RESUMEN
Diabetes mellitus and malignant tumors are among the most common and complex diseases. Epidemiological studies have shown a strong relationship between these pathologies. The causality of this relationship has not yet been unambiguously established, but a number of probable biological mechanisms have been proposed to explain it through the effects of hyperglycemia, hyperinsulinemia on the process of oncogenesis. An important role in this is played by the axis of insulin-like growth factors, their receptors and binding proteins (IGF / IGFR / IGFBP). The review provides data on the structural elements of the insulin / IGF / IGFR / IGFBP signaling axis and their internal relationships in diabetes mellitus and in the development of malignant tumors. Significant changes in the axis that occur during the formation of the diabetic environment prepare the background, which, under certain conditions, can lead to the stimulation or inhibition of tumor development. The considered signaling system, playing a significant role in the physiology of normal cells, often functions as a decisive factor in the survival of tumor cells, providing fine context-dependent regulation of many cellular processes associated with oncogenesis. However, despite many years of in-depth studies of the pathogenesis of diabetes mellitus and malignant tumors, the molecular mechanisms of the relationship between these pathologies are still largely unclear, and the internal heterogeneity of pathologies complicates research and interpretation of the results, leaving many questions.
Asunto(s)
Diabetes Mellitus , Neoplasias , Humanos , Insulina/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina , Neoplasias/complicacionesRESUMEN
The experimental model of synchronous multiple primary malignant tumors (MPMT) was created. B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline) and sarcoma 45 (0.5 million tumor cells in 0.5 ml saline) were simultaneously subcutaneously inoculated to male BALB/c nude mice. In the model of synchronous MPMT, the tumors appeared faster by 2.4 times and had greater volumes: melanoma by 2.2 times and sarcoma by 3.2 times; melanoma metastasized into sarcoma in 71.4% cases; the survival of mice with MPMT was lower. The altered dynamics of malignant growth in the MPMT model is based on the mutual influence of tumors, which results in the exchange of "structural information".
Asunto(s)
Neoplasias Pulmonares/patología , Melanoma Experimental/patología , Trasplante de Neoplasias/métodos , Neoplasias Primarias Múltiples/patología , Enfermedades de Inmunodeficiencia Primaria/patología , Neoplasias Cutáneas/patología , Animales , Línea Celular Tumoral , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Ratas , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunologíaRESUMEN
The phenomenon of multiple primary malignant tumors (MPMT) is characterized by the presence of several primary neoplasms in the same patient. An experimental model of MPMT with one dominating tumor was developed. Female BALB/c nude mice received simultaneous subcutaneous inoculation of Guerin's carcinoma (5×105 tumor cells in 0.5 ml saline) and B16/F10 melanoma (0.5 ml suspension diluted 1:20 with saline). Control females received transplantation of either melanoma or carcinoma alone in the same doses and volumes. In animals with MPMT model, tumors appeared 3-fold faster than after isolated transplantation of melanoma or Guerin's carcinoma and were larger by 7.5 and 2.2 times, respectively; the survival of mice with MPMT was lower. Guerin's carcinoma in the MPMT model metastasized to melanoma and almost completely suppressed its growth. Thus, a MPMT model was created with carcinoma suppressing the malignant growth of melanoma.
Asunto(s)
Carcinoma/patología , Melanoma Experimental/patología , Neoplasias Primarias Múltiples/patología , Enfermedades de Inmunodeficiencia Primaria/patología , Neoplasias Urológicas/patología , Animales , Carcinoma/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Inyecciones Subcutáneas , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Primarias Múltiples/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunología , Ratas , Factores de Tiempo , Carga Tumoral , Neoplasias Urológicas/inmunologíaRESUMEN
The aim of the study was to determine the level of sex steroid hormones in white matter of the brain of rats with tumors combined with chronic neurogenic pain (CNP), which was modeled by bilateral sciatic nerve ligation. The study included albino male rats (n=74). In the main group, M1 sarcoma was transplanted subcutaneously (n=11) or into the subclavian vein (n=11) 45 days after CNP modeling. Two comparison groups (n=13 each) included sham operated animals (without CNP) with M1 sarcoma transplanted subcutaneously and intravenously. Control groups included animals with CNP and sham operated animals. Rats were euthanized on day 21 of the carcinogenesis. Levels of total and free testosterone (T), estrone (E1), estradiol (E2), estriol (E3) and progesterone (P4) in the brain white matter were measured using ELISA kits ("Cusabio", China). CNP caused a decrease in the total and free T by 1.5 times (p<0.05), E2 and P4 by 1.9 and 3 times, respectively, E3 by 1.6 times (p<0.05), as well as an increase in E1 by 1.4 times (p<0.05) as compared to the corresponding levels in the brain white matter of rats without CNP. CNP stimulated M1 sarcoma growth in both subcutaneous and intravenous transplantation. Regardless of the tumor site, the dynamics of total T, E2 and E3 in the brain had similar features, but the dynamics of free T, P4 and E1 differed. Thus, changes in the level of neurosteroids in the white matter of rat brain with CNP and tumor growth alone or associated with CNP are a reaction to stress.
Asunto(s)
Química Encefálica , Neoplasias Experimentales/patología , Neuroesteroides/análisis , Dolor/patología , Sarcoma/patología , Animales , Estradiol , Estrona , Masculino , Trasplante de Neoplasias , Progesterona , RatasRESUMEN
We developed a model of experimental melanoma. Intralienal xenogeneic transplantation of a suspension of melanoma cells B16 in physiological saline (0.1 ml; 1:10) was conducted to outbred male rats. In 6 months, histologically confirmed melanoma B16 in the spleen and its metastases in the liver, intestine, pancreas, adrenal glands, and lungs (hematogenous metastasis), as well as in the thymus and lymph nodes (lymphogenous metastasis) were revealed in rats. The proposed rat model of melanoma B16 metastasizes by the hematogenous and lymphogenous pathways, develops over 6 months, and allows receiving sufficient volume of material for analysis.
Asunto(s)
Modelos Animales de Enfermedad , Melanoma Experimental/patología , Trasplante de Neoplasias/métodos , Neoplasias Cutáneas/patología , Bazo/patología , Neoplasias del Bazo/secundario , Animales , Animales no Consanguíneos , Metástasis Linfática , Masculino , Melanoma Experimental/inmunología , Ratones , Ratas , Neoplasias Cutáneas/inmunología , Bazo/inmunología , Neoplasias del Bazo/inmunologíaRESUMEN
The activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), the content of reduced glutathione (GSH) and malondialdehyde (MDA) were investigated in the samples of the tumor, peritumoral zone and healthy tissue, taken at the line of resection, were obtained from 14 patients with primary squamous cell carcinoma of the vulva, and 13 patients with local recurrence appeared in the period from 3 months to 7 years. by conventional spectrophotometric methods. The content of GSH and the activity of SOD, GPx, GR, GST were significantly increased, while MDA was decreased in the tissue of the primary carcinoma of the vulva in compared with the healthy tissue. Differences in the functioning of the investigated system of enzymes in the peritumoral zone were also revealed in the primary and recurrent tumoral process. Similar but much less pronounced changes were also observed in the recurrent tumor. It is suggested that such dynamics of activity of the studied system with the progression of cancer process can be the result of adaptation to changes in the local biochemical status of healthy (nonmalignant) tissue of the organ carrying the tumor and reflect the metabolic features of the recurrent tumor.
Asunto(s)
Antioxidantes/metabolismo , Oxidación-Reducción , Neoplasias de la Vulva/metabolismo , Catalasa/metabolismo , Femenino , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Humanos , Malondialdehído/metabolismo , Recurrencia Local de Neoplasia , Superóxido Dismutasa/metabolismoRESUMEN
According to the World Health Organization, pathologies associated with ischemia/reperfusion occupy the leading position in the structure of mortality. The efficiency of localized kidney cancer surgery is limited by the damaging effects of prolonged warm ischemia and reperfusion. Ischemia/reperfusion damage to renal tissue may be related to changes in the expression profiles of pro- and antiapoptotic genes. Here, we have presented the longitudinal expression profiles of apoptosis-related genes in tissues of left and right (intact) kidneys of male rats exposed to unilateral ischemia followed by reperfusion. The profiles have been assessed at time points of 1, 3, and 48 h after the ischemic/reperfusion exposure by RT-qPCR quantification of mRNAs encoded by 13 genes, including BAX, p53, AIFM1, APAF1, CASP8, CASP3, CASP9,CASP7, MDM2, BCL2, CIAP1, XIAP, and ICAD, after normalization with respect to a reference gene ACTB. The study revealed a shift in the expression of pro- and antiapoptotic genes toward the predominance of proapoptotic processes, as was evinced by the increase in expression detected for the BAX, p53, AIFM1, APAF1, and CASP8 genes. One hour after the reperfusion, activation of mitochondrial, or intrinsic apoptosis was detected, while Ñ53-dependent and extrinsic, i.e., receptor-driven, apoptosis joined at later time points. Changes in the level of expression of caspase 7 (CASP7)-encoding mRNA have only been detected 48 h after the restoration of blood flow. Changes have been observed in the transcription of pro- and antiapoptotic genes in tissues of both kidneys, which suggests the involvement of the contralateral kidney in systemic pathological process that develops during unilateral ischemia/reperfusion.
Asunto(s)
Apoptosis/genética , Riñón/metabolismo , Biosíntesis de Proteínas/genética , Daño por Reperfusión/genética , Animales , Regulación de la Expresión Génica/genética , Humanos , Riñón/lesiones , Riñón/patología , Ratas , Daño por Reperfusión/patología , TranscriptomaRESUMEN
INTRODUCTION: Tumor progression and neovascularization during malignant processes are believed to be associated with plasminogen activators and the PAI-1 inhibitor, but their role and interactions in various types of brain tumors have been studied insufficiently. AIM: To conduct a comparative study of plasminogen regulation in optic nerve sheath meningiomas, glioblastomas, and brain metastases of breast cancer, as well as in perifocal tissues surrounding the tumors. MATERIAL AND METHODS: Tumors and perifocal areas of 19 breast cancer (BC) metastases, 24 glioblastomas, and 13 meningiomas without perifocal edema were investigated by ELISA in 56 patients aged 35-72 years. Histological control was carried out in each case. RESULTS: Significant differences were found in the levels of urokinase (uPA), tissue plasminogen activator (tPA), and PAI-1 inhibitor between glioblastomas and breast cancer metastases and the histologically unaltered (relatively intact) tissue around meningioma lesions (p≤0.05 in all cases). The levels of uPA-AG and uPA-act in meningioma were higher than those in the relatively intact tissue, while the levels of both tPA forms were reduced. The levels of uPA-AG and uPA-act in both malignant tumors and their perifocal areas were elevated compared to those in the relatively intact tissue. The levels of both tPA forms were reduced in all other tissues, except for glioblastoma. The level of PAI-1 inhibitor in malignant tissues was higher (being predominant in tumors) compared to that in the intact tissue surrounding meningioma, as well as relative to that in meningioma. The study proves that uPA and its inhibitor PAI-1 are directly involved in the metabolism of malignant gliomas and brain metastases of breast cancer. The role of tPA is to protect meningiomas; tPA activation in malignant brain tumors is suppressed.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioblastoma/metabolismo , Meningioma/metabolismo , Plasminógeno/metabolismo , Adulto , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Glioblastoma/patología , Glioblastoma/secundario , Humanos , Meningioma/patología , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Sex-related systemic status of pituitary and thyroid hormones and cortisol was studied in rats on days 7 and 14 after transplantation of sarcoma C-45 cells into the lung. Females demonstrated slower development of the tumor process (49.0±10.7 vs. 32.0±3.9 days in males). Injection of tumor cells causes similar disorders in the levels of ACTH, thyrotropic hormone, and prolactin in males and females and opposite disorders in the thyroid and glucocorticoid homeostasis associated in males (in contrast to females) with reduction of cortisol level (by 1.9 times) and increase in the concentrations of total thyroxine forms (by 1.4 times) and triiodothyronine (by 2.9 times) by day 14. Early sex-related shifts in the status of hormone that are a component of the adaptive system attest to their possible relationship with different course of the malignant process in male and female rats.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Neoplasias Pulmonares/genética , Hipófisis/metabolismo , Sarcoma/genética , Glándula Tiroides/metabolismo , Glándulas Suprarrenales/fisiopatología , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/genética , Animales , Femenino , Expresión Génica , Hidrocortisona/sangre , Hidrocortisona/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Trasplante de Neoplasias , Hipófisis/fisiopatología , Prolactina/sangre , Prolactina/genética , Ratas , Sarcoma/sangre , Sarcoma/mortalidad , Sarcoma/patología , Factores Sexuales , Análisis de Supervivencia , Glándula Tiroides/fisiopatología , Tirotropina/sangre , Tirotropina/genética , Tiroxina/sangre , Tiroxina/genética , Triyodotironina/sangre , Triyodotironina/genéticaRESUMEN
According to modern concepts cancer is a complex dynamic system having multiple relationships with both the immediate environment and with remote nonmalignant tissues and organs. Changes in the redox balance in them can result in disruption of the normal tissue control. Understanding of the biology of redox processes in a particular tumor and its surroundings, and of their functioning mechanisms is necessary for the development of new anti-cancer strategies based on the effects on the redox state of the tumor and surrounding tissue. Thus the aim of this work was to investigate activity of enzymatic systems influencing the redox state in the tumor tissue, peritumoral area and nonmalignant tissue (taken along the line of resection) for different histological types of tumors. The data obtained showed a similar level of reduced glutathione (GSH) in tumor tissues of gastric adenocarcinoma and vulvar squamous cell carcinoma, but its dynamics in the tissues surrounding the tumor was different. In contrast to the gastric adenocarcinoma the carcinoma of the vulva had a significant level of GSH and higher activity of glutathione dependent enzymes in the tumor tissue and its peritumoral area compared with the surrounding nonmalignant tissue. The results indicate that there are differences in the functioning of the redox regulatory systems in the tumor tissue and its surrounding tissues of various histological origin and localization, possibly due to different mechanisms involved in maintenance of the redox balance in the originally nonmalignant tissue.
Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias de la Vulva/metabolismo , Adenocarcinoma/patología , Anciano , Antioxidantes/metabolismo , Carcinoma de Células Escamosas/patología , Catalasa/metabolismo , Femenino , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Humanos , Masculino , Malondialdehído/metabolismo , Persona de Mediana Edad , Oxidación-Reducción , Neoplasias Gástricas/patología , Superóxido Dismutasa/metabolismo , Neoplasias de la Vulva/patologíaRESUMEN
Aim of the study was to analyze the dynamics of thyroid hormones in the pituitary gland, thyroid gland (TG) and blood serum (BS) in liver metastases to reveal thyroid profile of metastasis and to find thyroid markers-of metastasis in BS. MATERIAL AND METHODS: The experiment included 44 white male rats weighing 180-250 g. Sarcoma 45 (S-45) was transplanted intrasplenically after the spleen was brought under the skin. Levels of thyroid hormones: thyroid stimulating hormone (TSH) in the pituitary gland, TG, BS; free (FT4) and total (T4) thyroxine and free (FT3) and total (T3) triiodothyronine in TG and BS were studied by radioimmunoassay (Immunotech, Czech Republic; Arian analyzer, Russia). RESULTS: From the first days of the tumor development, pituitary gland strain with TSH hyperproduction was observed, and later TG hypofunctioning developed. Quantitative changes of thyroid hormones in organs did not correspond to their dynamics in BS. First diagnostic signs of experimental liver metastases, under the absence of formed metastases in the organ, were hyper-TSH-emy and the tendency to FT3 decreasing in BS. Typical characteristics of the "climax" of liver metastasis included formation of a marked "low TB" syndrome which transformed into a more severe "lowT3/lowT4" syndrome in secondary metastasis to the lungs. CONCLUSIONS: Thus, primary tumor growth and development of metastases are accompanied by the strain and imbalanced functioning of the thyroid system. Analysis of dynamics of the thyroid axis hormones in BS allows prognosis of liver metastases, as well as contributes to identifying the point of no return for the disease development which leads to secondary metastasis and irreversible progression of the process.
Asunto(s)
Neoplasias Hepáticas Experimentales/metabolismo , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/secundario , Masculino , Metástasis de la Neoplasia , Ratas , Glándula Tiroides/patologíaRESUMEN
AIM: comparative analysis of uPA-Ag, uPA-act, tPA-Ag, tPA-act, PAl--Ag and PAl-i-act in tissues of esophageal squamous cell carcinoma (ESCC) in men (M) and women (W) to clarify some pathogenesis issues. MATERIAL AND METHODS: Tumor tissue of ESCC and its perifocal area (19 M and 8 menopausal W aged 38-72 years, st 1I, G2, T,3N M0) were studied by ELISA using standard test kits. RESULTS: ESCC tissue of M showed an increase in both uPA types from the resection line (RL), while in W only uPA-act was increased. tPA-Ag was decreased in tumors of W, tPA-act - in tumors of all patients. Levels of both PAl-- types were higher in ESCC of M than in W. in M, tPA-Ag in perifocal area was lower than in RL, while in W, on the contrary, it was higher. tPA- Ag/tPA-act coefficient in M tumors was 5.7 times higher than in W; in perifocal area it was reduced in all patients, being at the same time in M lower than in W. Both PAl- types were increased in malignant tissues of all patients, prevailing in M tumors, and PAl-i-Ag in peritumoral tissue was higher in M than in W. CONCLUSIONS: Significant gender differences were found in expression of uPA, tPA and PAl-i in tissues of esophageal squamous cell carcinoma. Presence of tumor-associated uPA, PAH and tPA in men and uPA and PAl-i in women is possible in tumor tissue of esophageal squamous cell carcinoma and its perifocal area. Determination of plasminogen regulation system in tissues of esophageal squamous cell carcinoma can be used for the selection and individualization of postoperative treatments.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Activadores Plasminogénicos/metabolismo , Caracteres Sexuales , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Persona de Mediana Edad , Transducción de SeñalRESUMEN
AIM OF THE STUDY: determination of levelsofsometissuegrowth factors, fibrinolyticsystemindicesand MMP-3 for specifi- cation of the role of their changes in moderately differentiated adenocarcinoma of the rectum. MATERIALS AND METHODS. Levels of growth factors and neoangiogenesis, tissue fibrinolyticsystemindicesand MMP-3were studiedin cytosols of tissue obtained from 73 patients (primary adenocarcinomas, st. III, G2, 47 men and 26 women aged 38-74 years, T1-3N0M0) by the ELISA method using standard test kits. RESULTS: Increase in the content of growth factors VEGF-A, IGF and TGF-ß1, the receptor protein VEGF-R, plasminogen activator uPA and metalloproteinases MMP-3 was detected inadenocarcinoma of the rectum. Gender differences inVEGF-Aand TGF-ß1 content were found. Increase in levels and activity of uPA and MMP-3 only was detected in perifocal zone of the tumor. Changes in EGF content were found neither in adenocarcinoma tissue nor in its perifocal zone. No significant gender differenceswere observed intissue fibrinolyticsystemandMMP-3. Age differenceswere not found either. CONCLUSION. I. Concurrent expressionof IGF-I, IGF-II, TGF-ß1 and VEGF-Aanditsreceptorinmalignanttumortissue, as well as increasedplasmin release from proenzyme and MMP-3 activationis apparently associatedwith the formation ofpathogenic mechanism of vasculature development in moderately differentiated adenocarcinoma of the rectum. 2. Activation of uPA and MMP-3 in perifocal zone of the tumor can serve as an indexof its invasive activity. 3. Genderdifferencesin VEGF-A and TGF-ß1, content in tumor tissue were observed; significant association between natient gender and levels of IGF, EGF. fibinolvsis indices and MMP-3 was not found.
Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Plasminógeno/metabolismo , Neoplasias del Recto/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/patología , Neoplasias del Recto/patología , Caracteres SexualesRESUMEN
A new method for reproduction of metastatic involvement of the liver in outbred albino rats is proposed. The use of the method rules out the effects of stress factors (surgical intervention, total anesthesia) on malignant tumor metastasizing, making it maximally similar to the natural process. The method allows visual evaluation of the time course of the primary tumor node growth. The metastatic involvement of the liver develops only by the most significant route, hematogenic. The method can be used for the development of experimental therapy for this condition.