Fusobacterium nucleatum as a Marker for Epithelial to Mesenchymal Transition in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is both preventable and curable if diagnosed at early stage, and yet it is the second most common cause of cancer deaths in US. Recent emphasis on the role of human microbiome in cancer led us to investigate new microbial diagnostic marker for CRC. CRC originates in the colon or rectum as a polyp that may invade into surrounding tissue and metastasize to secondary sites through epithelial to mesenchymal transition (EMT) of the cancer cells. Fusobacterium nucleatum, an abundant opportunistic bacterium, is often found in the gut and oral cavity, and implicated in promoting colorectal carcinogenesis. F. nucleatum is known to bind E‐Cadherin, an epithelial cell surface adherence protein, through amyloid‐like adhesin fadA, which initiates EMT. FadA mediates the attachment and invasion of F. nucleatum and activates β‐catenin signaling, causing inflammatory and oncogenic responses. This study sought to assess F. nucleatum and EMT biomarkers in CRC. De‐identified formalin fixed paraffin embedded tissue samples of different stages in CRC, classified as normal, precancerous, and cancerous, were immunostained for E‐Cadherin and Vimentin as markers for epithelial and mesenchymal cells respectively. We used amyloid‐like adhesin fadA immunostaining as a marker for F. nucleatum. As expected, normal tissue specimens expressed E‐Cadherin exclusively in the mucosal epithelial cells while mesenchymal cells in the stroma specifically stained for Vimentin expression. However, E‐Cadherin was found to be downregulated in cancer tissue specimens, signifying a partial EMT. Further, some precancerous and cancerous specimens showed Vimentin‐positive foci within epithelial cells that lacked E‐Cadherin expression implicating EMT. We also observed the presence of F. nucleatum secreted amyloid‐like fadA in cancer tissue specimen. Amyloid‐like fadA plays a key role in transformation of F. nucleatum from commensal to pathogen, hence, its detection in the colon may aid in early detection of CRC and provide an opportunity for targeted intervention. Its role in EMT, however, requires detailed molecular analyses. Supplementing the routine histopathological evaluation with these specific biomarkers would provide more predictive and detailed analysis of cancer initiation and progression in tissue samples to aid in personalized treatment plan with the goal of improved disease outcome.