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Identifier 000432403
Title Ο ρόλος των αυξητικών παραγόντων και μορίων του εξωκυττάριου χώρου στους όγκους μεσεγχυματικής προέλευσης
Alternative Title The role of the grouth factors and the molecules of the extracellular matrix to tumors of mesenchymal origin
Author Παπουτσιδάκης, Αντώνιος
Thesis advisor Νικίτοβιτς-Τζανακάκη, Ντράγκανα
Reviewer Τζαρδή, Μαρία
Τσιαούσης, Ιωάννης
Abstract This thesis focuses on studying the mechanisms which regulate the biological functions of tumors with a mesenchymal origin. Sarcomas are types of tumor which develop from differentiated cells of the connective tissues of the human body, and therefore can rise from tissues, like bone, cartilage, blood or vessels. Sarcomas are classified into two categories depending on the tissue and the cell type of their origin. Thus, there are bone sarcomas, like osteosarcoma, chondrosarcoma, and sarcomas of soft tissues, like fibrosarcoma. In this study, we aimed to identify the signaling pathways which participate in sarcoma progression in three different human cell lines e.g., osteosarcoma (MG63), chondrosarcoma (HTB94), and fibrosarcoma (HT1080) respectively. Tumor cells produce a modified extracellular matrix compared to healthy tissues, and interaction with the deregulated ECM modulates these cells's biological functions. ECM consists of a complicated system of proteoglycans, fibrous proteins and hyaluronic acid, and its role is supportive, but also protective of each tissue's cells. Furthermore, ECM creates and transfers many different signals between cells/tissues, affecting their behavior and functions. ECM also acts as a reserve for growth factors like transforming growth factor-beta (TFG-β) or insulin-like growth factor I (IGF-I) and other biologically significant macromolecules able to change cellular behavior. Proteoglycans (PGs) are molecules that consist of glycosaminoglycan chains (GAGs) covalently bound into a protein core. These proteins undergo various post-translational changes, and they can affect cellular function and cancer progression through a plethora of signaling pathways. Many studies have shown that PGs are localized to the cell surface but are also secreted into the ECM, like small leucine rich proteoglycans (SLRPs). This direct interaction with the extracellular environment gives them the ability to transmit cues from the ECM to the cells and finally act as signaling molecules that control cellular functions, like proliferation, migration, differentiation, and further ECM composition. It is also shown that SLRPs interact with tyrosine kinase receptors, which affects their downstream signaling and cellular behavior. More specifically, some SLRPs, like biglycan and lumican, participate in bone formation and homeostasis regulation and have specific roles in the different phases of these processes. Furthermore, transmembrane proteoglycans, like syndecan 2, have essential roles in regulating cellular functions of fibrosarcoma and other types of malignancy. Therefore, PGs act like regulators of signaling molecules and pathways and could be used as target molecules either for therapeutic purposes or as diagnostic molecules for pathological conditions. IGF-I is a well-established anabolic hormone with proven oncogenic properties. Most of its functions are performed through two main signaling pathways, PI3K / Akt (phosphoinositide 3-kinase/ serine/threonine kinase Akt) and that of MAPK (mitogen-activated protein kinase). Biglycan, an SLRP, has an active role in bone formation, development, and homeostasis. This study shows how biglycan regulates the growth of MG63 human osteosarcoma cells positively. IGF-I increases the expression of this SLRP, while biglycandeficient cells have attenuated both basal and IGF-I induced proliferation. These effects were mediated through the IGF-IR receptor whose activation was strongly attenuated in biglycan-deficient MG63 cells. Previously, it has been shown that biglycan regulates Wnt/b-catenin signaling pathway, and our results indicate that biglycan increases b-catenin expression in all cellular fractions due to its co-localization with Wnt co-receptor LRP6. This interaction leads to reduced degradation of b-catenin in the cytoplasm and enhances its translocation to the nucleus, where it activates the transcription of target genes, responsible for controlling the cell cycle. Besides, we have shown an interaction between b-catenin and the activated IGF-IR, which is increased upon treating MG63 cells with exogenous biglycan. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I induced ERK1/2 activation, a molecule that mediates IGF-I signaling, as we have previously reported. In summary, biglycan, through a LRP6/IGF-IR/b-catenin signaling axis, enhances osteosarcoma cell growth. In the next part of the study, it was shown that lumican is the main expressed and secreted SLRP in HTB94 human chondrosarcoma cells, while decorin and biglycan are poorly expressed. Lumican positively affects the proliferation of HTB94 cells as lumican deficiency inhibited the basal and IGFI induced HTB94 cell growth significantly. The oncogenic action of IGF-I is mediated by its receptor, IGF-IR, whose phosphorylation levels are strongly attenuated in lumican-deficient cells. Furthermore, lumican levels affect ERK1/2 activation, which seems to be crucial to IGF-I dependent HTB94 cell growth. Moreover, lumican-deficient cells exhibit increased mRNA levels of p53 suggesting that lumican facilitates chondrosarcoma cell growth through an IGF-IR/ ERK1/2/p53 signaling cascade. In summary, we show that endogenous lumican is a novel regulator of HTB94 cell growth. Finally, we studied the action of IGF-I on HT1080 fibrosarcoma cells, and our results show that it enhances their migration ability. SDC2, a transmembrane PG, appears to act as a co-receptor for IGF-I since it colocalizes with IGF-IR. Suppression of this PG expression reduces IGF-I dependent cell migration. In order to investigate how SDC2 affects this signaling pathway and consequently, IGF-I induced cell migration, we studied its role in ERK1/2 activation. Our results indicate that SDC2 is essential for ERK1/2 phosphorylation and that it is necessary for IGF-I dependent HT1080 migration. Additionally, we looked at ezrin, a protein that connects membrane receptors to the cytoskeleton and is found to be colocalized with SDC2.The formation of an immunoprecipitative complex revealed an association between SDC2 and ezrin, which was enhanced through IGF-I action in HT1080 cells. Ezrin activation is also affected by IGF-I action.To conclude, SDC2 mediates directly IGF-I-induced ERK1/2 activation; it recruits ezrin, contributes to actin polymerization, and ezrin/actin specific localization to cell membranes, ultimately facilitating the progression of IGF-I dependent fibrosarcoma cell migration. The above-described mechanisms reveal PGs's involvement in mesenchymal origin tumor progression and their interaction with the IGF-I signaling pathway to regulate basal functions of these cancer cells.
Language Greek
Subject Mesenchymal tumors
Ινσουλινόμορφος παράγοντας 1
Μικρές πλούσιες σε λευκίνη πρωτεογλυκάνες
Issue date 2020-12-17
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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