Dissimilar associations of same metabolic parameters with main chronic noncommunicable diseases (cancer vs some other NCDs).

Hormone-dependent tissues' cancers (mainly breast and endometrial and several others) are among the most frequent malignancies in adults and are often discussed in context of their correlation with other chronic noncommunicable diseases (NCDs), for example, cardiovascular and cerebrovascular conditions, and their risk factors, which may also be hormone metabolic. An idea that is often expressed delineates common factors leading to NCDs of malignant and nonmalignant nature. However, this idea is not always confirmed by study results. The reasons for this discrepancy are not clear and require further analysis. This editorial tries to show the importance of this problem with a few examples (in particular, by attracting information on the role of birthweight, adult height and family history of diabetes) which may help us understand some mechanisms behind interconnections of major NCDs, including cancer.

Endocrinology of obese and nonobese endometrial cancer patients: is there role of tumor molecular-biological type?

Aim: To compare endocrine characteristics of  endometrial cancer (EC) patients based on recent molecular EC types classification. Materials & methods: A total of 234 treatment-naive EC patients as well their tumors were studied. Results: Patients with POLE mutations demonstrated tendency to lower body mass index (BMI) and higher serum estradiol. Patients with p53 overexpression were older and had higher diabetes incidence. In the without characteristic molecular profile group there was no difference in fasting serum insulin, estradiol and testosterone levels between women with BMI ≥30.0 and <30.0. The mismatch repair deficient group patients had a tendency toward later menarche compared with the without characteristic molecular profile group one. Conclusion: Studied endocrine characteristics are associated with BMI or tumor molecular-biological type that might be relevant to EC genesis, course and prognosis.

Endometrial cancer evolution: new molecular-biologic types and hormonal-metabolic shifts.

The question hidden in the title of this manuscript (whether the topic develops or remains constant) is important for all areas of science. It is also a serious problem for endometrial cancer (EC) study. In recent times the incidence of EC gradually increases in parallel with obesity epidemics. The main point of this review was evaluation of changes in EC area in last few decades, which are not only seen in tumor incidence, but also in its biology, hormonal-metabolic characteristics of patients and in the ratio of risk and anti-risk factors. One can hope that data accumulated recently and summarized here under the notion of EC evolution will find its use for advancement of EC prevention and treatment.

Features of omental adipose tissue in endometrial cancer patients with 'standard' or 'metabolically healthy' obesity: associations with tumor process characteristics.

PURPOSE: Adipose tissue products may contribute to endometrial cancer (EC) initiation and further growth that encourages the analysis of this issue in patients with different obesity phenotypes. METHODS/PATIENTS: Omental fat depot characteristics were studied in EC patients (n = 57) with "standard" (SO) or "metabolically healthy" (MHO) obesity. Collected omental samples were evaluated by immunohistochemistry /IHC/ for brown fat marker UCP1, CYP19 (aromatase) and macrophage infiltration markers (CD68, CD163, crown-like structures/CLS) expression. Total RNA extracted from the same samples was investigated for UCP1, CYP19, PTEN and adipokine omentin mRNA. RESULTS: Immunohistochemistry data revealed a statistically significant increase in aromatase and CD68 expression and tendency to increase of UCP1 expression in SO patients' omental fat compared to samples obtained from MHO patients. Additionally, positive correlation of EC clinical stage with UCP1 protein and its mRNA content in omental fat was pronounced in MHO as well as SO group, while with omentin mRNA it was discovered only in patients with SO. An inclination to the correlation with better tumor differentiation was seen for UCP1 and CD68 protein expression in patients with MHO and with worse (high grade) differentiation-for CD68 expression in the group with SO. CONCLUSIONS: In aggregate, this suggests that obesity phenotype has significant impact on omental fat tissue characteristics which is related to the clinical course of EC and may have practical consequences.

The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling.

Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IκBα, NF-κB, cyclin D1 and ERα; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the constitutive activation of Akt/Snail1/E-cadherin signaling that opens new perspectives to overcome the metformin/tamoxifen resistance of breast cancer.

Insulinemia, heterogeneity of obesity and the risk of different types of endometrial cancer: existing evidence.

Due to a number of reasons, endometrial cancer is a point of interest not only for oncologists, but also for a variety of specialists - especially endocrinologists. The endocrinology of endometrial cancer can be firmly divided into two categories - steroid and non-steroid. The steroid approach dominated during several decades due to hyperestrogenization signs observed in some patients. The balance was only regained in the last 15 years, when the role of diabetes and insulin resistance began to draw attention. This review aims to provide an update on connections between insulinemia (insulin resistance) and different obesity phenotypes as well to discuss their relation to development of endometrial cancer, its clinical-morphological features and the increasing number of its molecular-biological subtypes.

The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes.

In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 µg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation by ß-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

Potential and real 'antineoplastic' and metabolic effect of metformin in diabetic and nondiabetic postmenopausal females.

AIM: The goal of this study was to determine if the single nucleotide polymorphisms marking potential sensitivity to metformin (MF) correlate with hormone-metabolic status as well as with actual response to MF in postmenopausal cancer patients with or without Type 2 diabetes mellitus and in diabetics without cancer. PATIENTS & METHODS: The carriage of ten different SNPs was evaluated in all patients by PCR, and hormone-metabolic status was estimated by anthropometry, ELISA and enzyme colorimetric assays. The response to daily 1-1.7 g of MF was studied based on hormone-metabolic parameters and indirect end points (endometrium thickness, mammographic breast density). RESULTS & CONCLUSION: The changes in evaluated 'antineoplastic' and metabolic response marker values were seen in 33.3 and 61.8% of the cases, respectively. Several genetic markers were found that showed an inclination to less frequent 'antineoplastic' or more frequent metabolic response to MF which may be helpful in further studies of this drug in cancer patients.

Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases.

The changes in the brain signaling systems play an important role in etiology and pathogenesis of Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), being a possible cause of these diseases. Therefore, their restoration at the early stages of T2DM and MS can be regarded as a promising way to treat and prevent these diseases and their complications. The data on the functional state of the brain signaling systems regulated by insulin, IGF-1, leptin, dopamine, serotonin, melanocortins and glucagon-like peptide-1, in T2DM and MS, are analyzed. The pharmacological approaches to restoration of these systems and improvement of insulin sensitivity, energy expenditure, lipid metabolism, and to prevent diabetic complications are discussed.

Features of endometrial cancer in patients with 'metabolically healthy' versus 'standard' obesity: the decreasing frequency of metabolically healthy obesity.

BACKGROUND: As endometrial cancer (EC) prevalence increases with obesity, we aimed to determine whether EC characteristics depend upon obesity type: 'standard' (SO) or 'metabolically healthy obesity' (MHO). PATIENTS & METHODS: 258 EC patients were included. Data on anthropometry, blood hormones, lipids and glucose, and tumor features were collected. RESULTS: EC clinicopathologic characteristics and clinical stage correlate differently with BMI and obesity type. BMI is related inversely with tumor grade while SO patients are characterized by a more advanced clinical stage than those with MHO. Besides typical insulin resistance signs, EC patients with SO often display a higher serum leptin/adiponectin ratio compared with MHO patients. Historical data suggest a gradual increase in EC patient height and weight, and a decrease in MHO prevalence. CONCLUSION: It is currently unknown whether the latter observation reflects the evolution of EC, or obesity alongside the current epidemic. Regardless, the reduced MHO prevalence demonstrates the need for more intensive preventive measures aimed at obesity and obesity-associated conditions, including different EC subtypes.

Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer.

Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 ± 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naïve cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naïve cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1-R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1_rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone-binding globulin gene SHBG_D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1_G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1_R61C. In addition, carriers of OCT1_R61C and OCT1_rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation.

Snail/beta-catenin signaling protects breast cancer cells from hypoxia attack.

The tolerance of cancer cells to hypoxia depends on the combination of different factors--from increase of glycolysis (Warburg Effect) to activation of intracellular growth/apoptotic pathways. Less is known about the influence of epithelial-mesenchymal transition (EMT) and EMT-associated pathways on the cell sensitivity to hypoxia. The aim of this study was to explore the role of Snail signaling, one of the key EMT pathways, in the mediating of hypoxia response and regulation of cell sensitivity to hypoxia, using as a model in vitro cultured breast cancer cells. Earlier we have shown that estrogen-independent HBL-100 breast cancer cells differ from estrogen-dependent MCF-7 cells with increased expression of Snail1, and demonstrated Snail1 involvement into formation of hormone-resistant phenotype. Because Snail1 belongs to hypoxia-activated proteins, here we studied the influence of Snail1 signaling on the cell tolerance to hypoxia. We found that Snail1-enriched HBL-100 cells were less sensitive to hypoxia-induced growth suppression if compared with MCF-7 line (31% MCF-7 vs. 71% HBL-100 cell viability after 1% O2 atmosphere for 3 days). Snail1 knock-down enhanced the hypoxia-induced inhibition of cell proliferation giving the direct evidence of Snail1 involvement into cell protection from hypoxia attack. The protective effect of Snail1 was shown to be mediated, at least in a part, via beta-catenin which positively regulated expression of HIF-1-dependent genes. Finally, we found that cell tolerance to hypoxia was accompanied with the failure in the phosphorylation of AMPK - the key energy sensor, and demonstrated an inverse relationship between AMPK and Snail/beta-catenin signaling. Totally, our data show that Snail1 and beta-catenin, besides association with loss of hormone dependence, protect cancer cells from hypoxia and may serve as an important target in the treatment of breast cancer. Moreover, we suggest that the level of these proteins as well the level of AMPK phosphorylation may be considered as predictors of the tumor sensitivity to anti-angiogenic drugs.

High baby birth weight and risk of hormone-associated cancer in mothers: the cancer-cardiovascular disease dichotomy and its possible causes.

The idea of intrauterine or fetal factors being the cause of several prevalent noninfectious diseases in adults has recently gained the status of an axiom. One of the most thoroughly studied predictors is birth weight (BW). Although many published studies point at relations between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity. Available data suggest a sort of dichotomy in these relationships. Thus, cardiovascular risk is higher in mothers of babies with a reduced BW, while cancer risk, mainly of the breast and some other hormone-dependent cancers, is often higher among mothers of babies with a large BW (newborn macrosomia). This review addresses possible causes and endocrine mechanisms of this topic and suggests a 'particular' and 'general' solution for arising controversy. Emphasis is placed on a probable competition between chronic diseases (mainly, between female hormone-related cancer and cardiovascular pathology) within the concept of multiple causes of death. These associations should be remembered while studying the relation between offspring BW and maternal predisposition to hormone-associated cancers and other noncommunicable diseases.

Cancer endocrinology through own experience: areas for further thought and development. Interview by Natasha Galukande.

Lev Berstein speaks to Natasha Galukande, Assistant Commissioning Editor. Lev Berstein is Chief of Laboratory of Oncoendocrinology at the Petrov Research Institute of Oncology, St Petersburg, Russia. His main scientific interests include mechanisms of hormonal carcinogenesis, studying risk factors of hormone-associated tumors, and new approaches for prevention and treatment of the latter. As a clinician, he is involved in the management of cancer patients needing hormonal therapy or having endocrine pathology. Berstein has received several international distinctions (including an INTAS grant and UICC Translational Cancer Research Fellowship), serves as a Member of Council of the Russian Endocrine Association and is on the editorial boards of several international journals, including Future Oncology, was Guest Editor for a special focus issue of Expert Review of Endocrinology and Metabolism on hormones in breast and prostate cancer, and is a member of the European Association of Cancer Research and The Endocrine Society of the USA. His bibliography includes 11 monographs, 21 chapters and more than 200 papers in peer-reviewed journals. He graduated as a MD from Tartu University in Estonia and completed his PhD and Doctor of Medical Sciences degrees in cancer endocrinology at the NN Petrov Institute in St Petersburg (Russia).

Cancer and heterogeneity of obesity: a potential contribution of brown fat.

Obesity has lately been drawing additional attention as a potential cancer risk and, with some exceptions as a prognostic factor. As obesity is a complex issue characterized by different variants, mechanisms and manifestations, its role in cancer development is also a complex problem exceeding the basic fact of the fat content rising above certain limits. Therefore, in the present paper obesity is viewed as a heterogeneous entity, which has distinct connections with cancer pathogenesis. Among other issues, emphasis is made on the state of white and brown adipose tissue, in particular the association of specific brown fat features and the so-called white fat browning with the functions of normal and mutated tumor suppressor genes, such as PTEN and BRCA1. These connections are considered from the viewpoint implying the existence of two types of hormonal carcinogenesis and of hormonal mediation of the genetic predisposition to tumor development, and should be accounted for in prevention and treatment of both obesity and cancer.