Identification of putative immunologic targets for colon cancer prevention based on conserved gene expression from pre-invasive to malignant lesions
Menée in vitro et in vivo, cette étude identifie trois protéines immunogènes, exprimées dans des lésions cancéreuses, pouvant servir de base au développement d'un vaccin contre le cancer colorectal
The length of time required for pre-invasive adenoma (AD) to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in AD relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing AD and CRC microarray datasets and identified 160 genes that were ≥ 2-fold up-regulated in both AD and CRC relative to normal colon tissue. We further identified 23 genes that demonstrated protein over-expression in colon AD and CRC based on literature review. Silencing the most highly up-regulated genes, CDH3, CLDN1, KRT23, and MMP7, in AD and CRC cell lines resulted in a significant decrease in viability (p<0.0001) and proliferation (p<0.0001) as compared to controls and an increase in cellular apoptosis (p<0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability (MSI), CpG island methylator (CIMP) and chromosomal instability (CIN) phenotypes suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (p=0.006), KRT23 (p=0.0007), and MMP7 (p<0.0001) serum IgG in cases as compared to controls. These data demonstrate a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified 3 candidates suitable for vaccine development.