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Impact of factors related to the expression of hypoxia (HIF1 and VEGF), lipid metabolism (LXRA, LXRB and PPARG) and inflammatory infiltration in colon tumors clinical stage II and III

Grant number: 10/18843-6
Support type:Regular Research Grants
Duration: February 01, 2011 - January 31, 2013
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Ademar Lopes
Grantee:Ademar Lopes
Home Institution: Hospital A C Camargo. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Assoc. researchers: Adriano Carneiro da Costa

Abstract

Significant advances have been made in the study of colon cancer in recent years. A deeper understanding of the molecular basis for this disease, along with the development of new therapeutic approaches, has dramatically changed the way patients are conducted. The single most important prognostic factor for these tumors is the staging. We will study prognostic factors in our work not yet reported in the literature, such as inflammatory infiltration, hypoxemia and specific receptors in lipid metabolism in colon cancer stage II and III. We will not study the stages I and IV, due to changes in the way of treating these tumors in recent years, it will interfere with the results for these biological markers. The condition of hypoxia in tumor microenvironment leads to activation of a factor called HIF1 (hypoxia inducible factor-1). The HIF1 is a heterodimer composed of two units, HIF1 alpha (HIF1) and HIF1 beta (HIF1B). The HIF1 is an important transcriptional regulator involved in control of energy metabolism and adaptation to cellular stress caused by oxygen deficiency. Reduced levels of cellular oxygen is a key signal for induction of angiogenesis and a major angiogenic factors regulated by hypoxia is VEGF (vascular endothelial growth factor). HIF1 activates gene expression of VEGF. HIF1 and VEGF are important regulators of angiogenesis. Knowledge of the association of tumor biology to clinical characteristics is essential for the development of anti-angiogenic therapy. PPARs are nuclear receptors that antagonize the activity of transcription factors involved in inflammation and immunity, such as nuclear factor-KB, activator protein-1 (AP1) and nuclear factor of T cells (NFAT). Three different PPAR isotypes have been identified: PPAR, PPARd / PPARb and PPARg. The PPARg is expressed by monocytes, macrophages, T cells, dendritic cells, skeletal muscle, adipocytes, and cells of the gastrointestinal epithelium and is involved in various processes, including lipid and glucose homeostasis, inflammation and differentiation of adipocytes. As PPARs (peroxisome proliferator activated receptors) comprise a family of nuclear receptors involved in regulating the immune response are potential therapeutic targets for cancer of the colon. The levels of PPAR modulate inflammation and trigger actions antiproliferative and proapoptotic in epithelial cells, however, is abundantly expressed in colon cancer cells. The LXR (Liver X Receptors) are nuclear hormone receptors and are related to lipid metabolism and is activated by intermediates of cholesterol synthesis. They regulate the metabolism of cholesterol and fatty acids, and present two forms of LXR alpha (LXRA) and beta (LXRB). Are involved in cholesterol homeostasis, acting directly on your metabolism, thereby avoiding its overload intracellularly. Are key regulators in store energy through fatty acids and trigliccerídeos in adipose tissue and liver, where they are highly expressed. The LXRs act in the following ways: 1. Inhibition of intestinal absorption of cholesterol, 2. promoting the incorporation of cholesterol in high density lipoprotein 3. stimulation of reverse cholesterol transport from peripheral tissues to the liver, and 4. activation of the conversion of cholesterol to bile salts in fígado.Além to act on cholesterol metabolism. Receptors LXRs emerge as major regulators of innate inflammatory response, acting in the release of IL and TNF by macrophages. Some studies show decreased tumor growth in breast cancer and prostate cancer when used synthetic agonist of LXRs, which promoted apoptosis of tumor cells. There are no studies in the literature relating to colon cancer and receptors LXRs. (AU)