Abstract
The immune system is a significant determinant of epithelial tumorigenesis, but its role in colorectal cancer pathogenesis is not well understood. The function of the immune system depends upon the integrity of the protein network environment, and thus, we performed MELC immunofluorescence microscopy focusing on the lamina propria. By analyzing structurally intact tissues from colorectal cancer, ulcerative colitis, and healthy colonic mucosa, we used this unique and novel highly multiplexed robotic-imaging technology, which allows visualizing dozens of proteins simultaneously, and explored the toponome in colorectal cancer mucosa for the first time. We identified 1,930 motifs that distinguish control from colorectal cancer tissue. In colorectal cancer, the number of activated T cells is increased, explained by a lack of bax, caspase-3, and caspase-8. Whereas CD4(+)CD25(+) T cells are decreased and are, other than in ulcerative colitis, not activated, cytotoxic T cells are significantly increased in colorectal cancer. Furthermore, the number of activated human lymphocyte antigen (HLA)-DR(+) T-cells is increased in colorectal cancer, pointing to an altered antigen presentation. In colorectal cancer, CD3(+)CD29(+) expression and assembly of the LFA-1 and LFA-3 receptor are differentially changed, indicating a distinct regulation of T-cell adhesion in colorectal cancer. We also identified increased numbers of natural killer and CD44(+) cells in the colorectal cancer mucosa and nuclear factor-kappaB as regulator of apoptosis in these cell populations. High-content proteomic analysis showed that colorectal cancer induces a tremendous modification of protein expression profiles in the lamina propria. Thus, topological proteomic analysis may help to unravel the role of the adaptive immune system in colorectal cancer and aid the development of new antitumor immunotherapy approaches.
Highlights
Colorectal cancer is a common malignancy with an incidence of nearly 1 million cases per year worldwide
When mapping 23 surface and 9 intracellular proteins in single tissue samples from 10 control, 10 colorectal cancer, and 10 ulcerative colitis patients, we identified 1,930 combinatorial molecular phenotypes (CMP) motifs being distinct between colorectal cancer and control tissue and 539 CMP being different between colorectal cancer and ulcerative colitis on a significance level of a P value of
Our study focused on the proteomic changes in the subepithelial lamina propria
Summary
Colorectal cancer is a common malignancy with an incidence of nearly 1 million cases per year worldwide. Because an exact linear association between genome, transcriptome, and proteome of a cell does not exist, and translation and posttranslational modifications of proteins are not apparent from the DNA or mRNA sequence, providing a contribution to better understand the host response to colorectal cancer requires analyzing expression, function, and regulation of the entire set of proteins encoded by an organism – the aims of the emerging field of proteomics [3,4,5] This information will be invaluable for understanding how complex biological processes occur at a molecular level, how they differ in various cell types, and how they are altered in disease states. The identification of disease-relevant protein networks arising from detection of such protein expression patterns in inflammatory skin and bowel disease by using the advantages of the MELC technology has been shown [6, 7]
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