Неканоническая активность ретиноевой кислоты в отношении активации протеинкиназ в трансформированных клетках различного происхождения

Background. The non-canonical activity of retinoic acid (RA) was discovered relatively recently and consists in the rapid activation of intracellular signaling pathways by the mechanisms not related to the transcriptional activity of the RA nuclear receptors. Separate data suggest that this activity can stimulate the processes of malignancy and contribute to the formation of tumor cell resistance to RA as a therapeutic agent. However, little is known about the mechanisms of this activity. It is also unclear how universal this effect is; does the RA-dependent activation of different signaling protein kinases occur in the same cells, and whether activation of these kinases is interrelated.Materials and methods: cultivation of non-small cell lung cancer cells and neuroblastoma cells under standard conditions and with incubation with all-trans retinoic acid (ATRA); immunoblotting.Results. Here we studied the effect of ATRA on the activation of Akt and Erk1/2 protein kinases depending on the incubation time. The analysis revealed RA-dependent activation of both kinases in all studied non-small cell lung cancer and neuroblastoma cell lines. Activation of Akt and Erk1/2 occurred at five minutes of incubation, which corresponds to the non-transcriptional (non-canonical) activity of the RA, however, further activation kinetics of the two kinases differed essentially.Conclusion. We found that ATRA causes rapid activation of Erk1/2 and Akt protein kinases in both non-small cell lung cancer and neuroblastoma cells. The differences in the kinetics of RA-dependent stimulation of these two kinases suggest that their activation is mediated by independent mechanisms.Введение. Неканоническая активность ретиноевой кислоты (РК) обнаружена сравнительно недавно и заключается в быстрой активации внутриклеточных сигнальных путей с помощью механизмов, не связанных с транскрипционной активностью ядерных рецепторов РК. Отдельные данные свидетельствуют о том, что неканоническая активность может стимулировать процессы малигнизации и участвовать в формировании резистентности опухолевых клеток к терапевтическому воздействию РК. Однако о механизмах неканонической активности известно достаточно мало. Непонятно, насколько этот эффект универсален, происходит ли РК-зависимая активация различных сигнальных протеинкиназ в одних и тех же клетках, и насколько активация этих киназ взаимосвязана.Материалы и методы: культивирование клеток немелкоклеточного рака легкого и нейробластомы в стандартных условиях и при инкубации с полностью транс-ретиноевой кислотой (all-trans retinoic acid, ATRA); иммуноблоттинг.Результаты. В работе исследовали влияние ATRA на активацию протеинкиназ Akt и Erk1 / 2 в зависимости от времени инкубации. Анализ выявил РК-зависимую активацию обеих киназ во всех исследуемых линиях клеток немелкоклеточного рака легкого и нейробластомы. Активация как Akt, так и Erk1 / 2 возникала при 5 мин инкубации, что соответствует нетранскрипционной (неканонической) активности РК, однако дальнейшая кинетика активации двух киназ существенно различалась.Заключение. Мы показали, что ATRA вызывает краткосрочную активацию протеинкиназ Erk1 / 2 и Akt в клетках немелкоклеточного рака легкого и нейробластомы. Различия в кинетике РК-зависимой стимуляции двух киназ свидетельствуют о том, что их активация реализуется с помощью независимых механизмов

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2)

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995â\u80\u932009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005â\u80\u932009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Lancet

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Маркеры ранних стадий рака легкого у ликвидаторов Чернобыльской аварии

Persons exposed to inhaled radionuclides are at high risk for lung cancer, primarily, due to lung fibrosis development. This work studied lung fibrotic changes and lung cancer genetic markers in liquidators of the Chernobyl accident consequences. The study involved 33 men worked at the Chernobyl station area in 1986-1987, aged from 37 to 65 years (average 45.45±0.95; M±m), and 10 control group men comparable on the age, hazards, social and occupational status, lung pathology, but had never exposed to radiation.Lung function tests, fibreoptic bronchoscopy, histological examination of lung and bronchi tissues biopsy specimens, and lung computed tomography were performed. Oncogene c-myc, Ki-67 proliferation marker, and a deletion in the short arm of the chromosome 3 were investigated in the bronchial epithelium.The lung fibrosis was detected in 13 (42.4%) liquidators and in no-one of the control group. The liquidators also had more bronchial epithelium dysregenerative changes with significant prevalence of basement cell hyperplasia (0.58±.09 and 0.2±0.13 cases in the groups accordingly, p&lt;0.05). Meanwhile the control group had no mild dysplasia at all and demonstrated severe dysplasia rather more frequently (0.2±0.13 vs 0.06±0.04 in the liquidators, p&lt;0.05). The liquidators showed the 3p deletion in the bronchial epithelium cells more often (0.21±0.07 and 0.1±0.1 accordingly, p&lt;0.05) and tended to show other genetic lung cancer markers quite more frequent either.The correlation was found between the lung fibrosis and 3p deletion presence (r=0.45, p&lt;0.05) and also between a pneumonia number anamnestically and Ki-67 expression in the liquidators’ group (r=0.46, p&lt;0.05). The second patients’ group did not demonstrated such the correlaions.Thus, chronic respiratory pathology liquidators develop lung fibrosis earlier than other patients with the similar lung pathology. Basement cell hyperplasia and some oncogenes (3p deletion, c-myc) encounter considerably more often in liquidators that likely to be poor prognostic signs for lung cancer occurrence. Therefore, the Chernobyl accident liquidators are at higher risk for lung cancer compared to the similar lung pathology patients without radiation exposureЛица, ингалировавшие радионуклиды в результате профессиональных воздействий либо неблагоприятной экологической обстановки, имеют высокий риск заболевания раком легкого, в первую очередь, за счет развития пневмофиброза. В данной работе исследовались фиброзные изменения легочной ткани и ряд генетических маркеров рака легкого у ликвидаторов последствий Чернобыльской аварии. В исследование вошли 33 ликвидатора (все мужчины) в возрасте от 37 до 65 лет (в среднем 45,4±0,95 года; М±т) и 10 мужчин группы сравнения, сравнимые с “ликвидаторами” по возрасту, вредным привычкам, социально-бытовым и профессиональным условиям, характеру и длительности бронхолегочной патологии, но не контактировавшие с радиацией.Пациентам проводились исследования легочной функции, фибробронхоскопия с биопсией и последующим гистологическим исследованием ткани бронхов и легких, компьютерная томография легких. В биоптатах определяли онкоген c-myc и маркер пролиферации Ki-67, делецию в коротком плече 3-й хромосомы.Среди ликвидаторов пневмофиброз был выявлен у 13 (42,4%) человек, в группе сравнения не выявлен ни у кого. Также у ликвидаторов чаще, чем в группе сравнения, встречались дисрегенераторные изменения бронхиального эпителия с достоверным преобладанием базальноклеточной гиперплазии (0,58±0,09 и 0,2±0,13 случаев соответственно по группам, р&lt;0,05). Вместе с тем в группе сравнения совсем не обнаруживалась дисплазия 1 ст. и несколько чаще встречалась дисплазия 3 ст. (0,2±0,13 в группе сравнения и 0,06±0,04 у ликвидаторов, р&lt;0,05). Делеция Зр в клетках бронхиального эпителия у ликвидаторов определялась достоверно чаще, чем в группе сравнения (0,21±0,07 и 0,1±0,1 соответственно, р&lt;0,05). Имеется тенденция к более частому обнаружению в группе ликвидаторов и других генетических маркеров.Корреляционный анализ показал достоверную связь между наличием пневмофиброза и делеции в коротком плече 3-й хромосомы (r=0,45, р&lt;0,05), а также между числом перенесенных пневмоний и экспрессией Ki-67 в группе ликвидаторов (r=0,46, р&lt;0,05). В группе сравнения такой зависимости не получено.Таким образом, у ликвидаторов с ХОБЛ фиброз легочной ткани развивается значительно раньше, чем у обычных больных ХОБЛ. У ликвидаторов достоверно чаще обнаруживаются базальноклеточная гиперплазия и генетические маркеры рака легкого (делеция Зр, с-тус), что является прогностически неблагоприятным фактором в развитии этого заболевания. В результате ликвидаторы имеют больший риск заболевания раком легкого по сравнению с обычными больными ХОБЛ.

Changing geographical patterns and trends in cancer incidence in children and adolescents in Europe, 1991–2010 (Automated Childhood Cancer Information System): a population-based study

Background: A deceleration in the increase in cancer incidence in children and adolescents has been reported in several national and regional studies in Europe. Based on a large database representing 1·3 billion person-years over the period 1991–2010, we provide a consolidated report on cancer incidence trends at ages 0–19 years. Methods: We invited all population-based cancer registries operating in European countries to participate in this population-based registry study. We requested a listing of individual records of cancer cases, including sex, age, date of birth, date of cancer diagnosis, tumour sequence number, primary site, morphology, behaviour, and the most valid basis of diagnosis. We also requested population counts in each calendar year by sex and age for the registration area, from official national sources, and specific information about the covered area and registration practices. An eligible registry could become a contributor if it provided quality data for all complete calendar years in the period 1991–2010. Incidence rates and the average annual percentage change with 95% CIs were reported for all cancers and major diagnostic groups, by region and overall, separately for children (age 0–14 years) and adolescents (age 15–19 years). We examined and quantified the stability of the trends with joinpoint analyses. Findings: For the years 1991–2010, 53 registries in 19 countries contributed a total of 180 335 unique cases. We excluded 15 162 (8·4%) of 180 335 cases due to differing practices of registration, and considered the quality indicators for the 165 173 cases included to be satisfactory. The average annual age-standardised incidence was 137·5 (95% CI 136·7–138·3) per million person-years and incidence increased significantly by 0·54% (0·44–0·65) per year in children (age 0–14 years) with no change in trend. In adolescents, the combined European incidence was 176·2 (174·4–178·0) per million person-years based on all 35 138 eligible cases and increased significantly by 0·96% (0·73–1·19) per year, although recent changes in rates among adolescents suggest a deceleration in this increasing trend. We observed temporal variations in trends by age group, geographical region, and diagnostic group. The combined age-standardised incidence of leukaemia based on 48 458 cases in children was 46·9 (46·5–47·3) per million person-years and increased significantly by 0·66% (0·48–0·84) per year. The average overall incidence of leukaemia in adolescents was 23·6 (22·9–24·3) per million person-years, based on 4702 cases, and the average annual change was 0·93% (0·49–1·37). We also observed increasing incidence of lymphoma in adolescents (average annual change 1·04% [0·65–1·44], malignant CNS tumours in children (average annual change 0·49% [0·20–0·77]), and other tumours in both children (average annual change 0·56 [0·40–0·72]) and adolescents (average annual change 1·17 [0·82–1·53]). Interpretation: Improvements in the diagnosis and registration of cancers over time could partly explain the observed increase in incidence, although some changes in underlying putative risk factors cannot be excluded. Cancer incidence trends in this young population require continued monitoring at an international level. Funding: Federal Ministry of Health of the Federal German Government, the European Union's Seventh Framework Programme, and International Agency for Research on Cancer