Estrogen α and ß Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERß mRNA expression and an increase in ERα mRNA expression. In patient samples, ERß mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERß protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERß protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas.

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant glioma, difficult to detect and with the lowest survival rates among gliomas. Its greater incidence among men and its higher survival rate among premenopausal women suggest that it may be associated with the levels of androgens. As androgens stimulate the androgen receptor (AR), which acts as a transcription factor, the aim of this study was the investigate the role of AR in the progression of GBM. The study was conducted on tissues collected from three regions of GBM tumors (tumor core, enhancing tumor region, and peritumoral area). In addition, an in vitro experiment was conducted on U-87 cells under various culture conditions (necrotic, hypoxic, and nutrient-deficient), mimicking the conditions in a tumor. In both of the models, androgen receptor expression was determined at the gene and protein levels, and the results were confirmed by confocal microscopy and immunohistochemistry. AR mRNA expression was higher under nutrient-deficient conditions and lower under hypoxic conditions in vitro. However, there were no differences in AR protein expression. No differences in AR mRNA expression were observed between the tested tumor structures taken from patients. No differences in AR mRNA expression were observed between the men and women. However, AR protein expression in tumors resected from patients was higher in the enhancing tumor region and in the peritumoral area than in the tumor core. In women, higher AR expression was observed in the peritumoral area than in the tumor core. AR expression in GBM tumors did not differ significantly between men and women, which suggests that the higher incidence of GBM in men is not associated with AR expression. In the group consisting of men and women, AR expression varied between the regions of the tumor: AR expression was higher in the enhancing tumor region and in the peritumoral area than in the tumor core, showing a dependence on tumor conditions (hypoxia and insufficient nutrient supply).

CCL18 Expression Is Higher in a Glioblastoma Multiforme Tumor than in the Peritumoral Area and Causes the Migration of Tumor Cells Sensitized by Hypoxia.

Glioblastoma multiforme (GBM) is a brain tumor with a very poor prognosis. For this reason, researchers worldwide study the impact of the tumor microenvironment in GBM, such as the effect of chemokines. In the present study, we focus on the role of the chemokine CCL18 and its receptors in the GBM tumor. We measured the expression of CCL18, CCR8 and PITPNM3 in the GMB tumor from patients (16 men and 12 women) using quantitative real-time polymerase chain reaction. To investigate the effect of CCL18 on the proliferation and migration of GBM cells, experiments were performed using U-87 MG cells. The results showed that CCL18 expression was higher in the GBM tumor than in the peritumoral area. The women had a decreased expression of PITPNM3 receptor in the GBM tumor, while in the men a lower expression of CCR8 was observed. The hypoxia-mimetic agent, cobalt chloride (CoCl2), increased the expression of CCL18 and PITPNM3 and thereby sensitized U-87 MG cells to CCL18, which did not affect the proliferation of U-87 MG cells but increased the migration of the test cells. The results indicate that GBM cells migrate from hypoxic areas, which may be important in understanding the mechanisms of tumorigenesis.

Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.

Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE2. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.

The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases.

CXCL16 is a chemotactic cytokine belonging to the α-chemokine subfamily. It plays a significant role in the progression of cancer, as well as the course of atherosclerosis, renal fibrosis, and non-alcoholic fatty liver disease (NAFLD). Since there has been no review paper discussing the importance of this chemokine in various diseases, we have collected all available knowledge about CXCL16 in this review. In the first part of the paper, we discuss background information about CXCL16 and its receptor, CXCR6. Next, we focus on the importance of CXCL16 in a variety of diseases, with an emphasis on cancer. We discuss the role of CXCL16 in tumor cell proliferation, migration, invasion, and metastasis. Next, we describe the role of CXCL16 in the tumor microenvironment, including involvement in angiogenesis, and its significance in tumor-associated cells (cancer associated fibroblasts (CAF), microglia, tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), mesenchymal stem cells (MSC), myeloid suppressor cells (MDSC), and regulatory T cells (Treg)). Finally, we focus on the antitumor properties of CXCL16, which are mainly caused by natural killer T (NKT) cells. At the end of the article, we summarize the importance of CXCL16 in cancer therapy.

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review.

Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on ß chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4.

CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).

Fractalkine/CX3CL1 in Neoplastic Processes.

Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes-mainly NK cells, T cells and dendritic cells. Its increased levels in tumors improve the prognosis for cancer patients, although it is also associated with a poorer prognosis in some types of cancers, such as pancreatic ductal adenocarcinoma. This work focuses on the 'hallmarks of cancer' involving CX3CL1 and its receptor CX3CR1. First, we describe signal transduction from CX3CR1 and the role of epidermal growth factor receptor (EGFR) in this process. Next, we present the role of CX3CL1 in the context of cancer, with the focus on angiogenesis, apoptosis resistance and migration and invasion of cancer cells. In particular, we discuss perineural invasion, spinal metastasis and bone metastasis of cancers such as breast cancer, pancreatic cancer and prostate cancer. We extensively discuss the importance of CX3CL1 in the interaction with different cells in the tumor niche: tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and microglia. We present the role of CX3CL1 in the development of active human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) brain tumors. Finally, we discuss the possible use of CX3CL1 in immunotherapy.

Lead (Pb) as a Factor Initiating and Potentiating Inflammation in Human THP-1 Macrophages.

The aim of this study was to assess the influence of lead (Pb) at low concentrations (imitating Pb levels in human blood in chronic environmental exposure to this metal) on interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) concentrations and the activity and expression of COX-1 and COX-2 in THP-1 macrophages. Macrophages were cultured in vitro in the presence of Pb at concentrations of: 1.25 µg/dL; 2.5 µg/dL; 5 µg/dL; 10 µg/dL. The first two concentrations of Pb were selected on the basis of our earlier study, which showed that Pb concentration in whole blood (PbB) of young women living in the northern regions of Poland and in the cord blood of their newborn children was within this range (a dose imitating environmental exposure). Concentrations of 5 µg/dL and 10 µg/dL correspond to the previously permissible PbB concentrations in children or pregnant women, and adults. Our results indicate that even low concentrations of Pb cause an increase in production of inflammatory interleukins (IL-1ß and IL-6), increases expression of COX-1 and COX-2, and increases thromboxane B2 and prostaglandin E2 concentration in macrophages. This clearly suggests that the development of inflammation is associated not only with COX-2 but also with COX-1, which, until recently, had only been attributed constitutive expression. It can be concluded that environmental Pb concentrations are able to activate the monocytes/macrophages similarly to the manner observed during inflammation.

The Pathophysiology of Post-Traumatic Glioma.

Malignant glioma is a brain tumor with a very high mortality rate resulting from the specific morphology of its infiltrative growth and poor early detection rates. The causes of one of its very specific types, i.e., post-traumatic glioma, have been discussed for many years, with some studies providing evidence for mechanisms where the reaction to an injury may in some cases lead to the onset of carcinogenesis in the brain. In this review of the available literature, we discuss the consequences of breaking the blood⁻brain barrier and consequences of the influx of immune-system cells to the site of injury. We also analyze the influence of inflammatory mediators on the expression of genes controlling the process of apoptosis and the effect of chemical mutagenic factors on glial cells in the brain. We present the results of experimental studies indicating a relationship between injury and glioma development. However, epidemiological studies on post-traumatic glioma, of which only a few confirm the conclusions of experimental research, indicate that any potential relationship between injury and glioma, if any, is indirect.

The Trace Element Concentrations and Oxidative Stress Parameters in Afterbirths from Women with Multiple Pregnancies.

The aim of this study was to evaluate the intensity of oxidative stress by measuring the concentrations of lipid peroxidation products (LPO) in fetal membrane, umbilical cord, and placenta samples obtained from women with multiple pregnancies. Additionally, the effectiveness of protection against oxidative stress was assessed by measuring the activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR). Due to the role of iron (Fe), copper (Cu), and zinc (Zn) as cofactors for antioxidant enzymes, the concentrations of these elements were also analyzed in the studied afterbirths. The obtained data were compared with newborn parameters, selected environmental factors, and the health status of women during pregnancy to determine the relationship between oxidative stress and the health of women and their offspring during pregnancy. The study involved women (n = 22) with multiple pregnancies and their newborns (n = 45). The Fe, Zn, and Cu levels in the placenta, umbilical cord, and fetal membrane were determined using inductively coupled plasma atomic emission spectroscopy (ICP-OES) using an ICAP 7400 Duo system. Commercial assays were used to determine SOD, GPx, GR, CAT, and LPO activity levels. The determinations were made spectrophotometrically. The present study also investigated the relationships between trace element concentrations in fetal membrane, placenta, and umbilical cord samples and various maternal and infant parameters in women. Notably, a strong positive correlation was observed between Cu and Zn concentrations in the fetal membrane (p = 0.66) and between Zn and Fe concentrations in the placenta (p = 0.61). The fetal membrane Zn concentration exhibited a negative correlation with shoulder width (p = -0.35), while the placenta Cu concentration was positively correlated with placenta weight (p = 0.46) and shoulder width (p = 0.36). The umbilical cord Cu level was positively correlated with head circumference (p = 0.36) and birth weight (p = 0.35), while the placenta Fe concentration was positively correlated with placenta weight (p = 0.33). Furthermore, correlations were determined between the parameters of antioxidative stress (GPx, GR, CAT, SOD) and oxidative stress (LPO) and the parameters of infants and maternal characteristics. A negative correlation was observed between Fe and LPO product concentrations in the fetal membrane (p = -0.50) and placenta (p = -0.58), while the Cu concentration positively correlated with SOD activity in the umbilical cord (p = 0.55). Given that multiple pregnancies are associated with various complications, such as preterm birth, gestational hypertension, gestational diabetes, and placental and umbilical cord abnormalities, research in this area is crucial for preventing obstetric failures. Our results could serve as comparative data for future studies. However, we advise caution when interpreting our results, despite achieving statistical significance.

Reduced Expression of Very-Long-Chain Acyl-CoA Synthetases SLC27A4 and SLC27A6 in the Glioblastoma Tumor Compared to the Peritumoral Area.

This study aimed to analyze solute carrier family 27 (SLC27) in glioblastoma tumors. The investigation of these proteins will provide insight into how and to what extent fatty acids are taken up from the blood in glioblastoma tumors, as well as the subsequent fate of the up-taken fatty acids. Tumor samples were collected from a total of 28 patients and analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The study also sought to explore the relationship between SLC27 expression and patient characteristics (age, height, weight, body mass index (BMI), and smoking history), as well as the expression levels of enzymes responsible for fatty acid synthesis. The expression of SLC27A4 and SLC27A6 was lower in glioblastoma tumors compared to the peritumoral area. Men had a lower expression of SLC27A5. Notably, a positive correlation was observed between the expression of SLC27A4, SLC27A5, and SLC27A6 and smoking history in women, whereas men exhibited a negative correlation between these SLC27s and BMI. The expression of SLC27A1 and SLC27A3 was positively correlated with the expression of ELOVL6. In comparison to healthy brain tissue, glioblastoma tumors take up fewer fatty acids. The metabolism of fatty acids in glioblastoma is dependent on factors such as obesity and smoking.

Epidemiology of Glioblastoma Multiforme-Literature Review.

Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, with a median overall survival of approximately 15 months. In this review, we analyze the pathogenesis of GBM, as well as epidemiological data, by age, gender, and tumor location. The data indicate that GBM is the higher-grade primary brain tumor and is significantly more common in men. The risk of being diagnosed with glioma increases with age, and median survival remains low, despite medical advances. In addition, it is difficult to determine clearly how GBM is influenced by stimulants, certain medications (e.g., NSAIDs), cell phone use, and exposure to heavy metals.

Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men.

One line of research on the possible ways of inhibiting the growth of glioblastoma multiforme (GBM), a brain tumor with a very poor prognosis, is the analysis of its metabolism, such as fatty acid synthesis by desaturases and elongases. This study examines the expression of elongases ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, and ELOVL7 in GBM tumor samples from 28 patients (16 men and 12 women), using a quantitative real-time polymerase chain reaction (qRT-PCR). To demonstrate the influence of the tumor microenvironment on the tested elongases, U-87 MG cells were cultured in nutrient-deficient conditions and with cobalt chloride (CoCl2) as a hypoxia-mimetic agent. The results showed that the expression of ELOVL1 and ELOVL7 in the GBM tumor was lower than in the peritumoral area. The expression of six of the seven studied elongases differed between the sexes. Hypoxia increased the expression of ELOVL5 and ELOVL6 and decreased the expression of ELOVL1, ELOVL3, ELOVL4, and ELOVL7 in U-87 MG cells. These results indicate that the synthesis of fatty acids, especially polyunsaturated fatty acids (PUFA), in GBM tumors may be higher in men than in women. In contrast, the synthesis of saturated fatty acids (SFA) may be higher in women than in men.

Epidemiology of Anthropometric Factors in Glioblastoma Multiforme-Literature Review.

Although glioblastoma multiforme (GBM) is a widely researched cancer of the central nervous system, we still do not know its full pathophysiological mechanism and we still lack effective treatment methods as the current combination of surgery, radiotherapy, and chemotherapy does not bring about satisfactory results. The median survival time for GBM patients is only about 15 months. In this paper, we present the epidemiology of central nervous system (CNS) tumors and review the epidemiological data on GBM regarding gender, age, weight, height, and tumor location. The data indicate the possible influence of some anthropometric factors on the occurrence of GBM, especially in those who are male, elderly, overweight, and/or are taller. However, this review of single and small-size epidemiological studies should not be treated as definitive due to differences in the survey methods used. Detailed epidemiological registers could help identify the main at-risk groups which could then be used as homogenous study groups in research worldwide. Such research, with less distortion from various factors, could help identify the pathomechanisms that lead to the development of GBM.

The influence of selected gastrointestinal parasites on apoptosis in intestinal epithelial cells.

Studies on the parasite-host interaction may provide valuable information concerning the modulation of molecular mechanisms as well as of the host immune system during infection. To date, it has been demonstrated that intestinal parasites may affect, among others, the processes of digestion in the gastrointestinal system of the host, thus limiting the elimination of the parasite, the immune response as well as inflammation. However, the most recent studies suggest that intestinal parasites may also affect modulation of the apoptosis pathway of the host. The present paper presents the latest scientific information on the influence of intestinal parasite species (Blastocystis sp., Giardia sp., Cryptosporidium sp., Trichuris sp., Entamoeba histolytica, Nippostrongylus brasiliensis, Heligmosomoides polygyrus) on the molecular mechanisms of apoptosis in intestinal epithelial cells. This paper stresses that the interdependency between the intestinal parasite and the host results from the direct effect of the parasite and the host's defense reactions, which lead to modulation of the apoptosis pathways (intrinsic and extrinsic). Moreover, the present paper presents the role of proteins involved in the mechanisms of apoptosis as well as the physiological role of apoptosis in the host's intestinal epithelial cells.

Expression of SCD and FADS2 Is Lower in the Necrotic Core and Growing Tumor Area than in the Peritumoral Area of Glioblastoma Multiforme.

The expression of desaturases is higher in many types of cancer, and despite their recognized role in oncogenesis, there has been no research on the expression of desaturases in glioblastoma multiforme (GBM). Tumor tissue samples were collected during surgery from 28 patients (16 men and 12 women) diagnosed with GBM. The effect of necrotic conditions and nutritional deficiency (mimicking conditions in the studied tumor zones) was studied in an in vitro culture of human brain (glioblastoma astrocytoma) U-87 MG cells. Analysis of desaturase expression was made by qRT-PCR and the immunohistochemistry method. In the tumor, the expression of stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturases 2 (FADS2) was lower than in the peritumoral area. The expression of other desaturases did not differ in between the distinguished zones. We found no differences in the expression of SCD, fatty acid desaturases 1 (FADS1), or FADS2 between the sexes. Necrotic conditions and nutritional deficiency increased the expression of the studied desaturase in human brain (glioblastoma astrocytoma) U-87 MG cells. The obtained results suggest that (i) biosynthesis of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in a GBM tumor is less intense than in the peritumoral area; (ii) expressions of SCD, SCD5, FADS1, and FADS2 correlate with each other in the necrotic core, growing tumor area, and peritumoral area; (iii) expressions of desaturases in a GBM tumor do not differ between the sexes; and (iv) nutritional deficiency increases the biosynthesis of MUFA and PUFA in GBM cells.