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

Abstract

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.

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“…7 CSCs can sustain the viability of the tumor cell population due to their capacity for self-renewal and unlimited proliferation, as well as their ability to move and migrate, facilitating the metastasis of tumor cells. 8 Moreover, CSCs can remain in quiescence for long periods to evade chemotherapeutic drugs targeting proliferation 9,10 and are insensitive to external physicochemical factors that kill tumor cells, attributed to the high expression of multiple drug-resistant proteins. In the process of chemotherapy, due to the influence of the tumor microenvironment and the stimulation of various factors, the stemness characteristics of tumor cells are gradually enhanced, leading to an increased population of CSCs, and subsequently facilitating the development of drug resistance.…”

“…These mechanisms include mutations in key signaling pathway molecules, increased expression of antiapoptotic proteins, the presence of quiescent or drug-resistant tumor cells, and excessive activation of drug efflux pumps. , Additionally, cancer stem cells (CSCs) are considered to be the root cause of carcinogenesis and one of the main causes of disease recurrence and drug resistance . CSCs can sustain the viability of the tumor cell population due to their capacity for self-renewal and unlimited proliferation, as well as their ability to move and migrate, facilitating the metastasis of tumor cells . Moreover, CSCs can remain in quiescence for long periods to evade chemotherapeutic drugs targeting proliferation , and are insensitive to external physicochemical factors that kill tumor cells, attributed to the high expression of multiple drug-resistant proteins.…”