CD133 as a regulator of cancer metastasis through the cancer stem cells
Introduction
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 intracellular 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, macular 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 increased 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). Accumulating 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 types of cells (Hemmati et al., 2003; Singh et al., 2003, 2004; Yin et al., 1997), known as stem cell properties, CD133+ cancer cells are cancer stem cells (CSCs). In addition to CD133, other general cancer stem cell markers include CD44 and aldehyde dehydrogenase1A1 (ALDH1A1). Heterogeneous populations of the CSCs are present among different types of cancer according to their protein expression profiles. For example, pancreatic cancer stem cells express high levels of CD133, CD44, CD24, epithelial-specific antigen (ESA), ALDH1A1, CXCR4, DCLK-1 and BMI-1, while lung cancer stem cells have increased expression of ALDH1A1, ABCG2, CD90, CD117 and epithelial cellular adhesion molecule (EpCAM) (Hardavella et al., 2016; Proctor et al., 2013; Rao and Mohammed, 2015; Wang et al., 2014).
The CD133 expression is regulated by Notch, p53, hypoxia-inducing factor (HIF) and signal transducer and activator of transcription 3 (STAT3) in cancer (Fig. 1). It has been demonstrated that the intracellular domain of Notch 1 directly bound to the RBP-Jκ site of the 5′ promoter region of PROM1 to regulate CD133 transcription (Konishi et al., 2016). Knockdown of Notch1 or treatment of Notch inhibitors decreased CD133 expression in cultured gastric cancer and melanoma cells (Konishi et al., 2016; Kumar et al., 2016). There are 5 different promoters, including promoter 1 (P1) to promoter 5 (P5) in the 5´ untranslated region of CD133 for alternatively splicing variants. HIF increased the promoter activity of PROM1 through its direct binding to the P5 region of PROM1 where it interacted with ETS transcription factors such as Elk1 (Ohnishi et al., 2013). Recently, it has been reported that STAT3 activated by IL-6 can turn on the PROM1 gene through upregulation of HIF transcription in liver cancer cells (Won et al., 2015). In human lung cancer cells cultured at a hypoxia condition, binding of OCT4 and SOX2 to the P1 region of PROM1 was required for HIF-induced CD133 expression (Iida et al., 2012), revealing another mechanism that HIF modulates CD133 expression in addition to the P5 region of PROM1. Transcription factor p53 negatively regulates mRNA and protein levels of CD133 by directly binding to the P5 region of PROM1, and subsequent recruitment and activation of histone deacetylase 1 (HDAC1) (Park et al., 2015). Activation of HDAC1 removed the acetyl groups from lysine residues of the chromosome, and subsequently increased the binding between the histones and DNA, thus preventing transcription of PROM1.
This review provides the current updates on how CD133 regulates different stages of cancer development, including initiation, progression and advancement (metastasis) especially through transcription factors and cell signaling. In addition, recent findings on the mechanisms that CD133 utilizes to enhance cancer cells resistances to therapeutic treatments are also summarized for offering some insights into a potential modulation on CD133 and its mediated signaling for a therapeutic development purpose.
Section snippets
CD133 in cancer initiation
Cancer-initiating cells possess tumor-initiating capacity which is one of the characteristics of CSCs. CSCs are believed to be a major source of cancer-initiating cells during cancer onset. A major body of evidence has demonstrated that the isolated CD133+ cancer cells from patients are capable of forming cancers in immune-comprised xenograft mice, implicating the involvement of CSCs in cancer initiation. When using the renal capsule transplantation in immunodeficient mice to identify human
CD133 in cancer development and progression
In a xenograft mouse model, the size of tumor derived from the high CD133+ HEK293 cells is dramatically larger than that from the low CD133+ HEK293 cells (Canis et al., 2013), suggesting that a role of CD133 in regulating cell growth during cancer development. Overexpression of CD133 increased cell proliferation, cell cycle progression and telomerase activity in pancreatic cancer AsPC-1 cells (Weng et al., 2016), suggesting that CD133 promotes tumor progression through upregulation of cell
CD133 and its signaling in cancer metastasis
A little more than a decade ago after discovering CD133 as a marker of brain tumor stem cells, accuVmulating evidence suggested that CD133 modulates cancer cell invasion, metastasis and drug resistance in many types of cancer (Fig. 3).
In metastatic ovarian cancer, increased mRNA expression of CD133 is regulated by transcription factor ARID3B. Knockdown of CD133 in ARID3B overexpressed cancer cells leads to quicker tumor-caused deaths in the xenograft mice as compared to these of CD133+ARID3B+
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
Summary
Tumor metastasis and therapeutic resistance account for the majority of cancer-related deaths. Both properties are enhanced in a small population of CD133high cancer cells, known as cancer stem cells with abilities of self-renewal, tumor initiation, and pluripotency. Therefore, targeting cancer stem cells, such as CD133high cell populations remains one of top interest to combat fatalities of cancer patients. Elevated expression of CD133 resulted in increased tumor-initiating ability, tumor
Funding
This work was supported by the NIH Grant G12MD007590 and by the 2017 AACR-Bayer Innovation and Discovery Grant 17-80-44-LIOU.
Competing interests
The author declares no competing interests on publication of this article.
Ethics approval and consent to participate
All animal experiments were approved by the Atlanta University Center IACUC committee (protocol #: 17-20) and performed in accordance with relevant institutional and national guidelines and regulations.
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