| Author(s): |
Débora Campanella Bastos
Total Authors: 1
|
| Document type: | Master's Dissertation |
| Press: | Piracicaba, SP. , ilustrações. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba |
| Defense date: | 2009-02-26 |
| Examining board members: |
Edgard Graner;
Ana Lúcia Carrinho Ayroza Rangel;
Jacks Jorge Junior
|
| Advisor: | Edgard Graner |
| Field of knowledge: | Health Sciences - Dentistry |
| Indexed in: | Base Acervus-UNICAMP; Biblioteca Digital da UNICAMP |
| Location: | Universidade Estadual de Campinas. Biblioteca Central Cesar Lattes; T/UNICAMP; B297e; Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba. Biblioteca Prof. Dr. Carlos Henrique Robertson Liberalli; T/UNICAMP; B297e |
| Abstract | |
Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous biosynthesis of fatty acids. FASN is overexpressed in several malignant neoplasms and its activity seems to be necessary for the synthesis of membrane phospholipids in the tumor cells. The drug orlistat (Xenical ®), which is clinically used for the treatment of obesity, have shown anti-cancer properties in prostate and breast cancer and melanoma due to its ability to specifically block FASN activity. It was recently demonstrated that treatment of endothelial cells with orlistat blocks the synthesis of fatty acids and inhibits the proliferation and neovascularization. The lymphatic system is the component of the blood circulation responsible for the drainage of interstitial fluid, what is essential to the function of the immune system. Lymphatic vessels are also the primary route of metastasis in several malignancies such as melanoma, wich is originated in the skin or mucous membranes and shows high rates of metastasis and resistency to chemotherapy. Lymphangiogenesis is initiated by the release of growth factors that induce the proliferation and increased permeability of lymphatic endothelial cells. The growth factors VEGF-C and VEGF-D and their receptors VEGFR-2 and VEGFR-3 have been related with tumor progression. There is a positive correlation between lymphangiogenesis and the presence of metastasis in sentinel lymph nodes. An inverse correlation between lymphangiogenesis and disease-free survival has also been described, suggesting that lymphatic vessels could be a target against metastasis. We have shown, in a recent study done by our group, that the orlistat treatment was able to reduced by 50% the number of experimental melanoma metastasis to mediastinal lymph nodes. Since there is no information in the literature about the effect of FASN inhibition on lymphangiogenesis, the purpose of this work was to study the consequences of the orlistat treatment in lymphatic neoformation by using two experimental models. In the first, B16-F10 murine melanoma cells were injected in the ears of C57Bl6 mice in order to inducelynphangiogenesis around the tumors. In the second model, circular wounds were done in the ears of Balb-C mice to induce a local inflammatory reaction and lymphangiogenesis. Lymphatics vessels were observed with the aid of fluorescent microlymphangiography, that allows the observation of the lymphatic vessels by intradermal injection of a solution of 1% of FITC- conjugated dextran. The extension of the lymphatic network was determined by using the Scion Image software. The density of lymphatic vessels significantly increased in both Balb-C and C57Bl6 mice treated with orlistat in comparison to the controls. Moreover, the size of the primary tumors and metastastic lymph nodes were measured and their volumes calculated. In summary, our results show that the inhibition of FASN with orlistat increases the extension, branching and/or permeability of the lymphatics vessels in the peritumoral region and around surgical wounds. (AU) | |