A multi-institutional study found that colorectal cancer tumors displayed a significant imbalance in lipid mediators, showing a proinflammatory bias with minimal inflammation-resolving activity. The research employed both targeted quantitative analysis and untargeted profiling approaches.
The analysis, published in Gut, was led by researchers from the University of South Florida Health in collaboration with multiple institutions, including Hokkaido University and the Buck Institute. The researchers examined 81 paired tumor and normal tissue samples using liquid chromatography-mass spectrometry (LC-MS/MS). The investigation found that colorectal cancer (CRC) tumors contained elevated levels of proinflammatory mediators, particularly 5-HETE and its leukotriene derivatives (LTB4, LTC4, LTD4, and LTE4), while edxhibiting low levels of inflammation-resolving mediators such as lipoxins (LXA4, LXB4).
The researchers observed decreased levels of prostaglandins PGD2 and PGE2 in approximately 70% of the tumor samples compared with matched normal tissue. Additionally, genes encoding key PGE2 receptors (PTGER2, 3, 4) showed significantly reduced expression in tumor tissue. These prostaglandins are involved in "lipid class switching," a process that transitions from proinflammatory to inflammation-resolving states during wound healing.
Analysis of public single-cell RNA sequencing data from 62 patients revealed that tumor-associated macrophages in the tumor microenvironment (TME) were the main source of pro-inflammatory lipid mediator production. The integration of lipidomic findings with targeted, single-cell, and spatial transcriptomics analyses confirmed this pattern.
The analysis demonstrated that genes responsible for producing proinflammatory mediators (ALOX5, ALOX5AP, and LTA4H) showed higher expression in tumor tissue, whereas genes involved in inflammation resolution (ALOX12 and ALOX15) showed low expression. The study included samples from both colon (80%) and rectal (18%) tumors, comprising primary (85%) and metastatic (13%) cases. The patient cohort included various disease stages, with most being stage II to IV and microsatellite stable, in patients aged 30 to 85 years.
These findings suggested potential new therapeutic approaches for colorectal cancer through "resolution medicine"—either inducing the body's own resolution mechanisms or providing resolving mediators that could help break the cycle of chronic inflammation driving cancer growth.
Potential conflict of interest disclosures can be found in the study.
