Search

Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function. • Iron increases intracellular glucose accumulation in colon tumor cells. • Iron increases glycolysis via inhibiting PDH complex function in colon tumor cells. • Iron increases PDHE1α Ser293 phosphorylation via directly binding with PDHK3 that is abundant in human colon tumors. • Iron is required for TNKS activity to suppress Axin2-AMPK-PDH signaling. • Inhibition of GLUT1 or PDHK reactivates PDH complex function and reduces iron-driven colon tumorigenesis. [ABSTRACT FROM AUTHOR]

Context.-- Metastatic mucinous tumors present a diagnostic challenge for pathologists as tumor histomorphology is often nonspecific and optimal immunoprofiles are still under investigation. Objective.-- To present a head-to-head comparison of special AT-rich sequence-binding protein 2 (SATB2) and caudal type homeobox 2 (CDX2) expression in a diverse array of primary mucinous tumors. Design.-- SATB2 and CDX2 immunohistochemical stains were performed on whole sections from 44 mucinous colorectal carcinomas and 175 noncolorectal mucinous tumors. A nuclear scoring system measuring intensity (0--3+) and percentage staining (0 = <5%, 1 = 5%--49%, 2 = ≥50%) was implemented, producing an additive histologic score (H-score). Results.-- SATB2 demonstrated acceptable accuracy at low to moderate expression levels (H-scores of 1--4). With these H-score cutoffs, overall accuracy was greater than 90%. In contrast, CDX2's accuracy rivaled that of SATB2 only at an H-score of 5 (89.0%), as its specificity suffered at lower expression levels (<70.0% at H-scores of 1--4). Using a moderate H-score cutoff of 3 or higher, significant differences for both sensitivity and specificity were identified between SATB2 and CDX2 (P = .01 for sensitivity and P < .001 for specificity), though these stains were near equivalent when each was interpreted as positive at its respective optimal H-score (SATB2 ≥ 3 and CDX2 = 5). Conclusions.-- SATB2 is a more accurate marker of colorectal origin across a variety of expression levels compared with CDX2 when applied to mucinous tumors from a host of primary sites. However, these stains are near equivalent when each is interpreted at its optimal expression level. [ABSTRACT FROM AUTHOR]