Resumen de Abordaje molecular y computacional al nexo entre nutrición y cáncer
Several studies indicate that cancer is strongly associated with diet, in fact, diet constitutes an important risk factor in some types of cancer such as those related to the digestive system. Precision nutrition based on adapting nutrients or incorporating bioactive compounds to the specific individual circumstances, can contribute to a better comprehensive treatment of the disease, either by helping to inhibit its progression or by improving the effects associated with the use of chemotherapy.
This thesis analyzes the transcriptome of 1273 colorectal cancer patients to identify genes related to cellular sensing or metabolism of nutrients that are also associated with patient prognosis or survival. An integrative analysis identified two groups of genes whose differential expression (overexpression or repression) correlates with low survival in late stages of the disease (III and IV). The ten differentially expressed genes that show best association with poor prognosis in colorectal cancer are: DCBLD2, PTPN14, LAMP5, TM4SF1, NPR3, LEMD1, LCA5, CSGALNACT2, SLC2A3 and GADD45B. In addition, the 3-gene signature SLC2A3, NPR3 and LCA5 seems to be a strong survival marker related to nutrition, especially relevant in early stages I and II (HR: 3.60; CI: 3.43-3.77; p-val.:0.00187]).
This thesis also investigates two strategies based on precision nutrition with the intention of identifying its implication in the inhibition of cell viability, tumor growth and metastases development. At the molecular level, a strategy based on the inclusion of bioactive compounds in the diet is analyzed in colorectal cancer, a type of cancer that frequently correlates with malnutrition of patients. By means of a screening of several phenolic compounds and derivatives, 4,4 'Di-O-methyl ellagic acid is identified as a potent agent inhibiting cell proliferation in various colorectal cancer cell lines including a line resistant to 5-Fluorouracil. It is found that the inhibition of cell viability is mediated by the down regulation of Wnt16, a gene that signals various pathways involved in normal cell growth and proliferation during embryogenesis, carcinogenesis and chemotherapy resistance. Additionally, this work analyzes a second precision nutrition strategy centered in the restriction of nutrients in breast cancer, a type of cancer that frequently correlates with patient overweight and metabolic syndrome. More specifically, this Thesis explores the implication of an intervention with intermittent fasting cycles and two different diets (standard diet and plant-based diet) in tumor progression and metastasis development. It is identified that the intermittent fasting in young Balb/c female mice with induced breast cancer, decreases the size of the tumors regardless of the type of diet tested. In addition, it is found that mice subjected to intermittent fasting under the conditions analyzed here, show higher metastatic burden in the lung. This event occurs irrespective of the composition of the diet applied in the experiment.
