IL-12, an immunoregulatory cytokine, plays a key role in the development of cell-mediated immune responses. However, very little is known about the regulation and induction of the other members of this family, particularly IL-23 and IL-27. The regulation of these cytokines was studied in the human primary monocytes and monocyte-derived macrophages (MDMs) as they play a key role in innate and adaptive immune responses. THP-1 promonocytic cells were employed as a model system to confirm the results obtained with monocytes and MDMs. Two stimuli IFN-γ and LPS were used as both are strong inducers of IL-12 family cytokines. My results show that IFN-γ induced the production of IL-12/23p40 and IL-23p19 mRNA as well as IL-12p40 and IL-23 proteins in primary human monocytes isolated by positive selection. IFN-γ-induced IL-23 and IL-12/23p40 expression was positively regulated by the p38 mitogen-activated protein kinases (MAPK), independent of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling. In contrast, IL-12 and IL-23 were negatively regulated by the Jak/STAT, phosphoinositide-3 kinase (PI3K) and the c-Jun-N-terminal kinase (JNK) MAPKs in IFN-γ-stimulated monocytes. LPS significantly stimulated IL-23p19 and IL-12/23p40 mRNA expression as well as IL-12/23p40 and IL-23 protein production in THP-1 cells, while IFN-γ stimulation alone did not affect IL-23 mRNA or protein levels. THP-1 cells were pre-treated with ERK, JNK or p38 MAPK inhibitors and then stimulated with LPS. LPS-induced IL-12p40 and IL-23 proteins were positively regulated by the p38 and JNK MAPKs and PI3K, whereas LPS-induced IL-23p19 mRNA expression was negatively regulated by these kinases. These results were confirmed using siRNA in LPS-stimulated THP-1 cells. My results also show that IFN-γ/LPS-induced IL-23 expression is not regulated through MAPK or PI3K signaling pathways in human MDMs. My results also show for the first time that IFN-γ alone without any second stimulus induced IL-27p28 gene expression and IL-27 protein production in human monocytic cells. I investigated the signalling pathways governing the regulation of IL-27 protein and its subunit IL-27p28 following stimulation with IFN-γ in primary human monocytic cells. IFN-γ-mediated IL-27 protein, but not IL-27p28 gene expression was positively regulated by JNK MAPK and PI3K, independent of JAK/STAT signaling in primary human monocytes. I also investigated the signalling pathways governing the regulation of IL-27 and its α subunit, IL-27p28 following stimulation with IFN-γ alone or IFN-γ-primed LPS-stimulated macrophages (IFN-γ/LPS) and THP-1 cells. A differential regulation of IL-27p28 and IL-27 in response to stimulation by either IFN-γ or IFN-γ/LPS was observed. IFN-γ- and IFN-γ/LPS induced IL-27 expression was positively regulated by the JNK, p38 MAPK and PI3K, independent of Jak/STAT signaling in human MDMs and THP-1 cells. Taken together, my results show that IL-23 induction is differentially regulated by different pathways in response to different stimuli, whereas IL-27 expression is regulated by JNK, p38 MAPK and PI3K regardless in the stimulus in human myeloid cells. These results may provide additional strategies aimed at targeting disease, autoimmune disorders and cancer.

Colorectal cancer (CRC) is the fourth most common cause of cancer related deaths in the UK with the prognosis dependent on the degree of tumour invasion and presence of metastasis at diagnosis. An important step in the invasion and metastasis of solid tumours is the loss of cell-cell junctions and the acquirement of a more motile mesenchymal phenotype which is facilitated by the epithelial-mesenchymal transition (EMT). The presence of EMT is linked with a more aggressive, invasive tumour and subsequent poor prognosis. In addition to roles in motility and invasion, EMT can induce a cancer stem cell phenotype in a subset of tumour cells. Cancer stem cells (CSCs) are a subpopulation of cells capable of self-renewal and maintaining a cellular population whilst displaying increased therapeutic resistance. Induction of EMT and CSCs can be regulated by common signalling pathways with expression of EMT transcription factors inducing CSCs expression. Understanding the signalling pathways regulating EMT and CSC formation in cancer is important for preventing of metastasis and combating therapeutic resistance. Aspirin’s role in cancer prevention has been established for a number of years with aspirin treatment reducing the incidence of CRC. Recently, evidence has emerged suggesting aspirin treatment may have post-diagnosis benefits and increase survival rates of CRC patients. A potential mechanism for the post-diagnosis benefit of aspirin is the inhibition of EMT and CSC formation which both facilitate tumour progression and metastasis. Aspirin has been demonstrated to suppress the migratory and invasive capacity of lung cancer cell lines by inhibiting EMT. Whilst aspirin has been shown to inhibit platelet-induced EMT in CRC, the direct effects of aspirin on EMT in CRC cell lines has not been established. I hypothesis that aspirin inhibits cell migration, invasion and EMT in CRC which results in a reduction in the CSC population and contributes to the clinical benefit of post-diagnosis aspirin. Using CRC cell lines, I have demonstrated that aspirin treatment inhibits cell migration, invasion, motility and promotes an epithelial phenotype. These results have been confirmed in human organoids and mouse intestinal adenoma in vivo models. Aspirin also promotes a budding phenotype in Apc deficient organoids and reduces expression of stem cell markers in both mouse and human tissue. Aspirin inhibits the mTOR and Wnt signalling pathways in vivo which have the ability to regulate EMT and CSCs although signalling dependency has not been determined. Regardless, aspirin is decreasing the cancer stem cell population and promoting a non-invasive epithelial phenotype which may explain some of the previously described post-diagnosis benefits.

Pancreatic neuroendocrine tumours (PNETs) are the most common neuroendocrine tumours diagnosed in humans and dogs. Due to the highly heterogeneous nature of these tumours, definitive data are still lacking over the molecular mechanisms involved in their cancerous behaviour. This study focused on insulinoma (INS), as it is the most commonly diagnosed PNET in human and veterinary oncology. INS is an insulin-producing tumour that causes a hypoglycaemic syndrome related to the excessive insulin production. In humans, it is often a small benign neoplasm readily curable by surgical resection whereas, in dogs, INS is often malignant. Despite current treatment modalities, malignant canine and human INS have a poor prognosis as patients tend to develop metastases in liver and lymph nodes that do not respond to current therapies. From a comparative oncology perspective, the close resemblance of canine and human malignant INS makes canine INS an interesting study model for human INS. Cancer stem cells (CSCs) are critical for the engraftment and chemoresistance of many tumours. Although CSCs have been isolated from a range of solid tumours, a comprehensive characterisation of INS CSCs has not yet been reported. In this study, it was confirmed that INS CSCs can be enriched and are potential targets for novel INS therapies. Highly invasive and tumourigenic human and canine INS CSCs were successfully isolated and exhibited greater resistance to chemotherapy, which may play a significant role in the poor prognosis of this disease. To date, the mechanisms by which tumours spread and the clinical causes of chemoresistance remain only partially understood. Here, RNA-sequencing analysis was performed over a small set of canine INS tumour samples in order to identify mechanisms involved in INS carcinogenesis through different stages of the disease. Preliminary data showed that distinct gene profiles characterised early and late stage of canine INS. Interestingly, differential gene expression and gene pathways analysis, highlighted that sets of genes involved in pancreatic embryogenesis and insulin secretion were overexpressed in canine primary INS lesions compared with normal pancreas. The Notch pathway is fundamental in pancreatic embryogenesis and it has been previously associated with carcinogenesis of neuroendocrine tumours and with the CSC phenotype. Protein analysis showed that the Notch pathway is activated in both human and canine INS CSCs, particularly when treated with chemotherapy, indicating that the Notch pathway may be involved in chemoresistance. Additionally, it was demonstrated that inhibition of the Notch pathway decreased INS CSCs' survival and chemoresistance, both in vitro and in vivo. These findings provide preclinical evidence that anti-Notch therapy may improve outcomes for patients with malignant INS.

Growing incidence of infections caused by the tick-transmitted protozoan parasite Babesia spp. defines babesiosis as an emerging disease from the aspect of human and veterinary medicine. The thesis provides an insight to biology of two main agents of human babesiosis, Babesia microti and Babesia divergens. We introduce here the fully optimized quantification model of Babesia parasite enabling the detailed investigation of the parasite developmental cycle and identification of molecules playing a role in its acquisition and transmission by the vector Ixodes ricinus. Novel and detailed information about Babesia dissemination within the tick tissues are given by newly implemented visualization and quantification techniques. Special emphasis is paid to parasite development in the tick salivary glands, the primary site responsible for parasite transmission from the vector into the host. Using gene-specific silencing we screene the tick immune pathways including effector molecules and evaluate their role in Babesia acquisition. We also provide a detailed view to Babesia parasite sexual commitment by monitoring its kinetics upon various stimuli. Moreover, a new direction of anti-babesial therapy is proposed by validation of the Babesia proteasome as a drug target. Overall, the research presented in the thesis extends the current knowledge of the Babesia parasite biology including molecular interactions at the tick-Babesia interface and thereby could significantly contribute to a potential control of babesiosis.

IL-12, an immunoregulatory cytokine, plays a key role in the development of cell-mediated immune responses. However, very little is known about the regulation and induction of the other members of this family, particularly IL-23 and IL-27. The regulation of these cytokines was studied in the human primary monocytes and monocyte-derived macrophages (MDMs) as they play a key role in innate and adaptive immune responses. THP-1 promonocytic cells were employed as a model system to confirm the results obtained with monocytes and MDMs. Two stimuli IFN-γ and LPS were used as both are strong inducers of IL-12 family cytokines. My results show that IFN-γ induced the production of IL-12/23p40 and IL-23p19 mRNA as well as IL-12p40 and IL-23 proteins in primary human monocytes isolated by positive selection. IFN-γ-induced IL-23 and IL-12/23p40 expression was positively regulated by the p38 mitogen-activated protein kinases (MAPK), independent of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling. In contrast, IL-12 and IL-23 were negatively regulated by the Jak/STAT, phosphoinositide-3 kinase (PI3K) and the c-Jun-N-terminal kinase (JNK) MAPKs in IFN-γ-stimulated monocytes. LPS significantly stimulated IL-23p19 and IL-12/23p40 mRNA expression as well as IL-12/23p40 and IL-23 protein production in THP-1 cells, while IFN-γ stimulation alone did not affect IL-23 mRNA or protein levels. THP-1 cells were pre-treated with ERK, JNK or p38 MAPK inhibitors and then stimulated with LPS. LPS-induced IL-12p40 and IL-23 proteins were positively regulated by the p38 and JNK MAPKs and PI3K, whereas LPS-induced IL-23p19 mRNA expression was negatively regulated by these kinases. These results were confirmed using siRNA in LPS-stimulated THP-1 cells. My results also show that IFN-γ/LPS-induced IL-23 expression is not regulated through MAPK or PI3K signaling pathways in human MDMs. My results also show for the first time that IFN-γ alone without any second stimulus induced IL-27p28 gene expression and IL-27 protein production in human monocytic cells. I investigated the signalling pathways governing the regulation of IL-27 protein and its subunit IL-27p28 following stimulation with IFN-γ in primary human monocytic cells. IFN-γ-mediated IL-27 protein, but not IL-27p28 gene expression was positively regulated by JNK MAPK and PI3K, independent of JAK/STAT signaling in primary human monocytes. I also investigated the signalling pathways governing the regulation of IL-27 and its α subunit, IL-27p28 following stimulation with IFN-γ alone or IFN-γ-primed LPS-stimulated macrophages (IFN-γ/LPS) and THP-1 cells. A differential regulation of IL-27p28 and IL-27 in response to stimulation by either IFN-γ or IFN-γ/LPS was observed. IFN-γ- and IFN-γ/LPS induced IL-27 expression was positively regulated by the JNK, p38 MAPK and PI3K, independent of Jak/STAT signaling in human MDMs and THP-1 cells. Taken together, my results show that IL-23 induction is differentially regulated by different pathways in response to different stimuli, whereas IL-27 expression is regulated by JNK, p38 MAPK and PI3K regardless in the stimulus in human myeloid cells. These results may provide additional strategies aimed at targeting disease, autoimmune disorders and cancer.

La glucotoxicité, ou exposition prolongée à de hautes teneurs en glucose, altère la fonction des cellules ß-pancréatiques et participe au développement du diabète. Il a été démontré que dans les cellules ß, la glucotoxicité engendre des modifications de l’expression génique, des altérations des voies de signalisation Ca2+-dépendantes et de l’exocytose ainsi qu’une augmentation de l’apoptose. Les mécanismes moléculaires responsables de ces altérations sont encore peu connus, mais ces observations suggèrent que des changements du profil d’expression génique des cellules ß-pancréatiques en sont à l’origine. Afin de mieux comprendre les conséquences de la glucotoxicité, une étude génomique a été menée dans la lignée de cellules ß-pancréatiques INS-1E. Cette étude a révélé l’existence de variations significatives des taux d’expression de plusieurs gènes importants pour la fonction des cellules ß, codant pour des protéines impliquées notamment dans le métabolisme glucidique et les différentes étapes de la voie de sécrétion d’insuline. D’autre part, cette approche a également révélé de profonds changements dans les voies de signalisation dépendantes de l’AMPc. Si le rôle prédominant du Ca2+ dans la régulation de la voie de sécrétion de l’insuline a été mis en évidence et bien caractérisé, l’implication et l’importance de l’AMPc dans ce processus restent mal définies. L’AMPc, au même titre que le Ca2+, module l’activité de nombreuses protéines de signalisation, régule l’expression génique et intervient également dans le trafic vésiculaire et la sécrétion d’insuline. De manière intéressante, l’expression de l’adénylate cyclase 8 (ADCY8) est fortement diminuée en condition de glucotoxicité. Ceci suggère qu’un défaut de synthèse d’AMPc pourrait être à l’origine du remaniement des voies de signalisation impliquées dans la régulation de la sécrétion d’insuline. Nous avons donc décidé d’étudier, plus en profondeur, les conséquences fonctionnelles de la diminution de l’expression de l’ADCY8 sur ces voies. Nos résultats suggèrent que l’ADCY8, une isoforme peu exprimée dans les cellules ß- pancréatiques? et stimulée par le Ca2+, se trouve au carrefour des voies de signalisation activées par le glucose et le GLP-1. La diminution de son expression est ainsi partiellement responsable des effets induits par la glucotoxicité sur la régulation de la sécrétion d’insuline. D’autre part, plusieurs résultats récents suggèrent l’implication des voies de signalisation AMPc-dépendantes dans la protection des cellules ß contre l’apoptose et dans ce contexte, le rôle de l’ADCY8 dans ces cellules a été abordé. / Glucotoxicity, or prolonged exposure to elevated levels of glucose, alters the function of pancreatic??-cells and is involved in diabetes pathogenesis. It has been demonstrated that glucotoxicity modifies gene expression and induces considerable changes in [Ca2+]i and in cAMP-dependent signalling (Dubois et al, Endocrinology, 148(4):1605-14 ; 2007) as well as a it decreases insulin exocytosis in response to glucose and increases apoptosis. The molecular mechanisms of these effects are not known but several observations suggest that changes in gene expression profiles are involved. To address that, a genomic study has been done in the clonal b-cell line INS-1E and revealed important modifications in the expression rates of many genes involved in glucose metabolism and vesicular traffic. This approach also revealed the alteration of cAMP-mediated signalling pathways and as the role of calcium and the importance of the correlation between cAMP and Ca2+-mediated signalling pathways had been shown, it was interesting to address the role of this second messenger in this process. Actually, cAMP regulates the activity of a large number of signalling proteins, it is also an important messenger involved in vesicular traffic, insulin secretion and gene expression. Interestingly, we also found that the expression of the adenylyl cyclase VIII (ADCY8) was largely diminished by glucotoxicity and this suggests that an alteration of cAMP synthesis could be involved in the decrease of insulin secretion in this condition. For this reason, we decided to address the functional consequences of altered ADCY8 expression on cAMP-mediated signalling pathways and on its correlation with the decrease of insulin secretion in glucotoxicity. Our results demonstrate a requirement for ADCY8 in glucose as well as in GLP-1 activated signalling pathways and strongly suggest a central role for ADCY8 in glucotoxicity. Moreover, recent publications suggest the implication of cAMP-mediated signalling pathways in the protection of b-cells against apoptosis induced by glucotoxicity, and the role of ADCY8 in this process was investigated.

Aims Toll-like receptor (TLR)-mediated signalling pathways have been implicated in myocardial ischaemia/reperfusion (I/R) injury. Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway protects the myocardium from ischaemic injury. We hypothesized that the modulation of TLR2 would induce cardioprotection against I/R injury via activation of the PI3K/Akt signalling. Methods and results Mice were treated with TLR2 ligands, peptidoglycan (PGN) or Pam3CSK4, respectively, 1 h before the hearts were subjected to ischaemia (1 h), followed by reperfusion (4 h). Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac function and haemodynamic performance were evaluated. Infarct size was significantly reduced in PGN-or Pam3CSK4-treated mice compared with untreated I/R mice. Administration of TLR2 ligands improved cardiac function following I/R. PGN treatment increased the levels of phospho-Akt and phospho-GSK-3β (glycogen synthase kinase-3β), compared with untreated I/R hearts. PGN stimulation increased TLR2 tyrosine phosphorylation and association of the p85 subunit of PI3K with TLR2. To investigate the role of PI3K/Akt signalling in PGN-induced cardioprotection, we administered the PI3K inhibitor, Wortmannin, to the mice 15 min before PGN treatment. We also administered PGN to kinase-deficient Akt (kdAkt) transgenic mice 1 h before myocardial I/R. Both PI3K inhibition and kdAkt mice abolished the cardioprotection induced by PGN. To examine the role of TLR2 in PGN-induced cardioprotection, we administrated PGN to TLR2 knockout mice 1 h before the hearts were subjected to I/R. PGN-induced cardioprotection was lost in TLR2-deficient mice. Conclusion These results demonstrate that TLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism.

Les pDCs répondent aux infections virales par la production d'IFN-α. L'élimination du virus de l'hépatite C (VHC) chez plus de 50% des patients infectés par le traitement à l'IFN-alpha suggère que les pDCs jouent un rôle majeur dans le contrôle de l'infection VHC. Les pDCs exposées aux hépatocytes infectés par VHC, produisent beaucoup d'IFN-α. Néanmoins, en dépit de cette production par TLR7 par les pDCs, VHC continue à se répliquer dans le foie infecté. J'ai approfondi les connaissances des mécanismes moléculaires d'exploration des particules de VHC et des cellules infectées par le VHC par les pDCs. J'ai ciblé ma recherche sur le contact des particules de VHC avec la surface des pDCs, sur la voie de signalisation de déclenchée, sur leur effet sur la production des IFNs et des cytokines proinflammatoires et sur la différenciation cellulaire. Nos résultats suggèrent que le virus associé aux cellules signalise dans les pDCs via un mécanisme dépendant de l'endocytose et d'IRF7 mais pas de la voie NF-κB. En dépit de l'induction d'IFN-α, le VHC associé aux hépatocytes n'induit une réponse pleinement fonctionnelle des pDCs. Les particules virales de VHC inhibent, via la fixation de la glycoprotéine E2 aux CLRs, la production d'IFN-α et d'IFN-λ dans les pDCs exposées aux hépatocytes infectés par VHC et induisent dans les pDCs, une phosphorylation rapide d'Akt et Erk1/2, d'une manière similaire au crosslinking de BDCA-2 ou DCIR. Ainsi, le blocage de BDCA-2 et de DCIR avec des fragments Fab des anticorps monoclonaux préserve la capacité des pDCs à produire des IFNs de type I et III en présence des particules virales. / Plasmacytoid dendritic cells (pDCs) respond to viral infection by production of alpha interferon (IFN-alpha), proinflammatory cytokines, and cell differentiation. The elimination of hepatitis C virus (HCV) in more than 50% of infected patients by treatment with IFN-alpha suggests that pDCs play an important role in the control of HCV infection. pDCs exposed to HCV infected hepatoma cells produce large amounts of IFN-alpha. However, despite large amounts of Toll-like receptor 7-mediated IFN-α, produced by pDCs, HCV still replicates in infected liver. During my PhD training, I went into in depth to understand the molecular mecanisms used by HCV particles and HCV infected hepatocytes to explore pDCs. I focused my research on the binding of HCV particles with the pDC surface, on the triggered downstream signaling pathway, on the cellular differentiation. Our results suggest that cell-associated HCV signals in pDCs via an endocytosis-dependent mechanism and IRF7 but not via the NF-kappaB pathway. In spite of IFN-alpha induction, cell-associated HCV does not induce a full functional response of pDCs. HCV particles inhibit, via binding of E2 glycoprotein to CLRs, production of IFN-α and IFN-λ in pDCs exposed to HCV-infected hepatocytes, and induce in pDCs a rapid phosphorylation of Akt and Erk1/2, in a manner similar to the crosslinking of BDCA-2 or DCIR. Blocking of BDCA-2 and DCIR with Fab fragments of monoclonal antibodies preserves the capacity of pDCs to produce type I and III IFNs in the presence of HCV particles.

Das Leben und Überleben einer Zelle wird auf verschiedenen Ebenen streng reguliert. Diese Ebenen sind eng miteinander verknüpft: (i) Signalwege leiten extrazelluläre Signale in den Zellkern, wo (ii) Genregulation sie zu Proteinen übersetzt, und (iii) Proteine kontrollieren metabolische Funktionen, die Nährstoffe zu Energie und zellulären Bausteinen konvertieren. Diese Systeme sind hochkomplex und werden oft nur einzeln betrachtet. Systembiologie ist ein interdisziplinäres Forschungsgebiet, das Methoden anbietet, um Informationen aus heutigen Hochdurchsatz-Experimenttechnologien zu extrahieren. Diese Methoden können effektiv sein, um die vorgenannten Systeme einzeln oder im Ganzen zu untersuchen. In dieser Doktorarbeit wende ich Methoden an, um Signalwege und Zellmetabolismus zu erforschen, und ich präsentiere neue Arbeitsabläufe für das Modellieren und Analysieren dieser Systeme. Beide Methoden sind auf großskalige Netzwerkrekonstruktionen fokussiert. Da die Erhältlichkeit von xperimentellen Daten eines der größten Probleme der Systembiologie darstellt, befassen sich die Methoden explizit mit dem Umgang mit Wissenslücken. Sie werden auf den Snf1 Signalweg und den Metabolismus von Hefezellen angewendet und vermitteln neue Erkenntnisse über diesen Modellorganismus. Des Weiteren präsentiert diese Arbeit eine eingehende Analyse vom metabolischen Reprogrammieren in Darmkrebszellen, welche bisher unbekannte Zusammenhänge von metabolischer Funktionalität und Onkogenen beinhaltet. Zum Abschluss stelle ich unseren Vorschlag für ein standardisiertes Datenaustauschformat vor, welches seinen Schwerpunkt auf Datentabellen der Systembiologie legt. Zusammenfassend behandelt diese Doktorarbeit die Signalwege und den Metabolismus von Zellen, inklusive neuer Modellierabläufe und biologischer Erkenntnisse. Diese Erkenntnisse werden in den Kontext unseres aktuellen Wissensstandes gesetzt und darauf aufbauend werden neue potentielle Ansatzpunkte für Experimente vorgeschlagen. / Cellular life is governed on different layers of regulation, which are tightly interconnected: (i) Signalling pathways transmit extracellular signals to the cells’ nucleus, where (ii) gene regulation translates these signals into proteins, and (iii) proteins control metabolic functions, which convert nutrients to energy and cell building blocks. Due to the complexity of each of these systems, they are often analysed individually or only partially. Systems Biology is an interdisciplinary field of research that offers techniques to harvest the information of todays high-throughput experiments. These techniques can be powerful approaches to investigate the aforementioned regulatory layers of a cell either individually or as a whole. In this thesis, I am employing means of Systems Biology to explore signalling pathways and metabolism, and I provide novel workflows for modelling and exploring these systems. Both workflows are focussed on accurate large-scale network reconstructions of the target system. Since one of the major problems in Systems Biology is the availability of experimental data, the workflows put emphasis on the handling of knowledge gaps. They are applied on the Snf1 pathway and metabolism in yeast and provide new findings about this model organism. Furthermore, this thesis presents an in-depth analysis of metabolic reprogramming in colorectal cancer cells, which yields previously unknown coherences of metabolic function and oncogenes. Finally, I am presenting a proposal for a standardised data format in Systems Biology, which is based on data tables. In summary, this thesis comprises works on signalling pathways and cell metabolism, which includes novel modelling workflows and new biological findings, analyses their impact on the scientific state of the art, and proposes directions for new experimental targets.

Το φαινόμενο της επιθηλιακής προς μεσεγχυματική μετατροπή είναι μια διδικασία που λαμβάνει χώρα κατά την εμβρυογένση και αφορά στη μετατροπή του φαινοτύπου των επιθηλιακών κυττάρων σε μεσεγχυματικά.Το φαινόμενο αυτό βρέθηκε ότι επανενεργοποιείται κατά τη διαδικασία της καρκινογένεσης και μετέχει στην ανάπτυξη των μεταστάσεων.Στην ανάπτυξη αυτού του φαινομένου συμβάλει η ενεργοποίηση μια σειρά απο σηματοδοτικά μονοπάτια / Epithelial to mesenchymal transition in carcinogenesis and metastasis.