Carcinona epidermóide é um prevalente tumor de cabeça e pescoço relacionado a altas taxas de mortalidade. Neste trabalho, verificamos se AG73 (RKRLQVQLSIRT, cadeia a1), peptídeo derivado da laminina-111, regula migração, invasão e secreção de protease em células de carcinoma epidermóide oral (OSCC). Cadeia a1 da laminina e MMP9 estão expressas neste tumor in vivo e in vitro. AG73 induziu aumento da taxa migratória de células OSCC em ensaios de ferida e migração, e também estimulou invasão em ensaio em câmaras bipartites com Matrigel. Células OSCC crescidas sobre AG73 exibiram aumento dose-dependente de MMP9, detectado por zimografia. Buscamos receptores de AG73 que regulariam atividade nesta linhagem. Células OSCC crescidas sobre AG73 exibiram colocalização de sindecana-1 e integrina b1, e silenciamento desses receptores com RNA de interferência promoveu diminuição de migração e invasão dependente de AG73 nestas células. Esses resultados sugerem que sindecana-1 e integrina b1, ativados por AG73, podem regular migração, invasão e secreção de MMPs em células OSCC. / Oral squamous cell carcinoma is a prevalent head and neck tumor, related to high mortality rates. Here we studied the role played by AG73 (RKRLQVQLSIRT, a1 chain) on migration, invasion and protease secretion of a cell line (OSCC) from human oral squamous cell carcinoma. Laminin a1 chain and MMP9 are expressed in oral squamous cell carcinoma cells in vivo and in vitro. AG73 increased migratory activity of OSCC cells, as shown by monolayer wound assays and migration assays. This peptide also stimulated cell invasion in chemotaxis chambers coated with Matrigel. OSCC cells cultured on AG73 showed a dose-dependent increase of MMP9 secretion, detected by zymography. We searched for AG73 receptors regulating activities in this cell line. OSCC cells grown on AG73 exhibited colocalization of syndecan-1 and b1 integrin, and siRNA knockdown of these receptors decreased AG73-dependent migration and invasion of OSCC cells. Our results suggest that syndecan-1 and b1 integrin signaling downstream of AG73 regulate migration, invasion and MMP secretion by OSCC cells

A terapia fotodinâmica (TFD) é uma modalidade clínica para tratar uma variedade de neoplasias, doenças de pele e representa um promissor tratamento estético. O presente trabalho avaliou os aspectos histopatológicos e moleculares do tratamento pela TFD mediada por azul de metileno (TFD-AM) no modelo experimental in vivo do Carcinoma Espinocelular Cutâneo (CEC) e na pele sadia de camundongos Swiss. O protocolo da TFD foi de uma única sessão, com aplicação da solução de AM a 1% seguido por irradiação com laser diodo na dose total de 24 J/cm2 nos tecidos tumorais e sadios. Os animais foram sacrificados em dois períodos, 24 horas e 15 dias após TFD. Alterações morfológicas foram pouco marcantes nos tecidos tumorais tratados, entretanto, foram mais pronunciadas nos tecidos sadios. Podemos concluir que os efeitos de uma única sessão da TFD mediada pelo AM na dose aplicada não conferiu melhora no tratamento do CEC. Estes resultados motivam novos estudos com ajustes no protocolo para melhorar a eficácia desta terapia. / Photodynamic therapy (PDT) is a clinical method for treating a variety of tumors, skin disorders and represents a promising cosmetic treatment. This study evaluated the histopathological and molecular aspects of the treatment by PDT mediated by methylene blue (PDT-MB) in vivo experimental model of cutaneous squamous cell carcinoma (SCC) and in healthy skin of swiss mice. The PDT protocol was a single session with the application of MB 1% solution followed by irradiation with diode laser at a total dose of 24 J/cm2 in tumor and healthy tissue. The animals were sacrificed at two periods, 24 hours and 15 days after PDT. Morphological changes were less marked in the tumor tissues treated, however, were more pronounced in healthy tissues treated. We can conclude that the effects of a single session of PDT mediated by MB in applied dose conferred no improvement in the treatment of SCC. These results motivate further studies with adjustments in the protocol to improve the effectiveness of this therapy.

No description available.

Background: Psoas abscess is a rare clinical disease of various origins. Most common causes include hematogenous spread of bacteria from a different primary source, spondylodiscitis or perforated intestinal organs. But rarely some abscesses are related to malignant metastatic disease. Case presentation: In this case report we present the case of a patient with known squamous cell carcinoma of the cervix treated with radio-chemotherapy three years prior. She now presented with a psoas abscess and subsequent complete inferior vena cava thrombosis, as well as duodenal and vertebral infiltration. The abscess was drained over a prolonged period of time and later was found to be a complication caused by metastases of the cervical carcinoma. Due to the massive extent of the metastases a Whipple procedure was performed to successfully control the local progress of the metastasis. Conclusion: As psoas abscess is an unspecific disease which presents with non-specific symptoms adequate therapy may be delayed due to lack of early diagnostic results. This case report highlights the difficulties of managing a malignant abscess and demonstrates some diagnostic pitfalls that might be encountered. It stresses the necessity of adequate diagnostics to initiate successful therapy. Reports on psoas abscesses that are related to cervix carcinoma are scarce, probably due to the rarity of this event, and are limited to very few case reports. We are the first to report a case in which an extensive and complex abdominal procedure was needed for local control to improve quality of life.

This thesis is focused on the epithelial mesenchymal interactions in tumors derived from squamous epithelium including tumors arising from minor cell population (melanocytes). This study is also reflecting aspects of epithelial glycobiology resp. the study of endogenous lectins, the galectins, in head and neck squamous carcinomas. Galectins represent, in the current concepts of cell and tumor biology molecules with a remarkable potential. Galectins participate, besides in regulation of pre- and postnatal homeostasis in normal tissues, also in many pathological processes such as autoimmune reactions or malignancies. In this thesis, we demonstrated the presence of galectin-1 and -2 and their glycoligands in interphasic and mitotic nuclei, which may contribute to regulation of the cell cycle. Furthermore, we demonstrated galectin-9 as a sensitive marker of transformation normal to the dysplastic squamous epithelium in head and neck. The epithelial mesenchymal interactions represent mechanisms, which are responsible for dynamic maintenance of the homeostasis of the organism during prenatal development, postnatal growth and during cyclic renewal of certain tissues. These interactions also participate in wound healing. On the other hand they play a crucial role in the process of tumor transformation,...

Das orale Plattenepithelkarzinom ist der weltweit häufigste Tumor der Mundhöhle und des Rachens. Das Ziel dieser retrospektiven Studie war die Evaluation der Treffsicherheit der flüssigkeitsbasierten oralen Bürstenbiopsie als Screening-Methode für das orale Plattenepithelkarzinom. Bei der Bürstenbiopsie handelt es sich um ein Verfahren, das ursprünglich aus der Gynäkologie kommt und dort schon seit Jahrzehnten erfolgreich als Abstrich-Methode eingesetzt wird. Die orale Bürstenbiopsie dient der Gewinnung von Zellen aus klinisch suspekten Läsionen der Mundhöhle, in dieser Studie unter Verwendung des Zellkollektors 'Orcellex'. Die Bürste wird mit Druck etwa zehn Mal auf der zu untersuchenden Läsion rotiert, um eine ausreichende Menge an Zellen zu gewinnen. Bei der Verwendung des flüssigkeitsbasierten Verfahrens wird der Bürstenkopf anschließend in ein Gefäß mit alkoholbasierter Flüssigkeit transferiert und die Probe in ein Labor versandt. Nach der Verarbeitung der Probe wird sie von einem erfahrenen Zythopathologen untersucht und in Wertungsgruppen eingeteilt. Lautet die Diagnose 'Positiv', so können Tumorzellen in der Probe nachgewiesen werden, 'Mit dringendem Verdacht' bedeutet, dass das Vorliegen von bösartigen Zellen sehr wahrscheinlich ist, 'Zweifelhaft', dass das Vorliegen von bösartigen Zellen nicht sicher ausgeschlossen werden kann und 'Negativ' bedeutet, dass keine Tumorzellen vorliegen. Anhand der Einteilung kann dann über das weitere Vorgehen entschieden werden. Die Ergebnisse der Studie zeigen das Vorliegen einer hohen Sensitivität und Spezifität der flüssigkeitsbasierten oralen Bürstenbiopsie. Sie ist nicht-invasiv und schnell und einfach durchzuführen und eignet sich daher optimal als Screening-Methode für das orale Plattenepithelkarzinom.:1. Einführung 1.1 Tumorentstehung 1.2 Risikofaktoren 1.3 Orale Bürstenbiopsie 1.4 Adjuvante Untersuchungsmethoden 1.4.1 DNA-Zytometrie 1.4.2 Intraorale Skalpellbiopsie mit histopathologischer Untersuchung 1.5 TNM-System 1.6 Zielsetzung und Fragestellung 2. Publikationsmanuskript 3. Zusammenfassung der Arbeit 4. Literatur 5. Darstellung des eigenen Beitrags 6. Erklärung über die eigenständige Abfassung der Arbeit 7. Lebenslauf 8. Danksagung

The immune system plays a critical role in the prevention and eradication of cancerous lesions. Indeed, cancer immunology is a rapidly growing area of study that has already generated several FDA-approved treatments and cellular therapies to address mechanisms by which various cancers evade immune clearance. Recent studies look to expand the clinical use of these current therapies and to identify novel targets for future treatments in order to meet the unmet medical needs of the cancer patient population. Recently, multiple correlative studies have identified Carabin (Tbc1d10c) as a potential biomarker for cancer prognosis, including head and neck squamous cell carcinoma (HNSCC), breast cancer, and melanoma. Two mechanistic studies have shown that Carabin acts as a negative feedback inhibitor of canonical TCR and BCR signaling during lymphocyte activation. One group demonstrated that Carabin inhibits CD4+ T-cell activation by binding to and inhibiting the actions of Ras and calcineurin, leading to decreased NFAT and AP-1 transcriptional activity. The second group corroborated the impact of Carabin signaling on the Ras/MAPK pathway in B cells and implicated a role for Carabin in autoimmune diseases in both mice and humans. Collectively, these studies suggest Carabin’s potential role in chronic inflammation and as a pro-tumorigenic target in human cancers. The data presented in Chapters 2-3 demonstrate an immunosuppressive role for Carabin in tumorigenesis. Using three murine tumor models, we identified a novel cancer phenotype in immune competent germline Carabin-ablated (Carabin-/-) mice: these mice showed a twofold decrease in tumor growth and an increase in tumor-free survival compared to wild-type (Carabin+/+) mice. Further assessment identified Carabin expression localized to cells of the immune lineage within the tumor microenvironment (TME), and tumor immunophenotyping showed a twofold increase in the percent of Carabin-/- total and activated CD8+ T cells infiltrating the tumors. Carabin-/- CD8+ T cells displayed an increase in TCR activation and tumor cell killing with no impact on proliferation or migration, indicating that the identified tumor outcome phenotype is due to a suppressive action on the CD8+ TCR activation pathway. Adoptive transfer of tumor antigen-restricted CD8+ T cells into immune-deficient Rag2-/- mice led to reduction of tumor growth in mice receiving Carabin-/- CD8+ T cells. Thus, the data in Chapters 2-3 demonstrate that Carabin deficiency confers tumor resistance via increased CD8+ T-cell anti-tumor activity. This anti-tumor activity is due to an increase in basal NF-κB activity specifically within CD8+ T cells. NF-κB perturbation is the result of a twofold increase in MEKK3 (Map3k3) protein and its downstream phosphorylation of the IKK complex to activate canonical NF-κB. MEKK3 knockdown by siRNA rescued the Carabin-/- in vitro molecular and cellular phenotype without impacting Carabin+/+ CD8+ T cells, and therefore supports the assertion that Carabin signaling is mediated by downstream MEKK3 activity. The NF-κB pathway is critical for T-cell activation and effector function. NF-κB perturbation was selective to CD8+ T cells and not found in CD4+ T cells. Thus, Carabin may be a novel target to mediate NF-κB signaling specifically in CD8+ T cells to improve their effector function within the TME without simultaneously impacting NF-κB in neoplastic or immunosuppressive cells. This is the first study to identify a causative link between Carabin and solid tumor malignancies, to demonstrate a unique mechanism for Carabin in the CD8+ T-cell response to tumorigenesis, and to suggest Carabin as a novel CD8+ T-cell-specific NF-κB inhibitor.

Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. They are associated with high morbidity and mortality. Despite considerable advances in surgical and oncological treatment over the past two decades, overall treatment outcome has only slightly improved. In my thesis I focused on serum gene expression analysis of head and neck cancer patients, which followed the tissue gene expression analysis in same patients. Further we investigated gene expression analysis in tumour stroma, which is now considered as significant factor in cancer initiation and progression. We revealed several candidate genes, which are involved in signalling pathways connected with cell differentiation and proliferation and are involved in apoptotic pathway (BCl-2, BCl-XL a MAX). As well we detected down-regulation of the main tumour suppressor p 53 protein. In peritumoural tissue we detected overexpression of cytokines typical for embryonal development and ectoderm differentiation - IGF-2 and BMP-4, which significantly influence the phenotype of normal keratinocytes. Further we identified several candidate genes relating with overexpression of Gal-1 in stromal myofibroblasts rich tissue (SPIN1, FUSIP1, TRIM23, SLC25A40, PTPLAD1, MP3K2). HNSCC is a heterogeneous disease despite the presence of...

This thesis is focused on the epithelial mesenchymal interactions in tumors derived from squamous epithelium including tumors arising from minor cell population (melanocytes). This study is also reflecting aspects of epithelial glycobiology resp. the study of endogenous lectins, the galectins, in head and neck squamous carcinomas. Galectins represent, in the current concepts of cell and tumor biology molecules with a remarkable potential. Galectins participate, besides in regulation of pre- and postnatal homeostasis in normal tissues, also in many pathological processes such as autoimmune reactions or malignancies. In this thesis, we demonstrated the presence of galectin-1 and -2 and their glycoligands in interphasic and mitotic nuclei, which may contribute to regulation of the cell cycle. Furthermore, we demonstrated galectin-9 as a sensitive marker of transformation normal to the dysplastic squamous epithelium in head and neck. The epithelial mesenchymal interactions represent mechanisms, which are responsible for dynamic maintenance of the homeostasis of the organism during prenatal development, postnatal growth and during cyclic renewal of certain tissues. These interactions also participate in wound healing. On the other hand they play a crucial role in the process of tumor transformation,...

Diagnosis of laryngeal and hypopharyngeal cancer is often in advanced stages of cancer, resulting in elimination of the possibility of treatment with the least mutilating effect for the patient. The huge progamination. ress in diagnostic process of mucosal tumors of the head and neck has been started with the development of new optical endoscopic imaging methods that are able to visualize initiating discrete mucosal changes with pathological vascularization easier and more accurately. The aim of this dissertation is to evaluate the benefit of Narrow Band Imaging (NBI), especially in the differentation of benign, precancerous and malignant changes in three groups of patients, it means in preoperative diagnostics in outpatient department (group I), during the endoscopic surgery (group II) and also in follow-up of patients after curative radiotherapy (group III). The vascular changes within the observed lesion or in close contact with the laryngeal/hypopharyngeal lesion were classified according to two classifications (Ni and Arens) and subsequently correlated with the histopathological results. The dissertation confirmed that NBI plays a key role in early detection of precancerous and malignant changes, in discrimination between benign and malignant vascular patterns with statistical significance. We...