The Role of Selected Chemokines and Their Receptors in the Development of Gliomas.

Among heterogeneous primary tumors of the central nervous system (CNS), gliomas are the most frequent type, with glioblastoma multiforme (GBM) characterized with the worst prognosis. In their development, certain chemokine/receptor axes play important roles and promote proliferation, survival, metastasis, and neoangiogenesis. However, little is known about the significance of atypical receptors for chemokines (ACKRs) in these tumors. The objective of the study was to present the role of chemokines and their conventional and atypical receptors in CNS tumors. Therefore, we performed a thorough search for literature concerning our investigation via the PubMed database. We describe biological functions of chemokines/chemokine receptors from various groups and their significance in carcinogenesis, cancer-related inflammation, neo-angiogenesis, tumor growth, and metastasis. Furthermore, we discuss the role of chemokines in glioma development, with particular regard to their function in the transition from low-grade to high-grade tumors and angiogenic switch. We also depict various chemokine/receptor axes, such as CXCL8-CXCR1/2, CXCL12-CXCR4, CXCL16-CXCR6, CX3CL1-CX3CR1, CCL2-CCR2, and CCL5-CCR5 of special importance in gliomas, as well as atypical chemokine receptors ACKR1-4, CCRL2, and PITPMN3. Additionally, the diagnostic significance and usefulness of the measurement of some chemokines and their receptors in the blood and cerebrospinal fluid (CSF) of glioma patients is also presented.

Specific Receptors for the Chemokines CXCR2 and CXCR4 in Pancreatic Cancer.

BACKGROUND: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. OBJECTIVES: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation-C-reactive protein (CRP). PATIENTS AND METHODS: The study comprised 64 subjects - 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. RESULTS: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV-ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. CONCLUSIONS: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.

The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer's Disease (AD).

Although the causative role of the accumulation of amyloid ß 1-42 (Aß42) deposits in the pathogenesis of Alzheimer's disease (AD) has been under debate for many years, it is supposed that the toxicity soluble oligomers of Tau protein (TauOs) might be also the pathogenic factor acting on the initial stages of this disease. Therefore, we performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. It was shown that soluble TauOs, especially granular forms, may be the most toxic form of this protein. Hyperphosphorylated TauOs can reduce the number of synapses by missorting into axonal compartments of neurons other than axon. Furthermore, soluble TauOs may be also responsible for seeding Tau pathology within AD brains, with probable link to AßOs toxicity. Additionally, the concentrations of TauOs in the cerebrospinal fluid (CSF) and plasma of AD patients were higher than in non-demented controls, and revealed a negative correlation with mini-mental state examination (MMSE) scores. It was postulated that adding the measurements of TauOs to the panel of CSF biomarkers could improve the diagnosis of AD.

Amyloid ß oligomers (AßOs) in Alzheimer's disease.

The causative role of amyloid ß 1-42 (Aß42) aggregation in the pathogenesis of Alzheimer's disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between production and clearance of Aß42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aß42. Currently, it is supposed that soluble oligomers of amyloid beta (AßOs) and not fibrillar Aß42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathological cascade. For example, soluble AßOs isolated from AD patients' brains reduced number of synapses, inhibited long-term potentiation, and enhanced long-term synaptic depression in brain regions responsible for memory in animal models of AD. Concentrations of AßOs in the cerebrospinal fluid (CSF) of AD patients are often reported higher than in non-demented controls, and show a negative correlation with mini-mental state examination scores. Furthermore, increased Aß42/oligomer ratio in the CSF of AD/MCI patients indicated that the presence of soluble AßOs in CSF may be linked to lowering of natively measured monomeric Aß42 by epitopes masking, and hence, concentrations of AßOs in the CSF are postulated to as useful AD biomarkers.

Cellular Receptors of Amyloid ß Oligomers (AßOs) in Alzheimer's Disease.

It is estimated that Alzheimer's disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients' brain composed of amyloid beta (Aß) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aß and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AßOs) aggregation in the pathogenesis of AD. Moreover, binding of AßOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AßO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aß oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AßO receptors related to toxic activity of oligomers.

Matrix Metalloproteinases and Their Tissue Inhibitors in Comparison to Other Inflammatory Proteins in Gastric Cancer (GC).

Gastric cancer (GC) remains a major cause of cancer-related deaths worldwide. The lack of management strategies for the diagnosis of GC in patients gives rise to the challenging questions about the new tumor markers for GC. Developing malignant process may induce local and systemic inflammatory responses. Cancer-associated inflammation is characterized by the infiltration of immune cells. Thus, the inflammation-related proteins, such as cytokines, chemokines, and selected matrix metalloproteinases, may facilitate the growth, proliferation, and migration of tumor cells, including GC. Based on our previous findings, we assessed the significance of various inflammatory mediators as candidates for tumor markers of GC.

Comparative Analysis of Neurodegeneration and Axonal Dysfunction Biomarkers in the Cerebrospinal Fluid of Patients with Multiple Sclerosis.

BACKGROUND: Given the significant role of neurodegeneration in the progression of multiple sclerosis (MS) and insufficient therapies, there is an urgent need to better understand this pathology and to find new biomarkers that could provide important insight into the biological mechanisms of the disease. Thus, the present study aimed to compare different neurodegeneration and axonal dysfunction biomarkers in MS and verify their potential clinical usefulness. METHODS: A total of 59 patients, who underwent CSF analysis during their diagnostics, were enrolled in the study. Quantitative analysis of neurodegeneration biomarkers was performed through immunological tests. Oligoclonal bands were detected by isoelectric focusing on agarose gel, whereas the concentrations of immunoglobulins and albumin were measured using nephelometry. RESULTS: Our studies showed that NfL, RTN4, and tau protein enabled the differentiation of MS patients from the control group. Additionally, the baseline CSF NfL levels positively correlated with the tau and MRI results, whereas the RTN4 concentrations were associated with the immunoglobulin quotients. The AUC for NfL was the highest among the tested proteins, although the DeLong test of the ROC curves showed no significant difference between the AUCs for NfL and RTN4. CONCLUSION: The CSF NfL, RTN-4, and tau levels at the time of diagnosis could be potential diagnostic markers of multiple sclerosis, although NfL seems to have the best clinical value.

Novel potential biomarkers for pancreatic cancer - A systematic review.

BACKGROUND: It is estimated that in developed countries the incidence rate of pancreatic cancer (PC) will continue to rise and by 2020 will be the second most fatal cancer. The mortality of PC patients closely parallels the incidence rate, as this malignancy remains asymptomatic until it reaches an advanced stage of disease. Thus, novel biochemical markers that improve the management of PC patients are necessary. The aim of the work that follows is to investigate whether selected inflammatory mediators might be used in the diagnosis of PC, with the aim of improving the prognosis for PC patients. METHODS: We performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. RESULTS: It has been proved that certain inflammatory mediators might be involved in tumor progression, such as growth, proliferation, migration and angiogenesis of tumor cells. In the present review, we summarized and referred to a number of original papers concerning the clinical significance of selected cytokines and specific inflammatory proteins such as C-reactive protein, as well as of various matrix metalloproteinases and their tissue inhibitors, as potential biomarkers for PC in comparison to well-established tumor markers for this malignancy. CONCLUSION: Presented proteins might be potential biomarkers in the diagnosis and progression of PC.

Serum chemokine CXCL8 as a better biomarker for diagnosis and prediction of pancreatic cancer than its specific receptor CXCR2, C-reactive protein, and classic tumor markers CA 19-9 and CEA.

Introduction Novel biomarkers are critically needed to improve the management of patients with pancreatic cancer (PC). Objectives We aimed to evaluate the clinical usefulness of serum CXCL8 in relation to its specific receptor CXCR2 in the diagnosis and prediction of PC compared with classic tumor markers (carbohydrate antigen 19-9 [CA 19-9] and carcinoembryonic antigen [CEA]) and C-reactive protein (CRP). Patients and methods The study included 76 subjects: 42 patients with PC and 34 healthy volunteers. Serum protein levels were measured by immunological methods. Results Serum CXCL8 and CXCR2 concentrations were significantly higher in PC patients compared with healthy controls, similarly to classic tumor markers and CRP. CXCL8 levels were significantly elevated in patients with lymph node metastasis compared with individuals without nodal involvement. The diagnostic sensitivity, accuracy, negative predictive value, and areas under the receiver operating characteristic curves for CXCL8 were higher than those for CXCR2, CRP, CA 19-9, and CEA. Moreover, serum CXCL8 was the only significant predictor of PC risk. Conclusions Our findings indicate the significance of the CXCL8-CXCR2 axis in the pathogenesis of PC. Serum CXCL8 is emerging as the strongest candidate for a potential PC biomarker among all proteins tested.

The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease.

BACKGROUND: It is known that YKL-40- a marker of glial inflammation, and VILIP-1- a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis. OBJECTIVE: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function. METHODS: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD patients, 18 MCI subjects, and 23 non-demented controls using ELISA method. RESULTS: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aß42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response. CONCLUSION: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis.