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Contents lists available at ScienceDirect
International Journal of Biochemistry
and Cell Biology
journal homepage: www.elsevier.com/locate/biocel
CD133 as a regulator of cancer metastasis through the cancer stem cells T
Clark Atlanta University, Center for Cancer Research & Therapeutic Development, and Department of Biological Sciences, 223 James P. Brawley Drive SW, Atlanta, GA 30314, USA
Cancer stem cell
Cancer stem 138908-40-4 are the cancer cells that have abilities to self-renew, diﬀerentiate into defined progenies, and initiate and maintain tumor growth. They also contribute to cancer metastasis and therapeutic resistance, both of which are the major causes of cancer mortality. Among the reported makers of the cancer stem cells, CD133 is the most well-known marker for isolating and studying cancer stem cells in diﬀerent types of cancer. The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly meta-static and resistant to therapy. Despite very limited information on physiological functions of CD133, many ongoing studies are aimed to reveal the mechanisms that CD133 utilizes to modulate cancer dissemination and drug resistance with a long-term goal for bringing down the number of cancer deaths. In this review, in addition to the regulation of CD133, and its involvement in cancer initiation, and development, the recent updates on how CD133 modulates cancer dissemination, and therapeutic resistance are provided. The key signaling path-ways that are upstream or downstream of CD133 during these processes are summarized. A comprehensive understanding of CD133-mediated cancer initiation, development, and dissemination through its pivotal role in cancer stem cells will oﬀer new strategies in cancer therapy.
CD133 is a glycosylated transmembrane protein, encoded by PROM1 “Prominin-1”. It has five transmembrane domains across the plasma membrane with an extracellular NH2 terminus and an in-tracellular COOH terminus. The physiological functions of CD133, so far, are mainly reported in retinal development. PROM1 mutations are harbored in the populations suﬀering from retinitis pigmentosa, ma-cular degeneration and cone-rod retinal dystrophy (Maw et al., 2000; Michaelides et al., 2010; Permanyer et al., 2010; Yang et al., 2008; Zhang et al., 2007). In addition, reduced adhesion abilities and in-creased cell damages were detected in the peripheral endothelial cells that harbor CD133 missense mutation (Arrigoni et al., 2011).
CD133 is originally discovered in the human hematopoietic stem and progenitor cells (Miraglia et al., 1997; Yin et al., 1997). Accumu-lating evidence indicated a presence of the high protein levels of CD133 in numerous types of cancer. The highly expressed CD133 predicts poor outcomes of cancer patients of ovarian cancer, colorectal cancer, prostate cancer, rectal cancer, lung cancer, and glioblastoma (Horst et al., 2009b; Merlos-Suarez et al., 2011; Ong et al., 2010; Silva et al., 2011; Artells et al., 2010; Hurt et al., 2008; Saigusa et al., 2009; Zeppernick et al., 2008; Zhang et al., 2008; Alamgeer et al., 2013; Huang et al., 2015; Wu et al., 2014). This is because cancer cells that express high levels of CD133 are more metastatic and resistant to chemotherapy and radiation therapy. Given that CD133+ cells are capable of self-renewal, proliferation and diﬀerentiation into diﬀerent
Abbreviations: 5-FU, 5-fluorouracil; ABCG2, ATP binding cassette subfamily G member 2; ALDH1A1, aldehyde dehydrogenase1A1; BMI-1, B cell-specific Moloney murine leukemia virus integration site 1; CAR, chimeric antigen receptor; CSC, cancer stem cell; DCLK1, doublecortin-like kinase 1; DKK1, dickkopf-related protein 1; EGFR, epithelial growth factor receptor; EMT, epithelial-mesenchymal transition; EpCAM, epithelial cellular adhesion molecule; ERK, extracellular-regulated kinase; ESA, epithelial-specific antigen; ESFT, Ewing’s sarcoma family tumors; ETS, E twenty-six; FACS, fluorescence-activated cell sorting; FAK, focal adhesion kinase; GLI1, glioma-associated oncogene homolog 1; HDAC1, histone deacetylase 1; HEK, human embryonic kidney; HIF, Hypoxia-inducible factor; HNCIC, head and neck cancer initiating cells; HNSCC, head and neck squamous cell carcinoma; IKKβ, IκB kinase β; IL-1β, interleukin 1 β; IL-6, interleukin 6; JAK2, Janus kinase 2; KITLG, ligand for the protein kinase KIT; KLF4, Kruppel like factor 4; LIN28B, Lin-28 homolog B; MDR1, multidrug resistance protein 1; NF-κB, nuclear factor κ-B; OCT4, octamer-binding transcription factor 4; OLIG2, oligodendrocyte transcription factor 2; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; PI3K, phosphoinositide 3 kinase; RBPJκ, recombination signaling binding protein for immunoglobulin kappa J; SCID, severe combined immunodeficiency; SIRT1, sirtuin 1; SOX2, SRY (sex determining region Y)-box 2; STAT3, signal transducer and activator of transcription 3; TCF/LEF, T-cell factor/lymphoid enhancer-binding factor