ABSTRACT
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
Subject(s)
Colorectal Neoplasms/metabolism , GPI-Linked Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/metabolism , Animals , Colorectal Neoplasms/physiopathology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/physiology , Gene Expression Regulation, Neoplastic , Genes, src , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/physiology , Mice , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Neoplastic Stem Cells/physiology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Spheroids, Cellular , Tumor Cells, CulturedSubject(s)
Anthropometry/methods , Birth Weight , Body Composition , Nutritional Status , Pediatric Obesity/etiology , Weight Gain , Female , Humans , MaleABSTRACT
OBJECTIVE: To evaluate the relationship between birth weight and rapid weight gain in infancy and markers of overweight/obesity in childhood, using different cutoff values for rapid weight gain. SUBJECTS/METHODS: Cross-sectional study involving 98 5-year old pre-school Brazilian children. Rapid weight gain was considered as weight gain in standard deviation score (SDS) above +0.67, +1 and +2 in relation to birth weight, at any time during the first 2 years of life. The nutritional status of the children was determined by anthropometry and electrical bioimpedance. Multiple linear regression analysis was used, considering fat mass percentage, body mass index (BMI), waist and neck circumferences as outcomes. RESULTS: Birth weight, rapid weight gain (assessed by different cutoff values) and maternal obesity were positively associated with increased fat mass percentage, BMI, waist and neck circumferences. Different cutoff values of rapid weight gain did not change the positive associations between rapid weight gain and fat mass percentage (>+0.67 SDS, P=0.007; >+1 SDS, P=0.007; >+2 SDS, P=0.01), BMI (>+0.67 SDS, P=0.002; >+1 SDS, P=0.007; >+2 SDS, P<0.001), waist circumference (>+0.67 SDS, P=0.002; >+1 SDS, P=0.002; >+2 SDS, P<0.001) and neck circumference (>+0.67 SDS, P=0.01; >+1 SDS, P=0.03; >+2 SDS, P<0.001). CONCLUSIONS: The use of different cutoff values for the definition of rapid weight gain did not interfere in the associations between birth weight and rapid weight gain with fat mass percentage, BMI, waist and neck circumferences. Children with the highest birth weight, those who undergo rapid weight gain in infancy and whose mothers were obese, seemed to be more at risk for overweight/obesity.
