Transcriptional regulation of endothelin-1 expression by advanced glycation end-products in human aortic endothelium is mediated via NF-kappaΒ and AP-1

Advanced Glycation End-products (AGEs) are produced by the non-enzymatic glycation of proteins, lipids and nucleic acids, resulting in an overload of highly reactive molecules of endogenous or exogenous (dietary) origin. Increased AGE levels in circulation and concomitant elevated tissue deposition have been associated with diabetic complications, atheromatosis, ageing and more recently with polycystic ovary syndrome pathogenesis. Interaction of AGEs with their receptor RAGE (Receptor for AGEs) activates intracellular signaling pathways which induce targeted gene expression in endothelium including upregulation of cell adhesion molecules and endothelin-1 (ET-1), implicated in vascular injury and endothelial dysfunction. The purpose of this study is to explore the molecular mechanism of AGE-induced regulation of ET-1 gene/protein expression in human endothelial cells and investigate its functional relevance in normal rat vascular endothelium

Polycystins and Mechanotransduction in Human Disease

Alterations in the process of mechanotransduction have been implicated in the pathogenesis of several diseases such as genetic diseases, osteoporosis, cardiovascular anomalies, and cancer. Several studies over the past twenty years have demonstrated that polycystins (polycystin-1, PC1; and polycystin-2, PC2) respond to changes of extracellular mechanical cues, and mediate pathogenic mechanotransduction and cyst formation in kidney cells. However, recent reports reveal the emergence of polycystins as key proteins that facilitate the transduction of mechano-induced signals in various clinical entities besides polycystic kidney disease, such as cancer, cardiovascular defects, bone loss, and deformations, as well as inflammatory processes like psoriasis. Herewith, we discuss data from recent studies that establish this role with potential clinical utility

Ο ρόλος των πολυκυστινών στην καρκινογένεση

Polycystin-1 and polycystin-2 (PC1, PC2) constitute a subset of proteins, which are expressed in a variety of epithelial cells and decisively participate in the pathogenesis of autosomal dominant polycystic kidney disease. PC1 and PC2 function as mechanosensors by regulating the respective cellular response and participate in homeostasis of dominant cellular properties that are being imlaired in cancer cells, therefore suggesting a biological contribution in invasion and metastasis. The aim of the study was to investigate for the first time the role of PC1 and PC2 in carcinogenesis using as a model colorectal cancer (CRC), a common and well-studied malignancy of both genders worldwide. The present study was conducted in three aspects. At first, we investigated the impact of the modification of PC1 and PC2 expression and activity in basic features of cancer cells in CRC cell lines in vitro. Subsequently, we evaluated the impact of PC1 inhibition in human CRC tumor xenografts and eventually we performed a thorough evaluation of PC1 and PC2 expression in 190 human CRC tumors.PC1 overexpression promoted epithelial-to-mesenchymal transition (EMT) in poorly differentiated cells and its inhibition reduced CRC cell viability, while PC2 overexpression resulted in activation of key-substrates of the mTOR (mammalian target of rapamycin) signaling pathway. Inhibition of PC1 in CRC xenografts showed a trend of enhanced tumor necrosis suppressing EMT and reducing the resistance of the apoptotic process. Furthermore, the increased expression of PC1 and PC2 in CRC patients was associated with adverse clinical and pathologic parameters for the patients (mucinous, poorly differentiated carcinomas with increased depth of filtration and higher chance of relapse), highlighting PC1 as an independent prognostic factor of reduced disease-free survival.In conclusion, PC1 and PC2 constitute two novel cancer-associated molecules acting as putative oncogenes. Polycystins become associated with parameters that form an aggressive tumor phenotype in CRC, emerging as new prognostic factors in CRC pathogenesis.Οι πολυκυστίνες 1 και 2 (PC1, PC2) είναι πρωτεΐνες που εκφράζονται σε πολλά είδη επιθηλιακών κυττάρων, συμμετέχοντας αιτιολογικά στην παθογένεια της αυτοσωμικής επικρατούσας πολυκυστικής νόσου των νεφρών. Λειτουργούν ως μηχανο-αισθητήρια μόρια που ρυθμίζουν την κυτταρική απόκριση και διαθέτουν ομοιοστατικό ρόλο σε βασικές λειτουργίες του κυττάρου που διαταράσσονται κατά την ογκογένεση, πιθανολογώντας τη βιολογική συμμετοχή τους κυρίως στις διαδικασίες επέκτασης και μετάστασης του όγκου. Στόχος της διδακτορικής διατριβής ήταν η διερεύνηση για πρώτη φορά του ρόλου των πολυκυστινών στην καρκινογένεση χρησιμοποιώντας ως μοντέλο τον ορθοκολικό καρκίνο (ΟΚΚ), που είναι μια συχνή κακοήθεια και στα δύο φύλα αρκετά καλά μελετημένη και ιεραρχικά δομημένη.Η διδακτορική διατριβή πραγματοποιήθηκε σε τρεις άξονες. Ο πρώτος περιλαμβάνει τη μελέτη της επίπτωσης της τροποποίησης της έκφρασης και της ενεργότητας των PC1 και PC2 (υπερέκφραση, αναστολή) σε βασικές ιδιότητες των καρκινικών κυττάρων ΟΚΚ σε κυτταρικές καλλιέργειες. Ο δεύτερος τη μελέτη της επίπτωσης της τροποποίησης της ενεργότητας της PC1 στην ανάπτυξη ανθρώπινων όγκων ΟΚΚ σε ξενομοσχεύματα ποντικιών και ο τρίτος την ενδελεχή διερεύνηση της έκφρασης των δύο πρωτεϊνών σε ιστούς ασθενών με ΟΚΚ.Η υπερέκφραση της PC1 προάγει την επιθηλιο-μεσεγχυματική μετατροπή (ΕΜΜ) στα κύτταρα χαμηλής διαφοροποίησης και η αναστολή της μειώνει την βιωσιμότητα των κυττάρων ΟΚΚ, ενώ η υπερέκφραση της PC2 έχει ως αποτέλεσμα την ενεργοποίηση βασικών υποστρωμάτων του σηματοδοτικού μονοπατιού mTOR (mammalian target of rapamycin). Η αναστολή της PC1 στα ξενομοσχεύματα ΟΚΚ δείχνει τάση νέκρωσης των όγκων, καταστολής της ΕΜΜ και μείωσης στην αντίσταση της αποπτωτικής διαδικασίας. Παράλληλα, η αυξημένη έκφραση των PC1 και PC2 σε 190 ασθενείς με ΟΚΚ συσχετίστηκε με δυσμενείς κλινικοπαθολογικές παραμέτρους για τους ασθενείς (βλεννώδη καρκινώματα, χαμηλή διαφοροποίηση, αυξημένο βάθος διήθησης, υψηλότερη πιθανότητα υποτροπής) με την PC1 να αναδεικνύεται ως ανεξάρτητος προγνωστικός παράγοντας μειωμένης επιβίωσης ελεύθερης νόσου.Συμπερασματικά, οι PC1 και PC2 αποτελούν δύο νέα μόρια της καρκινογένεσης που δρουν ως «ογκογονίδια», εμπλέκονται σε παθολογικούς μηχανισμούς ανάπτυξης επιθετικού φαινοτύπου στον ΟΚΚ και μπορούν να αποτελέσουν νέους προγνωστικούς δείκτες της νόσου

Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor–microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment

The Association of Human Herpesviruses with Malignant Brain Tumor Pathology and Therapy: Two Sides of a Coin

The role of certain viruses in malignant brain tumor development remains controversial. Experimental data demonstrate that human herpesviruses (HHVs), particularly cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6), are implicated in brain tumor pathology, although their direct role has not yet been proven. CMV is present in most gliomas and medulloblastomas and is known to facilitate oncomodulation and/or immunomodulation, thus promoting cancer cell proliferation, invasion, apoptosis, angiogenesis, and immunosuppression. EBV and HHV-6 have also been detected in brain tumors and high-grade gliomas, showing high rates of expression and an inflammatory potential. On the other hand, due to the neurotropic nature of HHVs, novel studies have highlighted the engagement of such viruses in the development of new immunotherapeutic approaches in the context of oncolytic viral treatment and vaccine-based strategies against brain tumors. This review provides a comprehensive evaluation of recent scientific data concerning the emerging dual role of HHVs in malignant brain pathology, either as potential causative agents or as immunotherapeutic tools in the fight against these devastating diseases

Polycystins in Colorectal Cancer

Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in signal transduction mechanisms and during alterations in calcium influx, which regulate cellular functions such as proliferation, differentiation, orientation, and migration in cancer cells. Recent findings implicate polycystins in the deregulation of such functions and the formation of CRC invasive phenotypes. Polycystins participate in all aspects of the cell’s biomechanical network, from the perception of extracellular mechanical cues to focal adhesion protein and nuclear transcriptional complexes. Therefore, polycystins could be employed as novel biomarkers and putative targets of selective treatment in CRC

Targeting STAT3 Signaling Pathway in Colorectal Cancer

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC

Polycystins in Colorectal Cancer

Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in signal transduction mechanisms and during alterations in calcium influx, which regulate cellular functions such as proliferation, differentiation, orientation, and migration in cancer cells. Recent findings implicate polycystins in the deregulation of such functions and the formation of CRC invasive phenotypes. Polycystins participate in all aspects of the cell's biomechanical network, from the perception of extracellular mechanical cues to focal adhesion protein and nuclear transcriptional complexes. Therefore, polycystins could be employed as novel biomarkers and putative targets of selective treatment in CRC

MicroRNAs in Colorectal Neoplasia: From Pathobiology to Clinical Applications

MicroRNAs (miRNAs) are small, non-coding RNAs that can post-transcriptionally regulate gene expression via messenger RNA (mRNA) targeting. During the past few years several miRNA groups emerged as critical components of developmental and pathological processes, among them being cancer. In colorectal cancer (CRC) specifically, numerous miRNA molecules have been identified up-or downregulated functioning as tumor-specific markers with oncogenic and tumor-suppressive properties. Their dysregulation impacts impaired cellular processes such as cell proliferation, apoptosis, angiogenesis, invasion and metastasis. The detection of extracellular miRNAs in plasma and fecal samples of CRC patients tends to provide novel, non-invasive biomarkers in favor of CRC diagnosis and, at the same time, data from in vivo and in vitro CRC models reveal promising therapeutic applications through miRNA inhibition and miRNA delivery