CC BY
6South Russian Journal of Cancer
South Russian Journal of Cancer 2023. Vol. 4, No. 1. P. 23-33 https://doi.org/10.37748/2686-9039-2023-4-1-3 https://elibrary.ru/gwlsqd ORIGINAL ARTICLE
INDICES OF INSULIN-LIKE GROWTH FACTORS FAMILY IN THE LUNG TISSUE OF PATIENTS WITH NON-SMALL CELL LUNG CANCER AFTER COVID-19 OF VARIOUS SEVERITY
O. I. Kit, E. M. Frantsiyants, D. A. Kharagezov, V. A. Bandovkina^, N. D. Cheryarina, Yu. A. Pogorelova, Yu. N. Lazutin, A. G. Milakin, I. A. Leyman, O. N. Stateshny
BY 4.0
National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation E valerryana@yandex.ru
ABSTRACT
Purpose of the study. An analysis of levels of IGF and their carrying proteins in lung tissues of cancer patients depending on the severity of the previous COVID-19 infection.
Patients and methods. The study included 60 patients with histologically verified non-small cell lung cancer (NSCLC) T1-3NxM0 receiving treatment at the Thoracic Department, National Medical Research Centre for Oncology, in 2020-2021. The control group included 30 NSCLC patients after asymptomatic or mild COVID-19 disease (15 males and 15 females); the main group included 30 (15 men and 15 women) patients after severe or moderate to severe COVID-19 infection. The mean age of patients was 59.11 ± 2.89 years; no significant differences were noted between the control and main groups. All participants gave their informed consent prior to the study approved by the Ethics Committee of National Medical Research Centre for Oncology. Qualitative assessment of IGF-I, IGF-II and IGFBP-1,2,3 levels in the tissues of the tumor, peritumoral area and resection line were measured by ELISA (Mediagnost, Germany). The statistical analysis was performed in the Statistica 10 program, the differences were considered statistically significant at p < 0.05.
Results. Regardless of the gender, levels of IGF-I and IGF-II in tumor and resection line samples in patients of the main group were higher than in the control group on average by 1.5-2.2 times, and IGFBP-1 in the tumor was lower by 1.3 times in men and by 5 times in women. The ratio of IGF and IGFBP-1-3 in patients of the control group in perifocal tissues changed towards the parameters in the tumor tissue. IGF/IGFBP-1-3 in men of the main group were lower or did not differ from the indices in the intact tissue, while in women they increased, similarly to the tumor tissue.
Conclusion. An increase in the ratio of IGF and carrier proteins in the tumor tissue of patients in the main group indicated an excessive accumulation of IGF in it, which may contribute to more aggressive growth of malignant tumors. The most pronounced disorders in the system of insulin-like growth factors were found in the tissues of the tumor and intact lung of patients with previous severe and moderate to severe COVID-19.
Keywords:
non-small cell lung cancer, COVID-19, IGF-I, IGF-II, IGFBP
For correspondence:
Valeriya A. Bandovkina - Dr. Sci. (Biol.), senior researcher of the laboratory for the study of pathogenesis of malignant tumors, National Medical
Research Centre for Oncology, Rostov-on-Don, Russian Federation.
Address: 63 14 line str., Rostov-on-Don 344037, Russian Federation
E-mail: valerryana@yandex.ru
ORCID: http://orcid.org/0000-0002-2302-8271
SPIN: 8806-2641, AuthorID: 696989
The work followed the ethical principles set forth by the Helsinki Declaration of the World Medical Association (World Medical Association Declaration of Helsinki, 1964, ed. 2013). The study was approved by the Ethics Committee of the National Medical Research Centre for Oncology (Protocol No. 6 of 02/17/2022). Informed consent was obtained from all participants of the study.
Funding: this work was not funded.
Conflict of interest: authors report no conflict of interest.
For citation:
Kit O. I., Frantsiyants E. M., Kharagezov D. A., Bandovkina V. A., Cheryarina N. D., Pogorelova Yu. A., Lazutin Yu. N., Milakin A. G., Leyman I. A., Stateshny O. N. Indices of insulin-like growth factors family in the lung tissue of patients with non-small cell lung cancer after COVID-19 of various severity. South Russian Journal of Cancer. 2023; 4(1): 23-33. https://doi.org/10.37748/2686-9039-2023-4-1-3, https://elibrary.ru/gwlsqd
The article was submitted 19.08.2022; approved after reviewing 09.01.2023; accepted for publication 06.03.2023.
© Kit O. I., Frantsiyants E. M., Kharagezov D. A., Bandovkina V. A., Cheryarina N. D., Pogorelova Yu. A., Lazutin Yu. N., Milakin A. G., Leyman I. A., Stateshny O. N., 2023
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33
https://doi.org/10.37748/2686-9039-2023-4-1-3
https://elibrary.ru/gwlsqd
3.1.6. Онкология, лучевая терапия
ОРИГИНАЛЬНАЯ СТАТЬЯ
ПОКАЗАТЕЛИ СЕМЕЙСТВА ИНСУЛИНОПОДОБНЫХ ФАКТОРОВ РОСТА В ТКАНИ ЛЕГКОГО БОЛЬНЫХ НЕМЕЛКОКЛЕТОЧНЫМ РАКОМ ЛЕГКОГО, ПЕРЕНЕСШИХ ОДШ-19 РАЗЛИЧНОЙ СТЕПЕНИ ТЯЖЕСТИ
О. И. Кит, Е. М. Франциянц, Д. А. Харагезов, В. А. Бандовкина^, Н. Д. Черярина, Ю. А. Погорелова, Ю. Н. Лазутин, А. Г. Милакин, И. А. Лейман, О. Н. Статешный
НМИЦ онкологии, г. Ростов-на-Дону, Российская Федерация И valerryana@yandex.ru
РЕЗЮМЕ
Цель исследования. Изучить содержание IGF и их белков-переносчиков в тканях легкого больных немелкоклеточным раком легкого (НМРЛ) в зависимости от тяжести перенесенного COVID-19.
Пациенты и методы. В исследование включены 60 больных с гистологически подтвержденным НМРЛ стадии T1-3NxM0, проходивших лечение в торакальном отделении ФГБУ «НМИЦ онкологии» Минздрава России с 2020 по 2021 гг. В контрольную группу вошли 30 больных раком легкого с бессимптомными или легкими случаями COVID-19 (15 мужчин и 15 женщин), в основную группу - 30 больных (15 мужчин и 15 женщин), перенесших болезнь в тяжелой или среднетяжелой форме. Средний возраст больных составил 59,11 ± 2,89 года, значимых отличий между контрольной и основной группами не отмечали. Перед началом исследования от участников было получено письменное информированное согласие, одобренное советом по этике ФГБУ «НМИЦ онкологии» Минздрава России. Количественную оценку содержания в ткани опухоли, перифокальной зоне и линии резекции IGF-I, IGF-II и IGFBP-1,2,3 выполняли методом иммуноферментного анализа (ИФА методом (Mediagnost, Германия)). Статистический анализ проводили с использованием программы Statistica 10, значение p < 0,05 рассматривалось как показатель статистической значимости. Результаты. У больных основной группы, по сравнению с контрольной группой, вне зависимости от пола, в образцах опухоли и линии резекции уровень IGF-I и IGF-II был выше в среднем в 1,5-2,2 раза, а IGFBP-1 в опухоли был ниже в 1,3 раза у мужчин и в 5 раз у женщин. Соотношение IGF и IGFBP-1-3 у больных контрольной группы в ткани перифокальной зоны изменялись в сторону показателей ткани опухоли. В основной группе у мужчин IGF/IGFBP-1-3 оказались ниже или не отличались от условно интактной ткани, а у женщин повышались, как и в ткани опухоли. Заключение. Повышение соотношения IGF и белков-переносчиков в ткани опухоли больных основной группы свидетельствовало об избыточном накоплении в ней IGF, что может способствовать более агрессивному росту злокачественной опухоли. Наиболее выраженные нарушения в системе инсулиноподобных факторов роста мы обнаружили в ткани опухоли и интактного легкого больных, перенесших COVID-19 в тяжелой и среднетяжелой форме.
Ключевые слова:
немелкоклеточный рак легкого, COVID-19, IGF-I, IGF-II, IGFBP
Для корреспонденции:
Бандовкина Валерия Ахтямовна - д.б.н., старший научный сотрудник лаборатории изучения патогенеза злокачественных опухолей,
ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.
Адрес: 344037, Российская Федерация, г. Ростов-на-Дону, ул. 14-я линия, д. 63
E-mail: valerryana@yandex.ru
ORCID: http://orcid.org/0000-0002-2302-8271
SPIN: 8806-2641, AuthorID: 696989
В работе соблюдались этические принципы, предъявляемые Хельсинкской декларацией Всемирной медицинской ассоциации (World Médical Association Déclaration of Helsinki, 1964, ред. 2013). Исследование одобрено этическим комитетом ФГБУ «НМИЦ онкологии» Минздрава России (протокол № 6 от 17.02.2022 г.). Информированное согласие получено от всех участников исследования.
Финансирование: финансирование данной работы не проводилось. Конфликт интересов: авторы заявляют об отсутствии конфликта интересов.
Для цитирования:
Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А., Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г., Лейман И. А., Статешный О. Н. Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших COVID-19 различной степени тяжести. Южно-Российский онкологический журнал. 2023; 4(1):23-33. https://doi.org/10.37748/2686-9039-2023-4-1-3, https://elibrary.ru/gwlsqd
Статья поступила в редакцию 19.08.2022; одобрена после рецензирования 09.01.2023; принята к публикации 06.03.2023.
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33 Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А.н, Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г., Лейман И. А., Статешный О. Н. / Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших
COVID-19 различной степени тяжести
INTRODUCTION
At the end of 2019, a new coronavirus infection (COVID-19) spread rapidly around the world, causing more than 105 million cases of the disease and more than 2.3 million deaths [1]. The destruction of lung cells caused by COVID-19 infection triggers a local immune response, recruiting macrophages and monocytes, releasing chemokines and pro-inflammatory cytokines, thereby triggering adaptive immune responses of T- and B-lymphocytes [2]. In most patients with COVID-19, the recruited cells clear the lungs of infection, then the immune response decreases, and patients carry the disease asymptomatically or in a mild form that does not require hospitalization. On the other side, some patients have a severe course of the disease and even die. At the same time, the deterioration of the condition is often associated with unbridled inflammatory damage caused by a cytokine storm, an uncontrolled immune response leading to acute respiratory distress syndrome (ARDS) [3; 4]. In addition, there is evidence that patients who have undergone COVID-19 with a severe course have a significant transcriptional shift, including the genes of the G protein-linked receptor family, DNAJB1, IGF, EGFR and HDGF, which can lead to tissue remodeling, mitochondrial dysfunction, and serious systemic disorders [1; 2].
Among all types of cancer during the pandemic, lung cancer patients are of particular interest, since the lungs are the organs most involved in the initial focus of infection, with a high risk of pneumonia and, in severe cases of ARDS, often with irreversible scarring of lung tissue and respiratory problems that persist largely after recovery [2; 4]. In fact, lung cancer is one of the most common types of cancer among COVID-19 patients, due to a local violation of immunity [5; 6].
It is known that the neuroendocrine system plays an important role in the regulation of immune responses [7]. Steroid and peptide hormones, growth factors, including insulin-like factors are synthesized and secreted by various immune cells, and are able to modulate the humoral and cellular immune response by stimulating and proliferating immunocompetent cells [8].
Determination of the important role of the components of the insulin-like growth factor (IGF) family in the carcinogenesis of a number of tumors, including lung cancer, is based on numerous epidemiological
and preclinical studies, in vivo and in vitro experiments and attempts to use drugs that affect the IGF axis [9; 10]. It is known that in lung cancer, the copyicity of genes responsible for the regulation of apoptosis, proliferation, DNA repair, as well as the expression of a number of growth factors changes [11].
Previous studies have confirmed IGF activity in lung tissue. In other words, IGF signaling plays an essential role in lung pathology. Dysregulation of the IGF axis has been demonstrated at all stages of lung carcinogenesis, ranging from dysplastic lesions of the bronchial epithelium to advanced forms of cancer. In addition, IGF-I has been shown to be involved in various diseases, including metabolic disorders, congenital disorders, inflammation, fibrosis, cancer, acute lung injury and ARDS. Additional studies have shown that high IGF-I and IGF-II expression, as well as IGFBP-3 aberrations, are associated with poor prognosis, metastases and progression of malignant diseases [11; 12]. IGF-I is a biomarker in patients with hyperoxia-induced lung damage. IGF-I levels are elevated in lung biopsy samples in ARDS compared to those in healthy people [11]. Serum levels of IGF-I and growth factor-3 binding protein (IGFBP-3) were found to be elevated in patients with early respiratory distress syndrome when epithelial cells are damaged and die. However, their level was low in the late stages of ARDS [13]. In a prospective case-control study, it was shown that the initial plasma levels of IGF-I and IGFBP-3 were significantly lower in cases of ARDS than in the control [14]. Among ARDS cases, IGF-I and IGFBP-3 levels were lower in patients who did not survive than in survivors, and both groups were negatively associated with the risk of 60-day mortality [14].
Although the role of IGF-I in COVID-19 has not been fully determined, it is known that it modulates influenza A-mediated lung damage in rats [15]. Elevated concentrations of inflammatory cytokines, such as IL-6, TNF-a, are considered as one of the main causes of ARDS in patients infected with COVID-19. Therefore, effective suppression of the cytokine storm is important to prevent deterioration and reduce mortality from COVID-19 [3]. It is assumed that patients with lung cancer are at a higher risk of this severe form of COVID-19 [5; 6]. Recent studies have shown that the mortality rate of lung cancer patients is higher than that of the general population when infected with COVID-19 [16].
The accuracy of treatment prescriptions in patients with non-small cell lung cancer depends on the exact histological classification of the tumor, analysis of specific markers and genetic mutations, which allows choosing the most effective individual method of therapy, excluding the use of empirical treatment and the associated risk of side effects [11; 12].
Given the role of the IGF system in lung development and its involvement in immune responses, the assessment of IGF levels and their binding proteins may further shed light on the mechanisms underlying the pathogenesis of lung cancer against the background of COVID-19.
The purpose of the study: to examine the system of insulin-like growth factors and their carrier proteins in the lung tissues of patients with NSCLC, depending on the severity of COVID-19.
PATIENTS AND METHODS
Before the start of the study, oral and written informed consent was received from the participants, approved by the Ethics Council of the National Medical Research Centre for Oncology. The study included men and women (60 people in total) with histologically or cytologically confirmed stage T1-3NxM0 NSCLC, ECOG(PS) < 2 working status, adequate organ function based on standard laboratory tests, including a general blood test, serum biochemistry and coagulogram. The main exclusion criteria were previous treatment of NSCLC, type II diabetes mellitus, as it could affect IGF levels, and other concomitant neoplasms over the past five years, with the exception of non-melanoma skin carcinomas. The stage was determined according to the TNM classification. The step-by-step examination included computed tomography (CT) of the chest, abdominal cavity and brain. Bone scans were performed based on symptoms. All patients were examined before the start of treatment.
The control group included 30 patients with lung cancer with asymptomatic or mild cases of COVID-19 (15 men and 15 women), the main group included 30 patients (15 men and 15 women) who had the disease in severe or moderate form. The average age of the patients was 59.11 ± 2.89 years, no significant differences between the control and main groups were noted.
According to the recommendations, a PCR smear
from the nasopharynx for COVID-19 was obtained in all patients. The selection criteria included patients of both sexes, over the age of 18, and the absence of drug or alcohol dependence. In addition, patients with a known prior inflammatory condition were excluded. There were no significant differences between the groups by gender.
Quantitative assessment of IGF-I, IGF-II and IG-FBP-1,2,3 content was performed by the ELISA method (Mediagnost Germany).
Statistical analysis was carried out using the Sta-tistica 10 program. Normality was assessed using Kolmogorov-Smirnov methods, differences between groups were determined using the Student's t-test or the Mann-Whitney U-test, depending on the normality of the distribution. The value of p < 0.05 was considered as an indicator of statistical significance.
RESEARCH RESULTS
Initially, it was of interest to study the lung tissue not affected by the malignant process - conditionally intact tissue (resection line). The results are presented in table 1. In the control group, there were differences in the content of some IGF system factors in intact lung tissue between men and women. Thus, men had 2.6 times higher IGF-I level, 2 times higher IGFBP-1 level, and women had 1.4 times higher IGF-II level. There was no difference in the content of IGFBP-2 and IGFBP-3.
In the intact lung tissue of patients of the main group, a statistically significant increase was found relative to the indicators in the control group of IGF-I and IGF-II levels: in men - 1.6 times and 1.8 times, respectively, in women - 2.2 times and 1.8 times, respectively. At the same time, the higher content of IGF-I in men and IGF-II in women remained. Of the studied carrier proteins, the difference between the control and the main groups was found only for IGFBP-2: an increase of 1.3 times in men and 1.9 times in women.
Next, the tumor tissue was studied. It was found that in the tumor tissue of the control group of men and women, the level of IGF-I was 1.5 times and 1.9 times higher than in the corresponding conditionally intact tissue, respectively, and IGF-II - 1.5 times and 2.1 times, respectively. The level of carrier proteins was reduced: IGFBP-1 by 1.75 times in men, IGFBP-2 by 1.4 times in men and 2.2 times in women, and IGFBP-3 by 1.6 times in men and 6.4 times in women.
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33 Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А.н, Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г, Лейман И. А., Статешный О. Н. / Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших
COVID-19 различной степени тяжести
In the tumor tissue of the main group, an increase in the level of IGF-I in men and women relative to the corresponding intact tissue was also found by 1.6 times and 1.3 times, respectively, IGF-II - by 1.6 times and 2 times, respectively. The level of IGFBP-1 in men was 2 times lower relative to the corresponding intact tissue, in women - 6 times. The level of IGFBP-2 was 3.3 times lower only in women, and IGFBP-3 was 1.7 times lower in both men and 4.4 times lower in women. At the same time, the higher content of IGF-I in men and IGF-II in women also remained.
It turned out that in the tumor samples in men of the main group, the level of IGF-I and IGF-II was 1.7 times and 2 times higher than in the control group, respectively, against the background of 2.1 times increased IGFBP-2 and the absence of significant changes in the levels of other binding proteins, whereas in women of the main group in the samples Compared with the control tumor, the level of IGF-I and IGF-II was increased by 1.5 times and 1.7 times, respectively, but IGFBP-1 was reduced by 5 times.
The perifocal zone of the tumor is a kind of buffer area between the tumor and conditionally unaffected lung tissue. It seems that the individual absolute values of the family of insulin-like growth factors and their carrier proteins in the tissues of the perifocal zone in patients of both sexes of the control and main groups are more close to the values in the tumor tissue than in the resection line. Thus, in patients of both sexes of the control group, the level of IGF-I and IGF-II in the perifocal zone was 1.3-1.7 times higher on average, compared with conditionally intact tissue; compared with the indicators in the tumor, there were no significant differences in men, and in women IGF-II was 1.4 times lower. The content of carrier proteins in the perifocal zone in men of the control group was 1.6 times lower on average than in the resection line, in women IGFBP-2 and IGFBP-3 were 1.4 times and 6.9 times lower, respectively, but all indicators of carrier proteins did not significantly differ from the tumor and only IGFBP-2 in women were 1.5 times higher. In patients of the main group, the situation was different: in men in the n/a zone, the level of IGF-II and IGFBP-1 was higher than in the resection line, but lower IGF-II and higher IGFBP-1 than in the tumor, while the indicators of IGF-I and other carrier proteins in men of the main group did not differ from the resection line. In the women of the main group, the content of IGF-II in the n/a was
lower than in the resection line and the tumor, all the carrier proteins were in greater numbers in the resection line, and IGF-I had no significant differences from the indicators in the conditionally intact tissue and in the tumor.
Of particular interest was the ratio of IGF to carrier proteins, on the one hand demonstrating the bioavailability of the studied growth factors, and on the other hand indicating the possible prevailing biological effects of IGFBP (Table 2).
When studying the ratio of insulin-like growth factors and carrier proteins in the intact tissue of all lung cancer patients, sexual differences were found. Thus, the indicators of IGF-I/IGFBP-2 and IGF-I/IGFBP-3 in women were 2.3 times and 4 times lower than in men in the control group, respectively, and in the main group, on average 2.3 times, IGF-II/IGFBP-1 and IGF-II/IGFBP-2, on the contrary, is higher: in the control group 2.7 times and 1.6 times, respectively, in the main group IGF-II/IGFBP-1 is 1.8 times higher; whereas IGF-I/IGFBP-1 and IGF-II/IGFBP-3 had no significant differences in the control group and IGF-I/ IGFBP-1, IGF-II/IGFBP-2 and IGF-II/IGFBP-3 - in the main group.
At the same time, most of the calculated coefficients in intact tissue, with the exception of IGF-I/ IGFBP-2 and IGF-II/IGFBP-2, were higher in patients of the main group, compared with the control group. Thus, in the intact tissue of men of the main group, the level of IGF-I/IGFBP-1, IGF-I/IGFBP-3, IGF-II/IG-FBP-1 and IGF-II/IGFBP-3 was on average 1.9 times higher than in the corresponding control group. In intact tissue of women, the level of IGF-I/IGFBP-1, IGF-I/IGFBP-3, IGF-II/IGFBP-1 and IGF-II/IGFBP-3 was 1.7-3.3 times higher than in the corresponding control group.
It is obvious that there was also a dissonance between the level of IGF and carrier proteins in the tumor tissue, since the content of growth factors increased in tumor samples, and proteins, with rare exceptions (IGFBP-2 in men of the main group and IGFBP-1 in women of the control group), on the contrary, decreased. Moreover, this concerned the tumor tissue of patients of both groups. In the tumor tissue of male and female patients of the control group, all the studied coefficients significantly exceeded similar values in the corresponding intact tissues. In men, the level of IGF-I/IGFBP-1, IGF-I/IGFBP-2, IGF-I/IGFBP-3, IGF-II/IGFBP-1, IGF-II/IGFBP-2 and IGF-II/IGFBP-3 was
Table 1. Levels of insulin-like growth factors and their carrier proteins in lung tissues of cancer patients, depending on the
severity of COVID-1 9
Groups Sex IGF-I ng/g t IGF-II ng/g t IGFBP-1 ng/g t IGFBP-2 ng/g t IGFBP-3 ng/g t
Resection line tissue
Control Males 9.6 ± 0.75 p1 = 0.0000 6.7 ± 0.57 p1 = 0.0000 0.35 ± 0.04 p1 = 0.0000 22.8 ± 1.28 226.9 ± 14.8
Females 3.7 ± 0.31 9.4 ± 0.83 0.18 ± 0.02 20.3 ± 1.78 296.7 ± 21.3
Main Males 14.9 ± 1.18 p1 = 0.0000 p2 = 0.0000 11.8 ± 1.1 p1 = 0.0000 p2 = 0.0000 0.3 ± 0.02 p1 = 0.0000 30.4 ± 2.3 p1 = 0.0000 p2 = 0.0000 204.4 ± 15.8 p1 = 0.0000
Females 8.3 ± 0.64 p2 = 0.0000 16.7 ± 1.3 p2 = 0.0000 0.24 ± 0.02 39.3 ± 2.5 p2 = 0.0000 255.8 ± 19.4
Tumor tissue
14.1 ± 1.8 9.8 ± 1.9 0.2 ± 0.03 p3 = 0.0000 16.1 ± 1.5 142.2 ± 30.7
Males p1 = 0.0000 p3 = 0.0000 p1 = 0.0000 p3 = 0.0000 p1 = 0.0000 p3 = 0.0000 p1 = 0.0000 p3 = 0.0000
Females 7.1 ± 1.3 p3 = 0.0000 19.7 ± 1.4 p3 = 0.0000 p4 = 0.0000 0.2 ± 0.03 9.3 ± 2.6 p3 = 0.0000 p4 = 0.0000 46.2 ± 2.5 p3 = 0.0000
Main Males 24.4 ± 3.4 p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000 19.3 ± 2.4 p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 0.15 ± 0.01 p1 = 0.0000 p3 = 0.0000 p4 = 0.0000 33.1 ± 2.6 p1 = 0.0000 p2 = 0.0000 123.4 ± 9.2 p1 = 0.0000 p3 = 0.0000 p4 = 0.0000
33.3 ± 2.5 0.04 ± 0.01 58.7 ± 5.0 p3 = 0.0000 p4 = 0.0000
Females 10.7 ± 1.6 p3 = 0.0000 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000 11.8 ± 1.5 p3 = 0.0000
Perifocal zone tissue
Control Males 12.0 ± 0.94 p1 = 0.0000 p3 = 0.0000 8.6 ± 0.65 p1 = 0.0000 p3 = 0.0000 0.2 ± 0.03 p3 = 0.0000 16.6 ± 1.2 p3 = 0.0000 135.3 ± 10.0 p1 = 0.0000 p3 = 0.0000
Females 6.3 ± 0.65 p3 = 0.0000 14.6 ± 1.1 p3 = 0.0000 0.17 ± 0.02 14.2 ± 1.2 p3 = 0.0000 43.3 ± 3.5 p3 = 0.0000
Main Males 12.3 ± 1.0 16.8 ± 1.3 p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 0.41 ± 0.03 p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 34.5 ± 2.7 p1 = 0.0000 p2 = 0.0000 261.3 ± 21.0 p1 = 0.0000 p2 = 0.0000
Females 10.3 ± 0.88 p2 = 0.0000 11.5 ± 1.0 p2 = 0.0000 p3 = 0.0000 0.08 ± 0.009 p2 = 0.0000 p3 = 0.0000 14.2 ± 1.2 p3 = 0.0000 77.9 ± 5.9 p2 = 0.0000 p3 = 0.0000
Note: statistically significant in relation to: 1 - to the indicator for women in the corresponding group; 2 - to the corresponding indicator in the control group; 3 - ro the corresponding indicator in tumor tissue; 4 - to the corresponding indicator in the perifocal zone tissue; "g t" stands "gram of tissue".
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33 Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А.н, Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г, Лейман И. А., Статешный О. Н. / Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших
COVID-19 различной степени тяжести
Table 2. Ratios of insulin-like growth factors to carrier proteins in lung tissues in cancer patients, depending on the severity of COVID-19
Groups
Sex
IGF-I/ IGFBP-1
IGF-I/ IGFBP-2
IGF-I/ IGFBP-3
IGF-II/ IGFBP-1
IGF-II/ IGFBP-2
IGF-II/ IGFBP-3
Resection line tissue
Males
Control
28.0 t 5.4
0.42 t 0.02 0.04 t 0.00б 19.б t 4.0
0.29 t 0.02
p1 = 0.0000 p1 = 0.0000 p1 = 0.0000 p1 = 0.0000
0.03 t 0.004
Females
20.7 t 1.4
0.18 t 0.009
0.01 t 0.0007
52.5 t 3.7
0.4б t 0.04 0.03 t 0.001
Males
Main
49.9 t 5.7
0.49 t 0.07
0.07 t 0.01
39.7 t б.1
0.0б t 0.009
,,2-nnnnn n^^nn p1 = 0.0000 p1 = 0.0000 0.39 t 0.05 , _ n nnnn p2 = 0.0000 p1 = °.°000 p2 = 0.0000 p2 = 0.0000 p2 = 0 0000
. 35.0 t 5.5 0.03 t 0.001 б9.7 t 3.4 „ x n 0.07 t 0.01
Females p2 = 0.0000 0 21 t 0 03 p2 = o.oooo p2 = o.oooo 043 t 0 03 p2 = o.oooo
Tumor tissue
Main
Control
70.б t 11.4 p1 = 0.0000 p3 = 0.0000
0.88 t 0.1б p3 = 0.0000
0.11 t 0.04 p1 = 0.0003
49.4 t 8.5 p1 = 0.0000
0.б1 t 0.1 p1 = 0.0000
0.07 t 0.02 p1 = 0.0000
p3 = 0.0000 p3 = 0.0000 p3 = 0.0000 p3 = 0.0000
Females
3б.4 t 9.4 p3 = 0.0000
0.82 t 0.28
0.15 t 0.03
p3 = 0.0000 p3 = 0.0000 p4 = 0.0000
100.0 t 13.9 p3 = 0.0000
2.3 t 0.7
0.43 t 0.04
p3 = 0.0000 p3 = 0.0000 p4 = 0.0000 p4 = 0.0000
Main
1б5.8 t 38.0
p1 = 0.000б 0.74 t 0.07
Males p2 = 0.0000 p3 = 0.0000
p3 = 0.0000 p4 = 0.0000 p4 = 0.0000
0.2 t 0.03 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000
128.7 t 9.б p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000
0.58 t 0.1 p1 = 0.0000 p3 = 0.0000 p4 = 0.00б2
0.1б t 0.02 p1 = 0.0000 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000
Females
2б7.5 t 34.8 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000
0.91 t 0.11 p3 = 0.0000
0.18 t 0.04 p3 = 0.0000 p4 = 0.0000
832.5 t 94.1 p2 = 0.0000 p3 = 0.0000 p4 = 0.0000
2.9 t 0.б
0.57 t 0.02
p3 = 0.0000 p3 = 0.0000 p4 = 0.0000 p4 = 0.0000
Perifocal zone tissue
Males
Control
б1.4 t 11.9 p1 = 0.0000
0.73 t 0.11 p1 = 0.0000
p3 = 0.0000 p3 = 0.0000
0.09 t 0.004 p1 = 0.0000 p3 = 0.0000
43.9 t 7.9 p1 = 0.0000
0.52 t 0.07 p1 = 0.0000
0.0б t 0.004 p1 = 0.0000
p3 = 0.0000 p3 = 0.0000 p3 = 0.0000
Females
37.8 t 7.1 p3 = 0.0000
0.45 t 0.08 p3 = 0.0000
0.15 t 0.02 p3 = 0.0000
87.1 t 13.2 p3 = 0.0000
1.03 t 0.08 p3 = 0.0000
0.34 t 0.05 p3 = 0.0000
Males
Main
30.б t 4.4 0.3б t 0.01 0.05 t 0.003
p1 = 0.0000 p1 = 0.0000 p1 = 0.0000 41.4 t 1.8
p2 = 0.0000 p2 = 0.0000 p2 = 0.0000 p1 = 0.0000
p3 = 0.0000 p3 = 0.0000 p3 = 0.0000
0.49 t 0.08 0.07 t 0.01
0.0000
0.0000
130.5 t 19.3 0.73 t 0.12 Females p2 = 0.0000 p2 = 0.0000 p3 = 0.0000 p3 = 0.0000
0.13 t 0.009 p3 = 0.0000
145.4 t 19.7 0.82 t 0.13 0.15 t 0.01 p2 = 0.0000 p2 = 0.0000 p2 = 0.0000 p3 = 0.0000 p3 = 0.0000 p3 = 0.0000
Note: statistically significant in relation to: 1 - to the indicator for women in the corresponding group; 2 - to the corresponding indicator in the control group; 3 - to the corresponding indicator in tumor tissue; 4 - to the corresponding indicator in the perifocal zone tissue;
"g t" stands "gram of tissue".
higher by more than 2 times, in women - 1.8 times, 4.6 times, 15 times, 1.9 times, 5 times and 14.3 times, respectively. At the same time, in the tumor tissue of women in the control group, almost all indicators exceeded similar values in the tissue of men.
The same pattern was observed in the tumor tissue of men and women of the main group. In men, the level of IGF-I/IGFBP-1, IGF-I/IGFBP-2, IGF-I/IGFBP-3, IGF-II/IGFBP-1, IGF-II/IGFBP-2 and IGF-II/IGFBP-3 was 1.5-3.3 times higher on average; in women, the values and the spread were wider: 7.6 times, 4.3 times, 6 times, 12 times, 6.7 times and 8.1 times, respectively. At the same time, in the tumor tissue of the women of the main group, almost all indicators (with the exception of IGF-I/IGFBP-3) exceeded similar values in the tissue of men.
In the tissue of the perifocal zone, the balance between growth factors and their carrier proteins also changed. In men and women of the control group, all the coefficients of the ratio of growth factors to carrier proteins were higher than in the resection line by an average of 1.7-2.5 times, only IGF-I/IGFBP-3 and IGF-II/IGFBP-3 in women by 15 times and 11.3 times, respectively, but in men all coefficients had no significant differences from those in the tumor, whereas in women with the exception of IGF-I/IG-FBP-2 and IGF-II/IGFBP-2.
In men of the main group in the perifocal zone, only the ratio coefficients of the first insulin-like growth factor to carrier proteins were lower than in the resection line: IGF-I/IGFBP-1, IGF-I/IGFBP-2, IGF-I/IGFBP-3 on average 1.5 times, the ratio of IGF-II to proteins the carriers had no significant differences from the indicators in the resection line. Compared with the tumor in the men of the main group in the perifocal zone, all the ratio coefficients, with the exception of IGF-II/IGFBP-2, were lower: IGF-I/IGFBP-1 by 5.4 times, IGF-I/IGFBP-2 by 2.1 times, IGF-I/IGFBP-3 by 4 times, IGF-II/IGFBP-1 by 3.1 times and IGF-II/IGFBP-3 by 2.3 times. In the women of the main group, all ratio coefficients in the perifocal zone were higher than in the resection line by 1.9-4.3 times, but lower than in the tumor by 1.3-5.8 times.
It turned out that in men in the main group, only the ratio coefficients of the first insulin-like growth factor to carrier proteins were lower than in the control group by an average of 2 times, while the ratio of IGF-II to carrier proteins had no significant differences. In the perifocal zone in women of the main
group, compared with the perifocal zone of the control group, IGF-I/IGFBP-1 was 3.5 times higher, IGF-I/ IGFBP-2 was 1.6 times higher, and IGF-II/IGFBP-1 was 1.7 times higher, but lower than IGF-II/IGFBP-2 1.3 times and IGF-II/IGFBP-3 2.3 times, only IGF-I/ IGFBP-3 had no significant differences.
That is, when considering the ratio of IGF and their carrier proteins in patients of the control group, the indicators in the tissue of the perifocal zone were closer to the values in the tumor tissue. Another trend was noted in the tissue of the perifocal zone of patients of the main group. Thus, the ratio of IFG and carrier proteins in men was closer to the values in the conditionally intact tissue, and in women - to the values in the tumor tissue.
DISCUSSION
Currently, there is no doubt that IGF-axis signaling is crucial for cellular survival, proliferation, antioxidant function and control of cell damage and death in various organs and tissues, including the lungs [17; 18]. The family of insulin-like growth factors includes IGF-I, IGF-II, their receptors - IGF-IR and IGF-IIR, and proteins binding insulin-like growth factors - IGFBP-1 -6 [19]. Studies have proven the role of IGF signaling in lung development, as well as in inflammatory diseases, cancer and fibrosis [20; 21]. IGF-I and IGF-II are involved in various physiological and pathophysiological processes, including fetal growth and development, metabolic disorders, congenital disorders, inflammation, fibrosis, cancer, acute lung injury [9]. IGF-II has also been found to be over-expressed in some types of cancer, which contributes to tumor growth and survival. At the tissue level, IGF-I and IGF-II are mainly overexpressed in various types of cancer and can serve as a mitogenic stimulus in a paracrine or autocrine manner, and a violation of the regulation of the IGF axis has been demonstrated at all stages of lung carcinogenesis [22].
In his research, Shin J. with co-authors (2022) deployed that COVID-19 infection disrupts the signaling pathway of insulin-like growth factor in respiratory, metabolic and endocrine cells and tissues [23], resulting in violations of innate immune functions, such as neutrophil chemotaxis, phagocytic cell function and recruitment of inflammatory macrophages in tissues [24].
It turned out that even conditionally intact lung tissue taken on the resection line had differences in the
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33 Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А.н, Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г., Лейман И. А., Статешный О. Н. / Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших
COVID-19 различной степени тяжести
studied parameters of the IGF axis in patients of the control and main groups, and it was in patients who underwent COVID-19 in severe form in the studied tissue that the level of IGF-I and IGF-II was elevated, and the carrier proteins either decreased, or did not change their concentration, with the exception of IGFBP-2. This fact may indicate that in patients with lung cancer, the tumor microenvironment changes under the influence of a severely suffered COVID-19 disease. In particular, it is known that persistent unregulated inflammation at the site of injury disrupts the regeneration process and ultimately leads to the formation of tissue fibrosis and scarring [25]. And human observational studies conducted by Shin and co-authors (2022) showed that higher basal expression of insulin-like growth factor receptors may be associated with an increase in the age of lung tissue in men, as well as with comorbid diseases such as obesity and type 2 diabetes mellitus, which are well-established risk factors for severity and COVID-19 mortality [23]. It is noteworthy that higher expression of IGF receptors and lower expression of IGF/insulin signaling pathway mediators are largely associated with unfavorable critical outcomes in patients with COVID-19 and worse molecular signs of the disease, such as elevated levels of IL-1 and IL-6, cell damage and death [23].
There are six known types of IGFBP, of which IG-FBP-3 is the most studied. One of the well-studied roles of IGFBP involves the delivery of IGF to target cells as its endocrine function. In addition, IGFBP-3 secretion has been reported in various tissues, which indicates its paracrine or autocrine function, in addition to endocrine. The role of IGFBP, depending on the insulin-like growth factor, includes facilitated delivery of IGF to its receptors on the cell surface and activation of the downstream signaling cascade associated with it [26].
It is noteworthy that the tumor tissue in patients with lung cancer of the main group, regardless of gender, contained significantly higher concentrations of IGF-I and IGF-II, but lower levels of IGFBP-1 binding
proteins, compared with those in men and women of the control group. This may be due to the greater aggressiveness of the tumor process in patients who have undergone COVID19 in severe form, with lung tissue damage. In addition, there is evidence that lung cancer tissue is characterized by increased local production of IGF-I, IGF-II and IGF-I receptor (IGF-IR), but reduced IGFBP expression. Modulated expression of these molecules is associated with aggressive disease, local lymph node metastases, and poor clinical outcomes [27]. Several IGF-IR inhibitors are under clinical development for the treatment of solid tumors, including lung cancer [22].
CONCLUSIONS
These literature data are consistent with the results obtained by us on an increase in the production of IGF-I, IGF-II in the tumor tissue of men and women of the control group and a decrease in the expression of IGF-binding protein-3. In addition to this, we showed a change in the level of two more carrier proteins, which is of a gender nature: in the tumor tissue of men, the expression of IGFBP-1 and IGFBP-2 was also increased, and in the tumor tissue of women - IGFBP-2. Violations in the system of insulin-like factors were especially clearly reflected in the study of the ratio of IGF and carrier proteins. The increase in the ratio of IGF and carrier proteins in the tumor tissue shown by us in this study may indicate an excessive accumulation of IGF in it, which contributes to the growth and survival of neoplasm. The most pronounced disorders in the system of insulin-like growth factors were found in the tumor tissue and intact lung of patients who underwent COVID-19 in severe and moderate form. Considering that IGF-I is involved in inflammation, fibrosis, cancer, acute lung injury and ARDS, and is also a biomarker in patients with hyperoxia-induced lung damage, the results obtained can be considered as a reaction of patients' lung tissue to the infection and its intensive therapy.
References
1. Hammoudeh A, Hammoudeh M, Bhamidimarri PM, Mahboub B, Halwani R, Hamid Q, et al. Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology. World J Gastroenterol. 2021;27(21):2850-2870. https://doi.org/10.3748/wjg.v27.i21.2850
2. Lemos AEG, Silva GR, Gimba ERP, Matos ADR. Susceptibility of lung cancer patients to COVID-19: A review of the pandemic data from multiple nationalities. Thorac Cancer. 2021 Oct;12(20):2637-2647. https://doi.org/10.1111/1759-7714.14067
South Russian Journal of Cancer 2023. Vol. 4, No. 1. P. 23-33
Kit O. I., Frantsiyants E. M., Kharagezov D. A., Bandovkina V. A.H, Cheryarina N. D., Pogorelova Yu. A., Lazutin Yu. N., Milakin A. G., Leyman I. A., Stateshny O. N. / Indices of insulin-like growth factors family in the lung tissue of patients with non-small cell lung cancer after COVID-19 of various severity
3. Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol. 2020 Jun 16;11:1446. https://doi.org/10.3389/fimmu.2020.01446
4. Ruggiero V, Aquino RP, Del Gaudio P, Campiglia P, Russo P. Post-COVID Syndrome: The Research Progress in the Treatment of Pulmonary sequelae after COVID-19 Infection. Pharmaceutics. 2022 May 26;14(6):1135. https://doi.org/10.3390/pharma-ceutics14061135
5. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020 Mar;21(3):335-337. https://doi.org/10.1016/s1470-2045(20)30096-6
6. Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. JAMA Oncol. 2020 Jul 1;6(7):1108-1110. https://doi.org/10.1001/jamaoncol.2020.0980
7. ThyagaRajan S, Priyanka HP. Bidirectional communication between the neuroendocrine system and the immune system: relevance to health and diseases. Ann Neurosci. 2012 Jan;19(1):40-46. https://doi.org/10.5214/ans.0972.7531.180410
8. Hazrati E, Gholami M, Farahani RH, Ghorban K, Ghayomzadeh M, Rouzbahani NH. The effect of IGF-1 plasma concentration on COVID-19 severity. Microb Pathog. 2022 Mar;164:105416. https://doi.org/10.1016/j.micpath.2022.105416
9. Chen YM, Qi S, Perrino S, Hashimoto M, Brodt P. Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug. Cells. 2020 Apr 29;9(5):1098. https://doi.org/10.3390/cells9051098
10. Blyth AJ, Kirk NS, Forbes BE. Understanding IGF-II Action through insights into receptor binding and activation. Cells. 2020;9(10):2276. https://doi.org/10.3390/cells9102276
11. Krein PM, Sabatini PJB, Tinmouth W, Green FHY, Winston BW. Localization of insulin-like growth factor-I in lung tissues of patients with fibroproliferative acute respiratory distress syndrome. Am J Respir Crit Care Med. 2003;167(1):83-90. https://doi.org/10.1164/rccm.2201012
12. Kasprzak A, Kwasniewski W, Adamek A, Gozdzicka-Jozefiak A. Insulin-like growth factor (IGF) axis in cancerogenesis. Mutat Res Rev Mutat Res. 2017 Apr-Jun;772:78-104. https://doi.org/10.1016/j.mrrev.2016.08.007
13. Soliman AR, Sadek KM. Relation between insulin growth factor 1 and survival after SARS-CoV-2(COVID 19) infection in elderly kidney transplant recipients. Ren Fail. 2021 Dec;43(1):388-390. https://doi.org/10.1080/0886022x.2021.1886115
14. Ahasic AM, Tejera P, Wei Y, Su L, Mantzoros CS, Bajwa EK, et al. Predictors of circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in critical illness. Crit Care Med. 2015;43(12):2651-2659. https://doi.org/10.1097/ccm.0000000000001314
15. Li G, Zhou L, Zhang C, Shi Y, Dong D, Bai M, et al. Insulin-Like Growth Factor 1 Regulates Acute Inflammatory Lung Injury Mediated by Influenza Virus Infection. Front Microbiol. 2019 Nov 26;10:2541. https://doi.org/10.3389/fmicb.2019.02541
16. Luo J, Rizvi H, Preeshagul IR, Egger JV, Hoyos D, Bandlamudi C, et al. COVID-19 in patients with lung cancer. Ann Oncol. 2020 Oct;31(10):1386-1396. https://doi.org/10.10Wj.annonc.2020.06.007
17. Varma Shrivastav S, Bhardwaj A, Pathak KA, Shrivastav A. Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3): Unraveling the Role in Mediating IGF-Independent Effects Within the Cell. Front Cell Dev Biol. 2020 May 5;8:286. https://doi.org/10.3389/fcell.2020.00286
18. Munoz K, Wasnik S, Abdipour A, Bi H, Wilson SM, Tang X, et al. The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury. Int J Mol Sci. 2021 May 15;22(10):5244. https://doi.org/10.3390/ijms22105244
19. Feizollahi P, Matin S, Roghani SA, Mostafaei S, Safarzadeh E, Taghadosi M. Evaluation serum levels of Insulin Growth Fac-tor-1 (IGF-1) and its association with clinical parameters in severe COVID-19. Inflammopharmacology. 2022 Feb;30(1):199-205. https://doi.org/10.1007/s10787-021 -00908-6
20. Mu M, Gao P, Yang Q, He J, Wu F, Han X, et al. Alveolar epithelial cells promote IGF-I production by alveolar macrophages through TGF-p to suppress endogenous inflammatory signals. Front Immunol. 2020 Jul 21;11:1585. https://doi.org/10.3389/fimmu.2020.01585
21. He J, Mu M, Wang H, Ma H, Tang X, Fang Q, et al. Upregulated IGF-I in the lungs of asthmatic mice originates from alveolar macrophages. Mol Med Rep. 2019 Feb;19(2):1266-1271. https://doi.org/10.3892/mmr.2018.9726
22. Kasprzak A, Kwasniewski W, Adamek A, Gozdzicka-Jozefiak A. Insulin-like growth factor (IGF) axis in cancerogenesis. Mutat Res Rev Mutat Res. 2017 Apr-Jun;772:78-104. https://doi.org/10.1016/j.mrrev.2016.08.007
23. Shin J, Toyoda S, Nishitani S, Onodera T, Fukuda S, Kita S, Fukuhara A, Shimomura I. SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the lung, liver, adipose tissue, and pancreatic cells via IRF1. Metabolism. 2022 Aug;133:155236. https://doi.org/10.1016/j.metabol.2022.155236
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 23-33 Кит О. И., Франциянц Е. М., Харагезов Д. А., Бандовкина В. А.н, Черярина Н. Д., Погорелова Ю. А., Лазутин Ю. Н., Милакин А. Г., Лейман И. А., Статешный О. Н. / Показатели семейства инсулиноподобных факторов роста в ткани легкого больных немелкоклеточным раком легкого, перенесших
COVID-19 различной степени тяжести
24. Kelesidis T, Mantzoros CS. Cross-talk between SARS-CoV-2 infection and the insulin/IGF signaling pathway: Implications for metabolic diseases in COVID-19 and for post-acute sequelae of SARS-CoV-2 infection. Metabolism. 2022 Jul 25;134:155267. https://doi.org/10.1016/j.metabol.2022.155267
25. Fang J, Feng C, Chen W, Hou P, Liu Z, Zuo M, et al. Redressing the interactions between stem cells and immune system in tissue regeneration. Biol Direct. 2021 Oct 20;16(1):18. https://doi.org/10.1186/s13062-021-00306-6
26. Varma Shrivastav S, Bhardwaj A, Pathak KA, Shrivastav A. Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3): Unraveling the Role in Mediating IGF-Independent Effects Within the Cell. Front Cell Dev Biol. 2020 May 5;8:286. https://doi.org/10.3389/fcell.2020.00286
27. Velcheti V, Govindan R. Insulin-like growth factor and lung cancer. J Thorac Oncol. 2006 Sep;1(7):607-610. https://doi.org/10.1016/s1556-0864(15)30370-1
Information about authors:
Oleg I. Kit - Academician at the Russian Academy of Sciences, Dr. Sci. (Med.), professor, general director, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-3061-6108, SPIN: 1728-0329, AuthorlD: 343182, Scopus Author ID: 55994103100, ResearcherID: U-2241-2017
Elena M. Frantsiyants - Dr. Sci. (Biol.), professor, deputy general director for science, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: http://orcid.org/0000-0003-3618-6890, SPIN: 9427-9928, AuthorID: 462868, ResearcherID: Y-1491-2018, Scopus Author ID: 55890047700
Dmitriy A. Kharagezov - Cand. Sci. (Med.), oncologist, surgeon, head of the department of thoracic oncology, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-0640-2994, SPIN: 5120-0561, AuthorID: 733789, ResearcherID: AAZ-3638-2021, Scopus Author ID: 56626499300
Valeriya A. Bandovkinaa - Dr. Sci. (Biol.), senior researcher of the laboratory for the study of pathogenesis of malignant tumors, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: http://orcid.org/0000-0002-2302-8271, SPIN: 8806-2641, AuthorID: 696989
Natalya D. Cheryarina - doctor at the laboratory for the study of the pathogenesis of malignant tumors, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: http://orcid.org/0000-0002-371 1-8155, SPIN: 2189-3404, AuthorID: 558243
Yuliya A. Pogorelova - Cand. Sci. (Biol.), senior researcher at laboratory of malignant tumor pathogenesis study, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: http://orcid.org/0000-0002-2674-9832, SPIN: 2168-8737, AuthorID: 558241 Yuriy N. Lazutin - Cand. Sci. (Med.), associate professor, leading researcher of the department of thoracic surgery, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-6655-7632, SPIN: 5098-7887, AuthorID: 364457 Anton G. Milakin - MD, oncologist of the department of thoracic surgery, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-2589-7606, SPIN: 7737-4737, AuthorID: 794734
Igor A. Leyman - Cand. Sci. (Med.), MD, oncologist of the department of thoracic surgery, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-2572-1624, SPIN: 2551-0999, AuthorID: 735699
Oleg N. Stateshniy - MD, oncologist at the department of thoracic surgery, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-4513-7548, SPIN: 9917-1975, AuthorID: 1067071
Contribution of the authors:
Kit O. I. - scientific management of the research; final analysis of the research;
Frantsiyants E. M. - scientific guidance, research concept, material analysis, manuscript writing, final conclusions; Kharagezov D. A. - management of patients, surgical stages of treatment, critical analysis of the material; Bandovkina V. A. - preparation and editing of the manuscript, verification of critical intellectual content; Cheryarina N. D. - statistical analysis of the results obtained, editing of the manuscript; Pogorelova Yu. A. - ELISA tests, data analysis; Lazutin Yu. N. - analysis of clinical data of patients;
Milakin A. G. - management of patients, review of publications, technical editing of the article;
Leyman I. A. - patient management, critical data analysis;
Stateshny O. N. - patient management, critical data analysis.
All authors have made an equivalent contribution to the preparation of the publication.
