La glycosylation est un processus enzymatique permettant l'ajout de sucres à des composés (sucres, lipides ou protides), modifiant ainsi leurs propriétés. La glycosylation est impliquée dans la détoxification des xénobiotiques et des variations d'activité des enzymes responsables ont été identifiées comme facteur de risque de cancer en particulier dans les organes exposés aux xénobiotiques. Dans la première partie de notre travail nous étudions l'impact des polymorphismes génétiques de certaines enzymes responsables de la détoxification (UGT1A7, GST et XRCC1) sur le risque de carcinome hépatocellulaire. Nous montrons que la combinaison de certains polymorphismes génétiques peut entraîner une augmentation du risque de CHC. Des modifications d'expression des glycoprotéines de surface ont été observées dans les cellules cancéreuses jouant un rôle dans leurs interactions avec le microenvironnement. Dans la seconde partie, nous étudions l'effet de l'inhibition des interactions des cellules de CHC/cellules endothéliales par le blocage du couple sialyl Lewis x/E-sélectine sur la croissance tumorale. Ce blocage est obtenu, d'une part par transfert du gène de la Fucosyl-transferase I, inhibant l'expression de sLex à la surface des cellules de CHC, et d'autre part, par utilisation de cimétidine ou d'amiloride permettant une inhibition de l'expression de la E-sélectine par les cellules endothéliales. Nous obtenons une inhibition de la croissance tumorale in vivo par blocage de la néoangiogénèse. Ces travaux permettent donc d'identifier des facteurs de risque génétiques de CHC et d'envisager une autre voie de traitement du CHC. / Glycosylation is an enzymatic process that consists of the addition of glycosyl groups to compounds (sugars, lipids or proteins), thus modifying their properties. Glycosylation is involved in the detoxification of xenobiotics and variations in activity of enzymes responsible have been identified as a potential risk factor for cancer in particular in organs in contact with the external environment. In the first part of our work we study the impact of polymorphisms of detoxification enzyme (UGT1A7, GST and XRCC1) on the risk of hepatocellular carcinoma. We show that the combination of genetic polymorphisms of such enzymes may increase the risk of HCC. Modifications in the expression of surface glycoproteins have been observed in cancer cells and play a role in their interactions with the tumoral microenvironment. In the second part, we study the effect of inhibition of interactions of HCC cells / endothelial cells on tumor growth by blocking the interaction between sialyl Lewis x and E-selectin. First, we achieved the inhibition of the expression of sLex on the surface of HCC cells by introducing fucosyl transferase- I gene in HCC cells. In a second part of our work we used cimetidine and amiloride to inhibit the expression of E-selectin by endothelial cells. This approach resulted in inhibition of HCC cells / endothelial cells interaction and thereby tumor growth inhibition in vivo. This effect is mediated by an inhibition of tumor neoangiogenesis. This work therefore identifies genetic risk factors for HCC and allows considering another way of treatment of HCC.

Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest. The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered. The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells. Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth. This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.