How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

Key Words: Colorectal cancer, Colorectal cancer stem cells, Tumor microenvironment factors, Tumor stroma, Gut microbiota, Cancer progression

Core Tip: Colorectal cancer (CRC) represents one of the most prevalent tumors worldwide. The tumor microenvironment (TME) through its proinflammatory role, among others, actively participates in CRC progression and the disturbance of gut microbiota (dysbiosis) can influence this inflammatory process. CRC stem cells (CCSC) are a tumor cell subpopulation that drives CRC initiation, progression and treatment failure. The features and behavior of CCSC are modulated by several factors including TME and gut microbiota. Here, we will give an overview of the synergistic interaction among TME and intestinal microorganisms that condition the CRC environment and shape CCSC characteristics allowing CRC evolution.

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