Crossroad between Obesity and Cancer: A Defective Signaling Function of Heavily Lipid-Laden Adipocytes

Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue more visceral fat leading to abdominal adiposity, which shows a strong correlation with serious obesity-associated comorbidities, cardiovascular diseases and cancers. In contrast, obese females accumulate excessive fatty tissue predominantly subcutaneously enjoying strong protection from the obesity-related diseases. The health advantage of obese women as compared with obese men may be attributed to their higher estrogen production and an increased transactivation of estrogen receptors (ERs). The recently clarified intracrine, paracrine, and endocrine functions of adipose tissue illuminate that concentrations of estrogens and the suitable expression and activity of ERs strongly define all regulatory functions in both men and women. All well-known cancer risk factors are in correlation with defects of estrogen signaling in partnership with glucose intolerance as estrogen regulates all steps of glucose uptake. In central obesity, increased secretions of cytokines and growth factors are not causal factors of developing insulin resistance, and unrestrained cell proliferation, but rather, they are compensatory processes so as to increase estrogen synthesis and ER transactivation. In conclusion, a causal therapy against obesity and obesity-related diseases aims to improve estrogen signaling in both men and women

Az ösztrogénhiányon alapuló rákelmélet = Carcinogenesis theory based on estrogen deficiency

Az ösztrogénhormont hosszú ideig a női élettani folyamatok és a szaporodás legfontosabb szereplőjének tartották. Manapság már jól ismert tény, hogy a női nemi hormon döntő szerepet játszik a sejtdifferenciálódás és -proliferáció génregulációjában. A női nemi hormonok és a rák kapcsolatát illetően az irodalmi adatok nem egységesek. A daganatkutatás homlokterében vannak az erősen ösztrogénfüggő daganatok, amelyekről az a vélemény alakult ki, hogy hormonálisan indukálódnak. Ennek ellenére kiderült, hogy az ösztrogén carcinogen hatását bizonyító eredmények ellentmondásosak. Az utóbbi években klinikai vizsgálatok igazolták, hogy a posztmenopauzális nők hormonterápiája jótékony, rákmegelőző hatást fejt ki számos szervben, még a női emlőben is. Az újabban felfedezett kapcsolat az ösztrogénhiány és a szájüregi rák kockázata között ellentétben áll a hagyományos ösztrogénindukált rák koncepciójával. A mérsékelten és erősen ösztrogéndependens tumoroknak eltérő epidemiológiai sajátosságaik vannak. Az úgynevezett dohányzásfüggő daganatok a mérsékelten ösztrogénfüggő szervekből indulnak ki. Túlnyomó többségük a késői posztmenopauzális periódusban jelentkezik, amikor az ovárium ösztrogéntermelése már jelentősen csökkent. Ezzel szemben az erősen ösztrogénfüggő szervek rákjai (például emlő, endometrium és ovárium) premenopauzális és posztmenopauzális esetekben egyaránt jelentkeznek. A különböző epidemiológiai adatok ellenére feltételezhető, hogy a tumoriniciáció hátterében a génregulációs zavar nem alakulhat ki teljesen ellentétes ösvényeken. Feltételezhető, hogy a mérsékelten ösztrogénfüggő szervekben a súlyos, az erősen ösztrogéndependensekben pedig már az enyhe ösztrogénhiány is rákiniciációt provokálhat. Mind a dohányzásfüggő, mind a hormondependens rákokon tapasztalt új megfigyelések ugyanahhoz a konverzióhoz vezetnek; nem az ösztrogén, hanem a hiánya provokálja a rákiniciációt. | Earlier, estrogens were considered simply the most important hormones involved in female physiology and reproduction. Nowadays it has become familiar that they have pivotal roles in gene regulation of cell differentiation and proliferation. There are many contradictions concerning the associations of female sexual steroids and cancer. Cancers of the highly estrogen dependent organs are in the forefront of tumors as they are regarded as hormone associated ones. However, re-evaluation of earlier results supporting the carcinogenic capacity of estrogen exhibited many shortcomings and controversies. Recently, the clinical studies on hormone replacement therapy in postmenopausal women justified beneficial anticancer effects in several organs even in the female breast. The newly revealed association between estrogen deficiency and oral cancer risk also means a contradiction of the traditional concept of estrogen-induced cancer. Distinction between cancers of moderately and highly estrogen dependent tumors can be based on their different epidemiological features. The vast majority of the so-called smoking associated malignancies of the moderately estrogen dependent organs occur typically in the late postmenopausal life of women when the ovarian estrogen production is fairly decreased. However cancers of the highly estrogen dependent organs such as breast, endometrium and ovary exhibit both premenopausal and postmenopausal occurrence. In spite of the different epidemiological data of these two groups of cancers the mechanism of gene regulation disorder in the background of tumor initiation cannot act through quite opposite pathways. This suggests that in moderately estrogen sensitive organs a serious, in the highly estrogen dependent sites even a mild estrogen deficiency is enough to provoke gene regulation disorders. The new findings both on smoking associated and hormone related cancers might lead to the same conversion; not estrogen but rather its deficiency may provoke cancer initiation

Rosetta Stone for Cancer Cure: Comparison of the Anticancer Capacity of Endogenous Estrogens, Synthetic Estrogens and Antiestrogens

This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice

A p16 tumorszuppresszor expressziojanak prognosztikai szerepe magyarorszagi szajuregi laphamrakokban.

Beside smoking and alcohol consumption, human papillomavirus (HPV) infection is the most common risk factor of squamous cell carcinoma in the head and neck region (HNSCC). The latter group of patients associates with better prognosis. During HPV infection, the level of p16 tumor suppressor elevates, which could give an additional opportunity for diagnosis: instead of molecular diagnostic tools, the application of immunohistochemistry is acceptable. However, the majority of the published studies focused on the whole head and neck region and did not separately handled cancers of the oral cavity. Our recent work analyzed the expression of p16 in 67 oral squamous cancers, and compared to routine clinicopathologic parameters. From surgical samples tissue microarray blocks were prepared and expression of p16 as well as other molecular markers (p53, Ki67, EGFR) were studied. In contrast to previous studies on HNSCC, with the exception of recurrence, the expression of p16 was not found associated to clinicopathologic parameters. Nuclear stabilization of p53 appeared mainly in younger patients. The expression of p53 and EGFR significantly correlated to each other. We concluded that traditional molecular categorization of HNSCC could not be completely adaptable to Hungarian samples. Potential coexposition of common etiological factors (e.g. HPV, smoking, alcohol) could blur borders between distinct categories

Hormonális kockázati tényezők szerepe a szájüregi rák kialakulásában = Role of hormonal risk factors in oral cancer development

Az orális carcinoma (OC) esetek körében igen magas a férfi:nő arány. A nők alacsony száma a férfiakhoz viszonyítva arra utal, hogy endokrin tényezők is szerepet játszhatnak a daganat kialakulásában. Jelen vizsgálataink célja, hogy tisztázzuk, milyen különbségek vannak férfiak és nők között az OC rizikófaktoraira vonatkozóan. A Semmelweis Egyetem Arc-Állcsont-Szájsebészeti és Fogászati Klinikáján jelentkező 2660 beteget (2130 férfi és 530 nő) vontuk be a vizsgálatba. Regisztráltuk a dohányzást és az alkoholfogyasztást, az emelkedett szérumglükózszintet és a nőbetegek menopauzára vonatkozó adatait. A dohányzás és a túlzott alkoholfogyasztás, az irodalmi adatokkal megegyezően, fontos rizikófaktornak bizonyult az OC-esetekben férfiak és nők körében egyaránt. A mérsékelt alkoholfogyasztás viszont gyenge rizikófaktornak bizonyult férfiak körében, és egyáltalán nem jelentett kockázatot a nők számára. Az emelkedett éhomi glükózszint nem volt kimutatható OC-kockázat a férfi betegek körében, ugyanakkor a nők esetében jelentős rizikófaktornak bizonyult, különös tekintettel a gingivacarcinomára. A női OC-betegek csaknem valamennyien posztmenopauzálisak voltak, továbbá a menopauza és az OC diagnózisa között meglehetősen hosszú idő telt el (átlagosan 17 év). Ezek a vizsgálati leletek arra utalnak, hogy az ösztrogénhiány szerepet játszhat az OC iniciációjában. A női OC-esetekben szignifikánsan fiatalabb korban jelentkezett a menopauza, és a hysterectomia aránya is jóval magasabb volt a tumormentes kontrollokkal összehasonlítva, ami szintén alátámasztja az ösztrogénhiány-elméletet. Posztmenopauzális nőbetegekben mind az ösztrogénhiány, mind az emelkedett éhomi glükózszint OC-rizikófaktornak tűnik. Ezek az eredmények új megvilágításba helyezik az orális carcinomák etiológiáját, és magyarázatot adnak arra vonatkozóan, hogy hogyan alakulhatnak ki dohányzásfüggő tumorok dohányzás nélkül. | Male: female ratio of oral cancer cases (OC) is fairly high. Lower rate of female cases as compared with males suggests that some endocrine factors may play role in the development of tumors. The aim of the present study was to clarify the differences of risk factors for OC among male and female cases. In the Oral and Maxillofacial Department of Semmelweis University 2660 OC (2130 males and 530 females) patients were included into the study. Ratio of smoking, alcohol consumption, elevated serum glucose level and menopausal data of the female patients were registered. Concordant to the literary data, smoking and excessive alcohol consumption proved to be an important risk factor for OC both among male and female patients. However, moderate alcohol consumption was a weak risk factor among male and no risk factor among female cases. Elevated serum glucose level was not significant OC risk among male cases, but was a high risk factor among female patients, especially in gingival cancer cases. The female OC cases were near exclusively postmenopausal, and the term between the time of menopause and clinical OC diagnosis was fairly long (average: 17 year). These results suggest that estrogen-deficiency may play an important role in the initiation of OC. In the female OC cases menopause appeared in significantly younger age, and the rate of hysterectomy was also significantly higher as compared with the tumor-free control cases. These data also support the estrogen-deficiency theory of cancer initiation. In postmenopausal female patients both estrogen-deficiency and elevated fasting glucose proved to be risk factors for OC. These results reveal new aspects concerning the etiology of OC and give a possible explanation how smoking-associated tumors may develop even without smoking

A p16 tumorszuppresszor expressziójának prognosztikai szerepe magyarországi szájüregi laphámrákokban.

A fej-nyaki régió laphámrákjának legfontosabb rizikófaktorai az alkohol- és dohányexpozíció, illetve a humán papillómavírussal (HPV) való fertőzés, mely utóbbi alcsoport jóval kedvezőbb klinikai prognózist mutat. A p16 tumorszuppresszor sejten belüli szintje magas kockázatú HPV-fertőzés mellett megemelkedik, ami lehetőséget teremt arra, hogy molekuláris diagnosztikai módszerek helyett immunhisztokémia segítségével diagnosztizáljuk a fertőző ágens jelenlétét. A témában megjelent legtöbb kutatás a fej-nyaki régió egészére fókuszált, és nem kezelte külön a szájüregi lokalizációt. Munkánk során a szájüregi régióból műtétileg eltávolított 67 rosszindulatú laphámdaganat p16-expresszióját vizsgáltuk, és vetettük össze a fej-nyaki régióban rutinszerűen meghatározott klinikopatológiai paraméterekkel. A műtéti anyagokból tissue microarray (TMA) blokkokat készítettünk, majd immunhisztokémiai vizsgálat segítségével megvizsgáltuk a p16, illetve több más ismert molekuláris marker (p53, Ki67, EGFR) expresszióját. A fej-nyak régió laphámrákjait taglaló szakirodalmi adatokkal ellentétben saját szájüregi anyagunkban nem kaptunk összefüggést a fő klinikai paraméterekkel, a p16-pozitivitás csupán a recidíva tekintetében jelentett kedvező prognózist. A magi p53-pozitivitás főként a fiatalabb betegcsoportra volt jellemző. A p53- és az EGFR-expresszió statisztikailag szignifikáns korrelációt mutatott egymással. Megállapítottuk, hogy a fej-nyaki laphámrákokban alkalmazott molekuláris csoportosítás nem adaptálható teljes egészében a hazai szájüregi laphámrákokra. Felmerül az egyes etiológiai tényezők (HPV, dohányzás, alkohol) ko-expozíciós szerepe, ami megnehezíti az egyes kategóriák elkülönítését

Reconstructive periodontal therapy with simultaneous ridge augmentation. A clinical and histological case series report

Treatment of intrabony periodontal defects with a combination of a natural bone mineral (NBM) and guided tissue regeneration (GTR) has been shown to promote periodontal regeneration in intrabony defects. In certain clinical situations, the teeth presenting intrabony defects are located at close vicinity of the resorbed alveolar ridge. In these particular cases, it is of clinical interest to simultaneously reconstruct both the intrabony periodontal defect and the resorbed alveolar ridge, thus allowing insertion of endosseous dental implants. The aim of the present study was to present the clinical and histological results obtained with a new surgical technique designed to simultaneously reconstruct the intrabony defect and the adjacently located resorbed alveolar ridge. Eight patients with chronic advanced periodontitis displaying intrabony defects located in the close vicinity of resorbed alveolar ridges were consecutively enrolled in the study. After local anesthesia, mucoperiosteal flaps were raised, the granulation tissue removed, and the roots meticulously scaled and planed. A subepithelial connective tissue graft was harvested from the palate and sutured to the oral flap. The intrabony defect and the adjacent alveolar ridge were filled with a NBM and subsequently covered with a bioresorbable collagen membrane (GTR). At 11–20 months (mean, 13.9 ± 3.9 months) after surgery, implants were placed, core biopsies retrieved, and histologically evaluated. Mean pocket depth reduction measured 3.8 ± 1.7 mm and mean clinical attachment level gain 4.3 ± 2.2 mm, respectively. Reentry revealed in all cases a complete fill of the intrabony component and a mean additional vertical hard tissue gain of 1.8 ± 1.8 mm. The histologic evaluation indicated that most NBM particles were surrounded by bone. Mean new bone and mean graft area measured 17.8 ± 2.8% and 32.1 ± 8.3%, respectively. Within their limits, the present findings indicate that the described surgical approach may be successfully used in certain clinical cases to simultaneously treat intrabony defects and to reconstruct the resorbed alveolar ridge

Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations

Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. The artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. The laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. The capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure

Common soil of smoking-associated and hormone-related cancers: estrogen deficiency

Accumulation of non-smoker, non-drinker elderly postmenopausal female patients among smokingassociated oral cancer cases raised the plausible idea: estrogen deficiency maybe a cancer risk factor. On the other hand, the extremely rare cases of young women with oral cancer regularly exhibited hormonal disorders, such as irregular menstrual cycles and infertility. Furthermore, in the history of middle-aged female, oral cancer cases a primary ovarian failure or complete hysterectomy was a conspicuously frequent finding suggestive of an estrogen deficient milieu. There were many striking contradictions concerning the associations of female sexual steroids and cancer risk as well. Until now, breast and endometrial cancers were regarded as typically estrogen-induced tumors, particularly in postmenopausal cases. However, unexplained beneficial anti-cancer effects of hormonereplacement therapy were reported against cancers at several sites, even tumors of the highly hormone-responsive organs. Re-evaluation of results of the experimental and epidemiological studies, which endeavored to justify the carcinogenic capacity of estrogen, exhibited many shortcomings and controversies. The new findings both on smoking associated and on hormone related cancers added up to the same conversion; not estrogen but rather its deficiency might provoke cancer initiation. Thorough review of the literary data justified that the exquisite regulatory capacity of estrogen and its surveillance on growth, development, differentiation, and metabolism are indispensable, whereas an estrogen-deficient milieu may induce a breakdown in gene-regulation. Recognition of the anticancer capacity of estrogen may provide new insights into the etiology of malignancies and leads to new strategies for cancer prevention and cure