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Epiploic Adipose Tissue (EPAT) in Obese Individuals Promotes Colonic Tumorigenesis: A Novel Model for EPAT-Dependent Colorectal Cancer Progression

ABSTRACT: The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied fat could serve as a tumor-promoting tissue and developed a novel microphysiological system (MPS) for human EPAT-dependent colorectal cancer (CRC-MPS). In CRC-MPS, obese EPAT, unlike lean EPAT, considerably attracted colon cancer HT29-GFP cells and enhanced their growth. Conditioned media (CM) from the obese CRC-MPS significantly increased the growth and migration of HT29 and HCT116 cells (p< 0.001). In HT29 cells, CM stimulated differential gene expression (hOEC867) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC867signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC867separated transcriptomes of colon cancer samples from normal with high significance (PCA,p =9.6 × 10−11). These genes, validated in CM-treated HT29 cells (p< 0.05), regulate the cell cycle, cancer stem cells, methylation, and metastasis, and are similarly altered in human colon cancer (TCGA). These findings highlight a tumor-promoting role of EPAT in CRC facilitated with obesity and establishes a platform to explore critical mechanisms and develop effective treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228532 | GEO | 2023/05/04

REPOSITORIES: GEO

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Project description:Rationale. Obesity is a risk factor for atherothrombosis and various cancers. However, the mechanisms are not completely uncovered. Objectives. We aimed to verify whether the microparticles (MPs) released from thrombin-activated platelets differed in obese and nonobese women for number, size, and proteomics cargo and the capacity to modulate in vitro the expression of genes related to the epithelial to mesenchymal transition (EMT) and the endothelial to mesenchymal transition (EndMT), and COX-2, a pro-angiogenic pathway. Methods and Results. MPs were obtained from thrombin activated platelets of four obese women and their matched, lean controls . MPs were analyzed by cytofluorimeter and protein content by liquid chromatography-mass spectrometry. Obese MPs were not different in number but were characterized by increased heterogeneity in size. In obese individuals, MPs containing mitochondria (mitoMPs) expressed lower CD41 levels and increased phosphatidylserine associated with enhanced Factor V representing a signature of a prothrombotic state. Proteomics analysis identified 44 proteins downregulated and 3 upregulated in obese versus nonobese MPs . A reduction in the proteins involved in mitophagy and antioxidant defenses, and of the -granular membrane was detected in the MPs of obese individuals. MPs released from platelets of obese individuals were more prone to induce the expression of marker genes of EMT and EndMT when incubated with HT29 cells and human cardiac microvascular endothelial cells(HCMEC), respectively. A protein, highly enhanced in obese MPs, was the pro-platelet basic protein with pro-inflammatory and tumorigenic actions. MPs from obese, but not nonobese, women induced COX-2 in HCMEC. Conclusions. Platelet-derived MPs of obese women showed higher heterogeneity in size and contained different levels of proteins relevant to thrombosis and tumorigenesis. Obese MPs presented enhanced capacity to induce changes in the expression of EMT and EndMT markers and COX-2. These effects might contribute to the increased risk for the development of thrombosis and multiple malignancies in obesity.

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Epiploic Adipose Tissue (EPAT) in Obese Individuals Promotes Colonic Tumorigenesis: A Novel Model for EPAT-Dependent Colorectal Cancer Progression

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