IFusobacterium/I Co. at the Stem of Cancer: Microbe–Cancer Stem Cell Interactions in Colorectal Carcinogenesis

Colorectal cancer is one of the most frequently diagnosed and deadly malignancies worldwide, but our understanding of why this life-threatening disease occurs is still limited. With trillions of bacteria inhabiting our intestines, especially the large intestine, where cancer most frequently develops, it is no surprise that gut microbes have been under scrutiny. One of the prime suspect microorganisms is Fusobacterium nucleatum, an oral pathogen believed to lodge in colon cancer at its initial stage and foster its progression to full malignancy. Based on a review of the available information, we propose that Fusobacterium facilitates colorectal cancer through a misguided attempt to heal the diseased mucosa gone tragically wrong. This provocative view aims at stimulating discussion and putting the healing wound-cancer analogy in the spotlight of future research on the role of gut bacteria in colon malignancy. Adult stem cells lie at the crossroads of tissue repair, inflammation, and malignancy. Intestinal microbiota and microbe-host interactions are pivotal to maintaining gut homeostasis and response to injury, and participate in colorectal carcinogenesis. Yet, limited knowledge is available on whether and how bacteria directly crosstalk with intestinal stem cells (ISC), particularly cancerous stem-like cells (CR-CSC), as engines for colorectal cancer initiation, maintenance, and metastatic dissemination. Among several bacterial species alleged to initiate or promote colorectal cancer (CRC), the pathobiont Fusobacterium Nucleatum has recently drawn significant attention for its epidemiologic association and mechanistic linkage with the disease. We will therefore focus on current evidence for an F. nucleatum-CRCSC axis in tumor development, highlighting the commonalities and differences between F. nucleatum-associated colorectal carcinogenesis and gastric cancer driven by Helicobacter Pylori. We will explore the diverse facets of the bacteria-CSC interaction, analyzing the signals and pathways whereby bacteria either confer "stemness" properties to tumor cells or primarily target stem-like elements within the heterogeneous tumor cell populations. We will also discuss the extent to which CR-CSC cells are competent for innate immune responses and participate in establishing a tumor-promoting microenvironment. Finally, by capitalizing on the expanding knowledge of how the microbiota and ISC crosstalk in intestinal homeostasis and response to injury, we will spec