Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer

Abstract

BackgroundA colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response.MethodsA set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software).ResultsHere we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue.ConclusionsThe systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.

Glyceraldehyde-3-phosphate dehydrogenase is overexpressed in colorectal cancer onset

“…Gene expression profiles of these samples have been performed as described in [15] and deposited in the Gene Expression Omnibus (GEO) database [16] through accession number GSE44076.…”

“…An independent dataset comprising a set of 98 paired adjacent-normal and tumour tissues from CRC patients (196 samples in total) were included in this work (Colonomics project [15], CLX-: www.colonomics.org; NCBI BioProject PRJNA188510). Patients were selected to form a homogeneous clinical group of stage II, microsatellite stable (MSS) colorectal tumours.…”

“…RNA extracted from an independent set of 98 paired adjacent-normal and tumour tissues from CRC patients (196 samples in total [15]) was hybridised in Affymetrix chips Human Genome U219. Gene expression profiles of these samples have been performed as described in [15] and deposited in the Gene Expression Omnibus (GEO) database [16] through accession number GSE44076.…”

Clinicopathological significance and prognostic value of Wilms' tumor gene expression in colorectal cancer

“…The concept of field cancerization implies that tumor carcinogenesis may even occur in the ANM. A previous study showed that gene expression in ANM cells in CRC patients was not quite normal, and this may have important implications for CRC prognosis and progression [22]. Moreover, in the present study, mRNA expression levels of WT1 were not detected in the CP samples.…”

“…However, in the present study, TAA expression was also detected in the ANM tissues. Although TAAs that decorate cancer cells are targets for the immune system, many are not truly cancer-specific because they can also be found on normal tissues [22]. This arises through the presence of pre-malignant cells that express TAAs in normal-appearing colorectal mucosal tissues.…”