; Leptin; Neoplastic Processes; Skin; Skin Neoplasms

Adipokine leptin functions through its transmembrane receptors (LEPR). In many malignant tumors it stimulates the growth, migration and invasion of malignant cells. The aim of our work is to examine the effect of LEPR expression on the clinical-morphological properties of squamous cell carcinoma of the skin (cSCC). The biopsy material obtained by excision of squamous cell skin cancer was used. The test group consisted of excision biopsies of squamous cell carcinoma of the skin (n = 62), and the control group (n = 62) consisted of excision biopsies of non-tumor tissue of the skin (from the tumor environment) from an operative preparation delivered to the Pathohistology Department. After routine processing and paraffin molding, histochemical Hematoxylin-Eosin and immunohistochemical ABC method with anti LEPR and Ki67 antibodies were applied at 4 μm sections. The statistical software package SPSS for Windows (26.0) was used to analyze obtained results. Intracytoplasmic and intramembranous LEPR expression was found in 100 % of examined cSCCs. LEPR expression was statistically significantly associated with proliferation index and histologic grade of tumors. Pronounced LEPR expression was associated with a high proliferation index in 66.7 % of cases and with poorly differentiated cSCC in 94.4 %. Multivariate regression analysis showed that cSCCs with pronounced LEPR expression were seven times more often poorly differentiated than tumors with moderate or LEPR expression in trace. Our results indicate that LEPR expression is a predictor of the malignant potential of cSCC, so that based on LEPR expression, it is possible to identify an aggressive cSCC phenotype, which provides the possibility of individualizing anti-tumor treatment using LEPR antagonists.

Topics: Carcinoma, Squamous Cell; Cell Proliferation; Female; Humans; Leptin; Male; Receptors, Leptin; Skin; Skin Neoplasms

Active transforming growth factor-β1 (TGF-β1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-β1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-β1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-β1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-β1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-β1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.

Topics: Adult; Aged; Cell Line, Tumor; Female; Humans; Leptin; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Obesity; Skin Neoplasms; Sleep Apnea, Obstructive; Transforming Growth Factor beta1

The incidence and mortality rates of cutaneous melanoma (CM) are increasing among fair-skinned populations worldwide. Ultraviolet radiation (UVR) is the principal risk factor for CM, but is also the main source of 25-hydroxyvitamin D (25(OH)D), which has been associated with reduced risk and better prognosis of some cancer types. However, both low and high 25(OH)D levels have been associated with increased risk of CM. Obesity as measured by body mass index (BMI) is associated with risk of several cancers and has also been suggested as a risk factor for CM, and may also be related to insufficient 25(OH)D and/or high leptin levels. Moreover, contracting a CM diagnosis has been associated with increased risk of developing second cancer. We aim to study whether low prediagnostic serum levels of 25(OH)D, high prediagnostic levels of BMI and high serum leptin levels influence CM incidence, Breslow thickness and CM mortality, and risk of second cancer and survival after a CM diagnosis.. Cohort and nested case-control studies will be carried out using the population-based Janus Serum Bank Cohort (archival prediagnostic sera, BMI, smoking and physical activity), with follow-up from 1972 to 2014. Additional data will be received from the Cancer Registry of Norway, the national Cause of Death Registry, Statistics Norway (education and occupation) and exposure matrices of UVR. Time-to-event regression models will be used to analyse the cohort data, while the nested case-control studies will be analysed by conditional logistic regression. A multilevel approach will be applied when incorporating group-level data.. The project is approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and in the news media.

Topics: Aged; Blood Banks; Body Mass Index; Case-Control Studies; Female; Humans; Incidence; Leptin; Male; Melanoma; Norway; Prospective Studies; Research Design; Skin Neoplasms; Survival Rate; Vitamin D

The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a "raw" (assay value) and an "adjusted" value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Complications; Female; Humans; Leptin; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Prospective Studies; Sentinel Lymph Node Biopsy; Skin Neoplasms; Texas

Obesity, owing to adiposity, is associated with increased risk and development of various cancers, and linked to their rapid growth as well as progression. Although a few studies have attempted to understand the relationship between obesity and melanoma, the consequences of controlling body weight by reducing adiposity on cancer progression is not well understood. By employing animal models of obesity, we report that controlling obesity either by orlistat treatment or by restricting caloric intake significantly slows down melanoma progression. The diminished tumor progression was correlated with decreased fat mass (adiposity) in obese mice. Obesity associated factors contributing to tumor progression were decreased in the experimental groups compared to respective controls. In tumors, protein levels of fatty acid synthase (FASN), caveolin (Cav)-1 and pAkt, which are tumor promoting molecules implicated in melanoma growth under obese state, were decreased. In addition, increased necrosis and reduction in angiogenesis as well as proliferative markers PCNA and cyclin D1 were observed in tumors of the orlistat treated and/or calorically restricted obese mice. We observed that growth of melanoma cells cultured in conditioned medium (CM) from orlistat-treated adipocytes was reduced. Adipokines (leptin and resistin), via activating Akt and modulation of FASN as well as Cav-1 respectively, enhanced melanoma cell growth and proliferation. Together, we demonstrate that controlling body weight reduces adipose mass thereby diminishing melanoma progression. Therefore, strategic means of controlling obesity by reduced caloric diet or with antiobesity drugs treatment may render obesity-promoted tumor progression in check and prolong survival of patients.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Cell Line, Tumor; Cell Proliferation; Diet; Diet, High-Fat; Disease Progression; Female; Humans; Lactones; Leptin; Male; Melanoma; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Obesity; Orlistat; Resistin; Skin Neoplasms

Skin tags (STs) are common benign dermal connective tissue neoplasms that are mainly composed of loose fibrous tissue. However, their exact etiology is not fully understood. Leptin is a major player in the biology and pathology of the skin and its appendages. It is linked to cell differentiation, proliferation, migration, and survival with pronounced effects on angiogenesis, blood flow, and tissue perfusion. This study aimed at investigating the possible role of leptin in STs pathogenesis and correlating its expression with different clinical and histopathological parameters. Using immunohistochemical techniques, we examined 90 subjects. These included 60 non-obese cases with STs and 30 age-, gender- and Body Mass Index-matched normal subjects as a control group. Leptin was overexpressed in STs compared with normal skin (p < .001). Nuclear and nucleocytoplasmic patterns were significantly associated with cases both in epidermis (p < .04) and dermis (p < .001). Higher epidermal leptin H score was significantly associated with female gender (p = .004) and haphazard collagen arrangement (p < .03). Higher dermal leptin H score was significantly associated with smooth skin tags (p = .01), dilated blood vessels (p = .04), presence of mast cells (MCs) (p = .002), presence of inflammatory cells (p = .004), and haphazard collagen arrangement (p < .001). In conclusion, leptin may play a role in STs pathogenesis through its effects on keratinocytes, fibroblasts and vascular endothelium. Further studies are recommended to clarify the molecular interplay between leptin and MCs in ST pathogenesis. Further studies are also needed to determine the significance of its nuclear expression.

Topics: Adolescent; Adult; Case-Control Studies; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Skin Neoplasms; Young Adult

In the present study, the ability of metformin to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity-inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low-dose combination of these two compounds displayed an additive inhibitory effect on tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments seemed to be at least as effective for inhibiting tumor formation in obese mice, and both metformin and rapamycin were more effective at reducing tumor size in obese mice compared with overweight control mice. The effect of metformin on skin tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMP-activated protein kinase (AMPK) and attenuated signaling through mTOR complex (mTORC)-1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin tumor promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin tumor promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1.

Topics: Adenylate Kinase; Adiponectin; Animals; Body Weight; Carcinogenesis; Carcinoma, Squamous Cell; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Mechanistic Target of Rapamycin Complex 1; Metformin; Mice; Mice, Obese; Multiprotein Complexes; Neoplasms, Experimental; Obesity; Overweight; Papilloma; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Skin Neoplasms; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases

Leptin is known to be abnormally expressed in a variety of cancers, and leptin receptors have been reported to be expressed on human melanoma cells. In this study, we evaluated the possibility that the serum levels of leptin receptor could be a tumor marker of malignant melanoma (MM). Serum samples were obtained from 71 patients with MM, and the serum levels of leptin receptor were measured by double-determinant ELISA. Interestingly, serum levels of leptin receptor decreased gradually with the stages of MM, being highest at in situ and lowest at stage IV. There was also a trend of reverse correlation between tumor thickness and serum levels of leptin receptor. To our knowledge, this is the first report investigating the serum levels of leptin receptor in MM, and serum leptin receptor levels may be used as a useful tumor marker of MM.

Topics: Biomarkers, Tumor; Body Mass Index; Case-Control Studies; Cell Line, Tumor; Cysteinyldopa; Disease Progression; Female; Humans; Insulin Resistance; Leptin; Male; Melanoma; Receptors, Leptin; Skin Neoplasms

Skin tags are common cutaneous lesions with an indefinite aetiology.. To assess serum leptin, insulin resistance and metabolic syndrome in different body mass index (BMI) patients with skin tags.. Three equally distributed groups of patients with multiple skin tags: 30 normal BMI, 30 overweight and 30 obese were included. Controls were age-, gender- and BMI-matched healthy subjects. Serum leptin, insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic syndrome were assessed in all groups.. Number and extent of skin tags increase with the increase in BMI. Highest leptin levels were found in obese patients, with significant differences when compared to normal BMI and overweight patients. Similar findings existed in controls. Significantly higher leptin levels were found in obese patients compared to obese controls. HOMA-IR was significantly higher in all groups of patients compared to BMI-counterpart controls. Seventy-one per cent of patients fulfilled criteria of metabolic syndrome. Number of skin tags, leptin and HOMA-IR were significantly higher in patients with metabolic syndrome compared to patients without the syndrome. Positive correlations were found between serum leptin and HOMA-IR in obese patients and obese controls. Positive correlations were also found between number of skin tags and waist circumference in all groups of patients.. Serum leptin displays an association with obesity and insulin resistance. Assessment of HOMA-IR in patients with skin tags may serve as a useful approach for diagnosis of insulin resistance. Waist circumference is the only criteria of metabolic syndrome that correlates with number of skin tags.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Humans; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Skin Neoplasms

Topics: Adipocytes; Adipose Tissue; Animals; Exercise; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Melanoma; Mice; Neoplasms; Obesity; Phenotype; Physical Conditioning, Animal; Skin Neoplasms

Epidemiological studies propose that obesity increases the risk of several cancers, including melanoma. Obesity increases the expression of leptin, a multifunctional peptide produced predominantly by adipocytes which may promote tumor growth. Several recently experiments have suggested that the tumors growth is in need of endothelial progenitor cell (EPC) dependent generation of new blood vessels.Our objectives in the present study were to examine the effects of leptin on melanoma growth, circulating EPCs number and plasma levels of nitric oxide metabolites (NOx).. 2 × 106 B16F10 melanoma cells were injected to thirty two C57BL6 mice subcutaneously. The mice were randomly divided into 4 groups (n = 8) in 8th day. Two groups were received twice daily intraperitoneal(i.p) injections of either PBS or recombinant murine leptin (1 μg/g initial body weight). Two groups were received i.p. injections of either 9F8 an anti leptin receptor antibody or the control mouse IgG at 50 μg/mouse every 3 consecutive days. By the end of the second week the animals were euthanized and blood samples and tumors were analyzed.. The tumor weight, EPC numbers and NOx level in leptin, PBS, 9F8, and IgG group were (3.2 ± 0.6, 1.7 ± 0.3, 1.61 ± 0.2,1.7 ± 0.3 g), (222.66 ± 36.5, 133.33 ± 171, 23.33 ± 18, 132.66 ± 27.26/ml of blood), and (22.47 ± 5.5, 12.30 ± 1.5, 6.26 ± 0.84, 15.75 ± 6.3 μmol/L) respectively. Tumors weight and size, circulating EPC numbers and plasma levels of NOx were significantly more in the leptin than 9f8 and both control groups (p < 0.05). The plasma concentration of NOx significantly decreased in 9f8 treated mice compare to control group (p < 0.05).. In conclusion, our observations indicate that leptin causes melanoma growth likely through increased NO production and circulating EPC numbers and consequently vasculogenesis.

Topics: Adipocytes; Animals; Endothelial Cells; Leptin; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nitric Oxide; Receptors, Leptin; Skin Neoplasms; Stem Cells

We have previously shown that melanoma cells proliferate in response to the metabolic hormones TRH and TSH. The objective of the present study was to test the hypothesis that a third metabolic hormone, leptin, serves as a growth factor for melanoma. Using western blotting, indirect immunofluorescence, and RT-PCR, leptin receptors were found to be expressed by human melanoma cells. In contrast, cultured melanocytes expressed message for the receptor without detectable protein. Melanoma cells responded to treatment with leptin by activating the MAPK pathway and proliferating. Melanoma cells but not melanocytes, also expressed leptin protein, creating a potential autocrine loop. Examination of human melanoma tumors by immunohistochemistry revealed that melanomas and nevi expressed leptin at a high frequency. Melanomas also strongly expressed the leptin receptor, whereas nevi expressed this receptor to a much lesser degree. We conclude that leptin is a melanoma growth factor and that a leptin autocrine-loop may contribute to the uncontrolled proliferation of these cells.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Leptin; Melanoma; Mitogen-Activated Protein Kinases; Nevus; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Skin Neoplasms

Topics: Animals; Cyclooxygenase 2; Leptin; Mice; Mitogen-Activated Protein Kinase 3; Obesity; Phosphatidylinositol 3-Kinases; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Ultraviolet Rays

We have previously shown thryotropin-releasing hormone expression in nevi and melanoma. Thryotropin-releasing hormone regulation by leptin has been shown in the hypothalamus. The present study was therefore undertaken to evaluate leptin and leptin receptor in nevi and melanoma. Leptin receptor expression as assessed using an anti-leptin receptor antibody showed uniform expression throughout the lesion in 14 of 17 melanomas; 3 melanomas lacked leptin receptor immunoreactivity. In contrast, out of 15 nevi, 10 showed weak to moderate leptin receptor immunoreactivity, with positivity present only in the superficial dermal component. Thus, maturation was present in nevi but not in melanoma with the anti-leptin receptor antibody (P<0.0001). Anti-leptin antibody, in contrast, did not show a significant difference in maturation between nevi and melanoma. We also compared leptin receptor in Spitz nevi and melanoma, as the two can sometimes be difficult to distinguish. Spitz nevi showed moderate to strong immunopositivity. Of 19 Spitz nevi, 7 showed lack of maturation, a finding statistically significant from both melanoma and nevi. Our results suggest a role for leptin receptor in melanoma, and we show for the first time that melanomas show more intense immunoreactivity as compared to nevi (but not Spitz nevi) and that maturation with anti-leptin receptor antibody may be a diagnostically useful tool in distinguishing melanomas, especially nevoid ones, from nevi in difficult cases.

Topics: Antibodies; Biomarkers, Tumor; Diagnosis, Differential; Humans; Immunohistochemistry; Leptin; Melanoma; Nevus; Receptors, Leptin; Skin Neoplasms

Solar radiation has been identified as a principal factor for the causation of melanoma, whereas changing lifestyle patterns associated with obesity and diabetes might also contribute to the increasing incidence of the malignancy. No study has investigated the role of leptin, a hormone whose levels increase in obesity and which has also been related to cancer.. Fifty-five patients with incident melanomas and 165 age- and gender-matched healthy controls were interviewed on the basis of a questionnaire that covers phenotypic features, sociodemographic and medical history variables, lifestyle habits and frequency of consumption of major food groups. Anthropometrical measures were also recorded and blood samples were obtained for determination of serum leptin levels. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses.. An excess melanoma risk was observed for sun sensitive individuals and those with high circulating levels of leptin (OR: 1.56, 95% confidence interval 1.07-2.28, P = 0.02), after controlling for obesity indices, diabetes mellitus and education. Increased physical exercise, lower alcohol consumption and plant food consumption seem to play a protective role against melanoma development.. Melanoma risk was found to be positively associated with serum leptin levels and inversely with healthy lifestyle factors. The findings need to be confirmed in prospective studies.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy, Needle; Case-Control Studies; Female; Humans; Immunohistochemistry; Incidence; Leptin; Life Style; Logistic Models; Male; Melanoma; Middle Aged; Neoplasm Staging; Odds Ratio; Probability; Prognosis; Reference Values; Risk Factors; Sensitivity and Specificity; Sex Distribution; Skin Neoplasms; Survival Analysis

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

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

Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-I, growth hormone, vascular endothelial growth factor, and proinflammatory Th2 cytokines, such as interleukin (IL)-1beta, IL-4, and IL-6, were elevated in A-ZIP/F-1 mice. Additionally, we examined multiple phosphorylated proteins (i.e., protein kinase B/Akt and ErbB2/HER-2 kinase) associated with cancer development. Results show that many of these phosphorylated proteins were activated specifically in the A-ZIP/F-1 skin but not in the wild-type skin. These findings suggest that adipokines are not required for the promotion of tumor development and thus contradict the epidemiologic data linking obesity to carcinogenesis. We postulate that insulin resistance and inflammation are responsible for the positive correlation with cancer observed in A-ZIP/F-1 mice.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Diabetes Mellitus, Type 2; Disease Susceptibility; Female; Inflammation; Insulin Resistance; Leptin; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Obesity; Resistin; Skin Neoplasms; Transcription Factors

Cancer cell-stromal cell interaction plays a crucial role in the malignant growth of cancer cells. In the skin, the main stromal cell types consist of dermal fibroblasts and subcutaneous adipocytes. Fibroblasts are shown to promote the invasive growth of various cancer cell types. The interaction between cancer cells and stromal adipocytes, however, has not been sufficiently studied even in cutaneous carcinoma. To address the effects of adipocytes on the biologic behavior of cancer cells, we examined the growth and differentiation of a squamous cell carcinoma cell line of the skin (DJM-1), using a three-dimensional collagen gel matrix culture with a cutaneous environmental factor, air exposure. The growth was estimated by the uptake of bromodeoxy-uridine (BrdU) for 24 h. The BrdU indices of DJM-1 cells in stromal-cell-free, fibroblast-containing, and adipocyte- containing conditions were 19.7 +/- 1.9%, 19.8 +/- 2.8%, and 4.7 +/- 1.4%, respectively, whereas the BrdU index on the gel containing both fibroblasts and adipocytes was 10.4 +/- 3.3%. In terms of differentiation, DJM-1 cells cocultured with adipocytes constructed the best-organized stratified layer with a cornified-like structure in all conditions above. The differentiation markers involucrin and cytokeratin 10 were immunohistochemically detected in this structure of DJM-1 cells. Adipocyte-induced phenomena were not affected distinctively by air exposure. These results indicate that adipocytes, but not fibroblasts, promote the differentiation of squamous cell carcinoma cells (DJM-1) and inhibit their growth. These adipocyte-induced phenomena were not completely inhibited by fibroblasts. In conclusion, we suggest that stromal adipocytes may be involved in the differentiating mechanisms of cutaneous carcinoma cells.

Topics: Adipocytes; Animals; Carcinoma, Squamous Cell; Cell Communication; Cell Culture Techniques; Cell Differentiation; Cell Division; Collagen; Extracellular Matrix; Gels; Humans; Insulin-Like Growth Factor II; Kidney; Leptin; Matrix Metalloproteinase 2; Skin; Skin Neoplasms; Stromal Cells; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha