• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • br As mentioned previously in the cancer initiation section


    As mentioned previously in the cancer initiation section, all colon cancer initiating BrefeldinA purified from a xenograft NOD/SCID mouse model expressed CD133 BrefeldinA (O'Brien et al., 2007). Of note, it has been shown that upon using the lineage tracing technique to track en-dogenous CD133+ cells in a transgenic mouse model during the de-velopment of colon cancer metastasis, CD133 is expressed in the colon cancer epithelium (Shmelkov et al., 2008). It suggested a role of CD133 in the initiation of colon cancer metastasis. Knockdown of CD133 in SW620 human colon cancer cells impaired cell migration through re-duced phosphorylations of Src-focal adhesion kinase (FAK) and this is due to a failure of forming a complex of CD133, Src, and FAK (Liu et al., 2016). Furthermore, the interaction between CD133 and Src is required for CD133-induced cell motility by activation of Src downstream target FAK.
    A large body of evidence demonstrated that activation of Wnt sig-naling is involved in controlling the malignant features of CSC through increased EMT, which leads to cancer invasion and metastasis (Katoh, 2017; Webster et al., 2015; Zhan et al., 2017). Knockdown of CD133 by the virally delivered short hairpins of RNA in human metastatic mela-noma FEMX-I cells impeded cell motility and their ability to form spheroids (Rappa et al., 2008). In addition, downregulation of CD133 in FEMX-I cells resulted in increased expression of several Wnt inhibitors such as DKK1. Besides plasma membrane, CD133 is also localized at 
    intracellular compartments such as Golgi apparatus and extracellular membrane vesicles. It has been shown that shCD133 expressing FEMX-1 cells produced less CD133 containing lipid droplets (Rappa et al., 2013). In addition, decreased nuclear β-catenin was detected in these cells, suggesting a reduced activation of Wnt signaling. These data implicated that CD133-containing membrane vesicles are involved in the activation of Wnt signaling to promote cancer metastasis of mela-noma. It has been demonstrated that in several types of cancer cells, histone deacetylase HDAC6 can physically interact with CD133 at the endosomes, α-tubulin, and β-catenin to form a tertiary complex (Mak et al., 2012). The stabilized β-catenin then translocated to the nucleus where it interacts with TCF/LEF transcription factors to upregulate gene expressions that modulate cancer cell migration and metastasis. Blockade of this tertiary complex formation by inhibiting HDAC6 leads to cancer cell differentiation via a deacetylation of α-tubulin, protea-somal degradation of β-catenin and endocytosis of CD133 followed by its lysosomal degradation. In colon cancer, CD133 and nuclear β-ca-tenin are biomarkers for disease progression and patient survival (Horst et al., 2009a). Treating CD133 expressing colon cancer HT29 and DLD1 cells with celecoxib reduced both CD133 expression and Wnt activation (Deng et al., 2013). Celecoxib inhibits TCF/LEF transcription factor activities and suppresses Wnt/β-catenin targeted gene expressions of cyclin D1 and survivin (Tang et al., 2018). Loss of E-Cadherin expres-sion at membranes not only impairs cell-cell adhesion but also has in-creased accumulation of nuclear β-catenin. Nuclear E-Cadherin was reported to be a negative regulator of Wnt pathway-induced cell inva-siveness in CD133+ lung cancer cells (Su et al., 2015). It reduced the Wnt/ β-catenin mediated transcriptional activity via disruption of the interaction between β-catenin and TCF4 transcription factor.
    CD44 is another cancer stem cell gene and cell adhesion molecule commonly associated with CD133+ cells in cancer metastasis such as gastric cancer, colorectal cancer, prostate cancer, and liver cancer (Chen et al., 2011a; Eaton et al., 2010; Hou et al., 2012; Huang et al., 2012; Wakamatsu et al., 2012). Among them, colorectal cancer is the best reported cancer type for the presence of the CD133+/CD44+ po-pulation in the metastatic site liver at an early stage of the disease. Several lines of evidence suggested that between CD133 and CD44, CD44 is the major player in tumor cell migration and invasiveness because of its regulation on extracellular matrices, whereas CD133 controls tumorigenic ability. However, for the malignant tumor cells that enable to metastasize to other sites require both properties.
    5. Potential of targeting CD133 in cancer therapy
    Several lines of evidence have suggested CD133 as a prognostic marker in many types of cancers including breast cancer, lung cancer, gastric cancer, colorectal cancer and so on (Alamgeer et al., 2013; Horst et al., 2009b; Ishigami et al., 2010; Wu et al., 2014; Xia, 2017). In addition to cancer initiation, development, and metastasis, CD133 also enhances therapeutic resistance including chemo drugs and radiation. Overexpression of CD133 in a head and neck squamous cell carcinoma (HNSCC) cell line rendered the cells insensitive to 5-FU- or cisplatin-induced cell death (Lee et al., 2017). Furthermore, the CD133+ HNSCCs were arrested at the G0/G1 phase of the cell cycle in response to 5-FU and cisplatin treatment. Similarly, ectopic expression of CD133 in rat C6 glioma cells increased the drug resistance of camptothecin and doxorubicin via upregulation of p-glycoprotein 1 (multidrug resistance protein 1/MDR1) transcription and ABC transporter activity (Angelastro and Lame, 2010). It has been shown that CD133+ cells FACS-sorted from the Ewing’s sarcoma family tumor (ESFT) cell line STA-ET-8.2 according to the CD133 expression are more resistant to chemotherapeutic agents including doxorubicin, etoposide, and vin-cristine than CD133− STA-ET-8.2 cells (Jiang et al., 2010). In cultured human gastric cancer cells, knockdown of CD133 rendered cells more sensitive to 5-FU induced cell death (Song et al., 2018; Zhu et al., 2014). This increased cell death effect was through downregulation of phosphatidylinositol-3 kinase activity and its downstream targets, in-cluding Akt, p-glycoprotein and BCL-2, and upregulation of Bax. Blockade of this pathway via the PI3K/Akt inhibitor LY294002 in CD133-expressed gastric cancer cells has the same effect as shCD133-expressed cells in response to 5-FU treatment. It suggested that CD133 promotes 5-FU drug resistance through activation of PI3K/Akt in gastric cancer. Colorectal cancer cells that are CD133high/CD44high survived better than CD133low/CD44low cancer cells after exposure to a high dose of gamma irradiation (Sahlberg et al., 2014). In addition, Akt expression was higher in the CD133high/CD44high cells as compared to the CD133low/CD44low cancer cells. Knockdown of Akt1 but not Akt2 abolished CD133 expression in the colorectal cancer cells without af-fecting CD44 expressions. It implicated a role of Akt1 in modulating radiation resistance of colorectal cancer through upregulation of CD133.