Abstract
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs’ therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
Highlights
Colorectal carcinoma (CRC) is the second most common cause of cancer-related death worldwide, with an estimated 862,000 deaths recorded in the year 2018 [1]
Patients with colon carcinoma can be managed with surgery alone, whereas patients with rectal carcinoma are often treated by chemotherapy e.g., with 5-fluorouracil (5-FU), followed by surgery [2]
Accumulating information in cancer research indicates that cancer stem cells (CSCs) is the root of cancer progression and therapy resistance
Summary
Colorectal carcinoma (CRC) is the second most common cause of cancer-related death worldwide, with an estimated 862,000 deaths recorded in the year 2018 [1]. Mutations in key signalling pathway molecules, the increased expression of anti-apoptotic proteins, the presence of quiescent and/or resistant tumour cells or the over-activation of drug efflux pumps are all potential causes of therapy failure [4,5]. In CRC, the numbers of CSCs increased in xenotransplanted mice after chemotherapy [10] These CSCs confer resistance to radiotherapy by the selective activation of DNA damage checkpoints [7,9,12]. The underlying mechanisms of CSCs in CRC attributed to therapy resistance include, the activation of growth signalling pathways such as Hedgehog, Notch, TGF- β, Wnt/β-catenin, Hippo, PI3/AKT etc., the dysregulation of microRNAs, acquisition of quiescent state, metabolic switch, phenotypic plasticity etc. The features represent special characteristics, crucial crucial signalling pathways and associated miRNAs of cancer stem cells (CSCs) in causing therapy resistance in colorectal carcinoma
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