CD133: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Jianhui Yang.

Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. CSCs refer to a small subset of cancer cells, theoretically, this can be even a single cancer cell, which can differentiate into a heterogeneous and hierarchy of cancer cells. Sharing a number of characteristics with normal somatic stem cells, CSCs are capable of self-renewing, asymmetric division, generation of heterogeneous lineage, differentiation into various cancer cells which make up the tumor bulk, manifesting more aggressive phenotypes and exhibiting resistance to anticancer treatment. The existence of CSCs was first reported in acute myeloid leukemia in 1997 and later in a broad spectrum of common solid tumors, including PC.

  • prostate cancer stem cells
  • CD133

1. The Identification, Isolation and Enrichment of Prostate CSancer Stem Cells (PCSCs)

The availability of reliable PCSC markers is essential to isolate PCSCs. Just like many other cancer stem cells (CSCs), the PCSC is likely to share similar antigen expression with PSCprostate stem cells (PSCs), its unmutated counterpart [14][1]. Accumulated evidence has shown that PCSCs express certain functional and non-functional (phenotypic) markers. With these markers labelled with antibodies, PCSCs can be identified by flow cytometry (FCM) and isolated by fluorescence-activated cell sorting (FACS) or magnetic cell sorting (MACS).
Identification of PCSCs was initially reported by three independent groups in 2005 [4,15,16][2][3][4]. All these initial PCSC research teams have isolated tumorigenic and self-renewing cells from prostate cancer tissues or cell lines with different PCSC markers. The most influential work was from Collins et al. group [4][2], who isolated PCSCs from human PC biopsies with CD44+/α2β1high/CD133+ phenotypes. The isolated PCSCs were capable of differentiation to AR+/PAP+/CK18+ luminal cells. The fundamental evidence to prove the existence of PCSC is the reconstitution of a cancer bulk by inoculation of a small number of cancer cells in a xenograft model. After CD44+/α2β1high/CD133 cells were implanted subcutaneously in mice, formed acini-like structures were found to resemble prostate differentiation [4][2]. After that some researchers have utilized a variety of tentative PCSC markers to isolate PCSCs, or PC cells with stemness features, from patient derived tissue or PC cell lines. These markers include: CD133 [4[2][5],17], CD44 [4,18[2][6][7][8],19,20], ABCG-2 [15][3], CD24 [20][8], CD166 [21][9], ALDH1 [22][10], integrin α2β1 (CD49b) [4[2][6],18], Sca-1 [23],[11] and so etc.on .
Most published papers utilized CD133 based combined markers, only a few research teams applied a single marker such as CD133 alone. In addition, the above PCSC markers can be divided into extracellular or intracellular molecules. Extracellular markers technically do not require fixation and permeabilization for antibody binding, so they are more suitable for isolating living cells, which later will be collected for downstream in vitro or in vivo experiments to analyze PCSC properties. It is noteworthy that current PCSC markers do not exclusively express on PC, most of them express in CSCs of other cancer types.
Apart from the isolation from human PC tissue, significant research work also has shown that differentiated PC cell lines can be reprogrammed to PCSCs or stem-like PC cells by exposure to a variety of harsh experiment conditions, including chemotherapy [24[12][13],25], radiotherapy [26,27][14][15], serum-free medium [24,28][12][16], low attachment culture systems [28][16], sphere cultures [29][17], and androgen deprivation [30][18].(Figure 1) These experimental conditions can also induce tentative CSCs or stem-like cancer cells in other types of cancers, because the induced and sorted cells are capable of constituting tumors in a xenograft mouse model. The possible mechanism for these reprogrammed CSCs is inducing de-differentiation [27][15] and/or selecting resistant stem-like cells, while most of the non-CSC cancer cells die in unfavorable environments. Notably, genetic manipulation, such as PTEN deletion, can also lead to the expansion of the PCSC phenotype and tumor initiation [13,31][19][20].
Cancers 14 05448 g001 550
Figure 1. PC cell lines can be de-differentiated to PCSCs or stem-like PC cells by chemotherapy, radiotherapy, serum starvation, sphere culture, and genomic manipulation.
As mentioned earlier, the most convincing evidence of PCSC is the ability to reconstitute a tumor by the limited dilution assay, in which only a tiny amount of the tentative CSCs can demonstrate a significant ability to reconstitute the cancer bulk in severe combined immunodeficiency (SCID) mice. The Collin group showed that a few CD133+ cells, as few as 10, were able to develop a tumor [32][21]. In glioma cells, 100 CD133+ stem cells were sufficient to reconstitute a brain tumor [33][22].

2. CD133 Is a Robust Biomarker to Identify PCSC

In 1997, it was reported that CD133 was expressed in a subset of human CD34(+) hematopoietic stem cells (HSC) derived from human bone marrow and cord blood, so CD133 was first regarded as a marker of HSC [34,35][23][24]. In 2003, brain tumor stem cells were exclusively isolated using neural extracellular stem cell marker CD133. These CD133+ cells differentiated into tumor cells bearing some resemblance to patient-derived tumors [33][22]. Since then, in a variety of solid tumors, CD133 has become the most frequently used extracellular marker to detect CSCs [4,33,36,37,38,39,40,41,42,43][2][22][25][26][27][28][29][30][31][32]. Such universal expression tends to confirm CD133 as an essential maker of CSCs, despite contradicting data regarding the ambiguous role of CD133 expression in certain CSCs [36,44][25][33].
In the past two decades, CD133 alone [17[5][17],29], or in the combination with other markers [4,45,46,47,48[2][34][35][36][37][38],49], is one of the most well-characterized biomarkers used to identify PCSCs. The CD133 based PCSC marker combination includes: CD133+/CD44 [46][35], CD133+/CD44+/integrin α2β1 [4[2][34],45], CD133+/CXCR4 [47][36], CD133+/Trop-2+/integrin α2β1 [48][37], CD133+/CD44+/ABCG2+/CD24- [49][38]. It is unclear whether combined markers are more valuable than CD133 alone to identify PCSCs, but in colorectal cancer, it has been suggested that the CSC marker pool is more precise than CD133 alone [50,51][39][40]. In the first and key publication of PC, the marker combination CD44+/α2β1high/CD133+ was used to isolate PCSCs from 40 patient biopsies [4][2].
It is not surprising that CD133 expressed at low levels in prostate cancer tissues and four patient -derived PC cell lines, including PC-3, CWR22Rv1, DU-145 and LNCaP [29][17]. However, in the combined PCSC markers such as CD44+/α2β1high/CD133+, not all markers are weakly expressed in all PC tissue or cell lines. For example, PC-3 and DU-145 expressed > 93% CD44+ cells, while CWR22Rv1 and LNCaP cells expressed < 4% CD44+ cells [52][41]. OurThe unpublished data confirmed the broad and strong expression of CD44 in PC-3 or DU-145 cells by FCM and Western blot. According to the definition of a CSC, cancer stem cells are less than 1% of all cancer cells, and the expression of a CSC marker in histological slides is supposed to be weak or not even expressed in non-CSC cancer cells. However, this general rule may not apply to all cancer cell lines because a cancer cell line was initially established from one or only a few cells, and the broad expression of CD44 or other markers cannot disqualify them as PCSC markers simplistically. As a well-recognized CSC marker in PC and other cancers, CD44+ PC cells displayed significantly enhanced tumorigenicity and metastasis compared with CD44- cells [19][7], and small numbers of CD44+/CD24- initiated tumors in a xenograft model [20][8]. The CSC marker combination CD133+/CD44+, with [4,45][2][34] or without [46][35] integrin α2β1, may help PCSC isolation from human PC tissue compared with CD133+ alone.

2. Gene Regulation and Functional Analysis of CD133 and CSC Stemness

The human CD133 (FROM1, prominin-1, AC133) gene locates on chromosome 4p15 and has 37 distinctive exons, resulting in the 12 alternatively spliced isoforms [58][42] of CD133 mRNA in a tissue-dependent manner. The CD133 gene transcription is regulated by five alternative promoters, three of which locate in the CpG island where DNA methylation occur. Methylation of these 133 promoters in vitro completely inhibits their activity, suggesting that methylation plays a vital role in gene regulation [59,60,61][43][44][45]. On the contrary, an abnormal DNA hypomethylation status of the CpG island in the promoter is positively correlated with elevated CD133 expression in some types of CSCs [59,62][43][46].
CD133 mRNA is detected in most adult tissues and in many cell lines, but CD133 protein expression is restricted and mainly expressed on normal stem cells [63[47][48][49][50],64,65,66], including prostate stem cells [65][49]. Only a few normal prostate cells express CD133, and most basal and luminal cells are negative, indicating CD133 expression is strictly defined during the development of epithelial hierarchy in prostate tissue. Due to heavy hypermethylation of the CpG island, DNA methylation inhibited CD133 expression in a number of prostate epithelial cell lines [67][51]. On the contrary, histone deacetylase inhibitors restored CD133 expression in prostate cell lines. However, in malignant prostate primary tissues, regulation of CD133 is under the dynamic control of chromatin condensation but not dependent on DNA methylation [67][51].
Three transcriptional factors are identified to regulate the transcription of CD133, which include the ALL1-fused gene from chromosome 4 protein (AF4), Sex determining region Y-box17(Sox17), and E26 transformation-specific (ETS). AF4 was identified to be a regulator of CD133 in Caco-2 cells (a colorectal carcinoma cell line) by shRNA screening [68][52]. Sox17 was identified as a critical regulator of self-renewal of fetal and adult HSC [69][53]. Forced expression of Sox17 induced expression of CD133 in CD133—cells, and reduction of SOX17 by siRNA induced a reduction in the level of CD133 in CD133 + cells [70][54]. The RAS/ERK/ETS conduct pathway was regulated at ETS binding site within the CD133 promoter [71][55], while suppression of the ERK pathway downregulated the expression of the CD133 protein.
CD133 is a 97kDa transmembrane glycoprotein with five transmembrane domains, and due to heavy glycosylation, its apparent molecular weight is about 130 kDa. CD133 null mice usually grow normally except for a progressive degeneration of photoreceptors [72][56], which is consistent with the critical function of CD133 in photoreceptor cells [73][57]. CD133 selectively expresses in some types of stem cells during tissue development, and its expression is regulated in a development-dependent manner. The presentation of CD133 is rapidly lost upon differentiation.
In PC, as discussed earlier, subpopulations of CD133+ cells isolated from primary prostate cancer tissues or established cell lines exhibited stem cell-like characteristics. Ectopic over-expression of CD133 rendered LnCap cells significant CSC properties such as higher expression of Oct-4 and Nanog [74][58], promoted bone metastasis, and increased epithelial-to-mesenchymal transition (EMT) properties, which include increased vimentin and decreased E-cadherin.

3. Multiple Functional Roles of CD133 and CSC Stemness

The upstream or pertaining molecular events inducing transcriptional, translational or epigenetic regulation of CD133 are still largely unknown. It was reported that certain conduct pathways, extracellular oxygen levels, or mitochondria metabolism were mutually interconnected with CD133 gene expression and stemness of CSCs, as summarized below and illustrated in Figure 2:
Cancers 14 05448 g002 550
Figure 2. Summary of some known upstream and downstream molecular events related to CD133. The upstream events result in the upregulation of CD 133, and downstream events after CD133 induction are directly or indirectly related to increased stemness properties of PC cells, mainly via CD133/PI3K/AKT/Wnt/β-Catenin signaling axis.
(1)
PI3K/Akt pathway: In glioma CSCs, phosphorylation of tyrosine-828 in the CD133 C-terminal domain mediated interaction between CD133 and the phosphoinositide PI3K 85 kDa subunit (p85), which further activated the PI3K/Akt conduct pathway. On the contrary, CD133 knockdown significantly inhibited the activation of the PI3K/Akt pathway, accompanied by reduced properties of self-renewal and tumor-forming in glioma CSCs. Taken together, CD133 activated the PI3K/Akt pathway and regulated stemness in glioma CSCs [12,75][59][60].
(2)
Wnt Signaling: In several patient-derived glioblastoma cell lines, compared with CD133 low cells, CD133 high cells showed higher levels of endogenous Wnt activity and self-renewal property, while inhibition of CD 133 by a novel anti CD133 antibody suppressed the function of CD133 as well as the activity of Wnt pathway. Interestingly, a pan-AKT inhibitor MK-2006 diminished overexpression of CD133 induced Wnt activation, indicating a CD133/AKT/Wnt signaling axis may play a role in regulating the stemness of glioblastoma [76][61].In PC, non-adherent prostaspheres cultures enriched stemness characteristics of prostate cell likes. Inhibition of Wnt signaling reduced the prostasphere size and the self-renewal properties of prostate cancer stem-like cells, while adding Wnt3α increased self-renewal and expression level of CD133 [77][62]. Therefore, Wnt-β-catenin signals promote the self-renewal of PCSC or progenitor cells [78][63], which may be independent of AR activity [77][62].
(3)
CD133-transferrin-iron: The low oxygen niche is the microenvironment where the stem cell resides. In the tumor microenvironment, hypoxia upregulated the expression of hypoxia -inducible factor-1(HIF-1) and then indirectly induced CD133 expression [79,80][64][65] and other stem cell markers of PCSC [81][66]. In addition, hypoxia also disturbs mitochondrial membrane potential (MMP) to regulate CD133 post-transcriptionally [82][67].
(4)
Reactive oxygen species (ROS): ROS are by-products of normal cellular metabolism but excess ROS leads to cell death. In CSCs, the Redox scavenger system is activated to keep ROS at a low level [83][68]. In PCSCs, CD133+ cells are more vulnerable to ROS-induced cell damage [84][69].

4. CD133 and Its Clinical Significance in PCSC

It is estimated that metastasis is responsible for about 90% of cancer deaths. [85][70]. An autopsy study showed that bone metastases were found in 90% of 1589 patients who died from metastatic prostate cancer, strongly suggesting this preponderance of bone metastasis in castrate resistance PC [86][71]. It is likely that bone metastasis is the ultimate result of PCSC disseminated from prostate cancer [87][72].
A cancer metastasis initiates from an invasion of cancer cells through the basement membrane, followed by multiple steps including angiogenesis, intravasation, extravasation, and colonization. In addition, cancer metastasis requires an epithelial status switch, including both an EMT [88][73] to leave the primary location and a Mesenchymal-to-Epithelial Transition (MET) to seed into the secondary site [89][74]. PCSCs are more apt to an epithelial status switch and metastasis because of the capacity of cell plasticity. CD133 may be involved in cancer metastasis, especially bone metastasis. In a group of 131 cancer patients (26% prostate cancers), 111 metastatic patients had a significantly increased expression of CD133 mRNA (p < 0.05), especially patients with bone metastasis (p < 0.001) [90][75].
It is reasonable to postulate that CD133 might be a progress factor in some solid cancers, and several reports correlated the expression of CD133 with poor prognosis in a variety of solid cancers [91,92,93,94,95][76][77][78][79][80]. In a group of metastatic castration-resistant prostate cancer (mCRPC) patients, circulating tumor cells (CTCs) with CD133+ have an AR-independent, increased proliferative potential [96][81]. Very recently, a clinical trial was conducted to evaluate the clinical significance of CD133 in CTCs of newly diagnosed mCRPC patients. It was found that using CD133 in circulating tumor cells can independently predict progression-free survival (PFS) in mCRPC patients who received androgen deprivation therapy (ADT) therapy (p < 0.05) [97][82].

References

  1. Kim, W.T.; Ryu, C.J. Cancer stem cell surface markers on normal stem cells. BMB Rep. 2017, 50, 285–298.
  2. Collins, A.T.; Berry, P.A.; Hyde, C.; Stower, M.J.; Maitland, N.J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005, 65, 10946–10951.
  3. Patrawala, L.; Calhoun, T.; Schneider-Broussard, R.; Zhou, J.; Claypool, K.; Tang, D.G. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 2005, 65, 6207–6219.
  4. Huss, W.J.; Gray, D.R.; Greenberg, N.M.; Mohler, J.L.; Smith, G.J. Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res. 2005, 65, 6640–6650.
  5. Kanwal, R.; Shukla, S.; Walker, E.; Gupta, S. Acquisition of tumorigenic potential and therapeutic resistance in CD133+ subpopulation of prostate cancer cells exhibiting stem-cell like characteristics. Cancer Lett. 2018, 430, 25–33.
  6. Patrawala, L.; Calhoun-Davis, T.; Schneider-Broussard, R.; Tang, D.G. Hierarchical organization of prostate cancer cells in xenograft tumors: The CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Res. 2007, 67, 6796–6805.
  7. Patrawala, L.; Calhoun, T.; Schneider-Broussard, R.; Li, H.; Bhatia, B.; Tang, S.; Reilly, J.G.; Chandra, D.; Zhou, J.; Claypool, K.; et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006, 25, 1696–1708.
  8. Hurt, E.M.; Kawasaki, B.T.; Klarmann, G.J.; Thomas, S.B.; Farrar, W.L. CD44+ CD24(−) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br. J. Cancer 2008, 98, 756–765.
  9. Jiao, J.; Hindoyan, A.; Wang, S.; Tran, L.M.; Goldstein, A.S.; Lawson, D.; Chen, D.; Li, Y.; Guo, C.; Zhang, B.; et al. Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PLoS ONE 2012, 7, e42564.
  10. Van den Hoogen, C.; van der Horst, G.; Cheung, H.; Buijs, J.T.; Lippitt, J.M.; Guzman-Ramirez, N.; Hamdy, F.C.; Eaton, C.L.; Thalmann, G.N.; Cecchini, M.G.; et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010, 70, 5163–5173.
  11. Xin, L.; Lawson, D.A.; Witte, O.N. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc. Natl. Acad. Sci. USA 2005, 102, 6942–6947.
  12. Wang, L.; Huang, X.; Zheng, X.; Wang, X.; Li, S.; Zhang, L.; Yang, Z.; Xia, Z. Enrichment of prostate cancer stem-like cells from human prostate cancer cell lines by culture in serum-free medium and chemoradiotherapy. Int. J. Biol. Sci. 2013, 9, 472–479.
  13. Hanrahan, K.; O’Neill, A.; Prencipe, M.; Bugler, J.; Murphy, L.; Fabre, A.; Puhr, M.; Culig, Z.; Murphy, K.; Watson, R.W. The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer. Mol. Oncol. 2017, 11, 251–265.
  14. Kyjacova, L.; Hubackova, S.; Krejcikova, K.; Strauss, R.; Hanzlikova, H.; Dzijak, R.; Imrichova, T.; Simova, J.; Reinis, M.; Bartek, J.; et al. Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells. Cell Death Differ. 2015, 22, 898–911.
  15. Cojoc, M.; Peitzsch, C.; Kurth, I.; Trautmann, F.; Kunz-Schughart, L.A.; Telegeev, G.D.; Stakhovsky, E.A.; Walker, J.R.; Simin, K.; Lyle, S.; et al. Aldehyde Dehydrogenase Is Regulated by beta-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Res. 2015, 75, 1482–1494.
  16. Zhang, J.; Zhang, Y.; Cheng, L.; Li, C.; Dai, L.; Zhang, H.; Yan, F.; Shi, H.; Dong, G.; Ning, Z.; et al. Enrichment and characterization of cancer stem-like cells in ultra-low concentration of serum and non-adhesive culture system. Am. J. Transl. Res. 2018, 10, 1552–1561.
  17. Portillo-Lara, R.; Alvarez, M.M. Enrichment of the Cancer Stem Phenotype in Sphere Cultures of Prostate Cancer Cell Lines Occurs through Activation of Developmental Pathways Mediated by the Transcriptional Regulator DeltaNp63alpha. PLoS ONE 2015, 10, e0130118.
  18. Sanchez, B.G.; Bort, A.; Vara-Ciruelos, D.; Diaz-Laviada, I. Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells. Cells 2020, 9, 1441.
  19. Wang, X.; Kruithof-de Julio, M.; Economides, K.D.; Walker, D.; Yu, H.; Halili, M.V.; Hu, Y.P.; Price, S.M.; Abate-Shen, C.; Shen, M.M. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 2009, 461, 495–500.
  20. Wang, S.; Garcia, A.J.; Wu, M.; Lawson, D.A.; Witte, O.N.; Wu, H. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc. Natl. Acad. Sci. USA 2006, 103, 1480–1485.
  21. Lang, S.H.; Anderson, E.; Fordham, R.; Collins, A.T. Modeling the prostate stem cell niche: An evaluation of stem cell survival and expansion in vitro. Stem Cells Dev. 2010, 19, 537–546.
  22. Singh, S.K.; Clarke, I.D.; Terasaki, M.; Bonn, V.E.; Hawkins, C.; Squire, J.; Dirks, P.B. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003, 63, 5821–5828.
  23. Miraglia, S.; Godfrey, W.; Yin, A.H.; Atkins, K.; Warnke, R.; Holden, J.T.; Bray, R.A.; Waller, E.K.; Buck, D.W. A novel five-transmembrane hematopoietic stem cell antigen: Isolation, characterization, and molecular cloning. Blood 1997, 90, 5013–5021.
  24. Yin, A.H.; Miraglia, S.; Zanjani, E.D.; Almeida-Porada, G.; Ogawa, M.; Leary, A.G.; Olweus, J.; Kearney, J.; Buck, D.W. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997, 90, 5002–5012.
  25. O’Brien, C.A.; Pollett, A.; Gallinger, S.; Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445, 106–110.
  26. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401.
  27. Yin, S.; Li, J.; Hu, C.; Chen, X.; Yao, M.; Yan, M.; Jiang, G.; Ge, C.; Xie, H.; Wan, D.; et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int. J. Cancer 2007, 120, 1444–1450.
  28. Hermann, P.C.; Huber, S.L.; Herrler, T.; Aicher, A.; Ellwart, J.W.; Guba, M.; Bruns, C.J.; Heeschen, C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1, 313–323.
  29. Eramo, A.; Lotti, F.; Sette, G.; Pilozzi, E.; Biffoni, M.; Di Virgilio, A.; Conticello, C.; Ruco, L.; Peschle, C.; De Maria, R. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008, 15, 504–514.
  30. Todaro, M.; Alea, M.P.; Di Stefano, A.B.; Cammareri, P.; Vermeulen, L.; Iovino, F.; Tripodo, C.; Russo, A.; Gulotta, G.; Medema, J.P.; et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 2007, 1, 389–402.
  31. Ricci-Vitiani, L.; Lombardi, D.G.; Pilozzi, E.; Biffoni, M.; Todaro, M.; Peschle, C.; De Maria, R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445, 111–115.
  32. Suetsugu, A.; Nagaki, M.; Aoki, H.; Motohashi, T.; Kunisada, T.; Moriwaki, H. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem. Biophys. Res. Commun. 2006, 351, 820–824.
  33. Shmelkov, S.V.; Butler, J.M.; Hooper, A.T.; Hormigo, A.; Kushner, J.; Milde, T.; St Clair, R.; Baljevic, M.; White, I.; Jin, D.K.; et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J. Clin. Investig. 2008, 118, 2111–2120.
  34. Wei, C.; Guomin, W.; Yujun, L.; Ruizhe, Q. Cancer stem-like cells in human prostate carcinoma cells DU145: The seeds of the cell line? Cancer Biol. Ther. 2007, 6, 763–768.
  35. Acikgoz, E.; Soner, B.C.; Ozdil, B.; Guven, M. CD133+/CD44+ prostate cancer stem cells exhibit embryo-like behavior patterns. Acta Histochem. 2021, 123, 151743.
  36. Miki, J.; Furusato, B.; Li, H.; Gu, Y.; Takahashi, H.; Egawa, S.; Sesterhenn, I.A.; McLeod, D.G.; Srivastava, S.; Rhim, J.S. Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res. 2007, 67, 3153–3161.
  37. Trerotola, M.; Rathore, S.; Goel, H.L.; Li, J.; Alberti, S.; Piantelli, M.; Adams, D.; Jiang, Z.; Languino, L.R. CD133, Trop-2 and alpha2beta1 integrin surface receptors as markers of putative human prostate cancer stem cells. Am. J. Transl. Res. 2010, 2, 135–144.
  38. Castellon, E.A.; Valenzuela, R.; Lillo, J.; Castillo, V.; Contreras, H.R.; Gallegos, I.; Mercado, A.; Huidobro, C. Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis. Biol. Res. 2012, 45, 297–305.
  39. Dalerba, P.; Dylla, S.J.; Park, I.K.; Liu, R.; Wang, X.; Cho, R.W.; Hoey, T.; Gurney, A.; Huang, E.H.; Simeone, D.M.; et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10158–10163.
  40. Haraguchi, N.; Ohkuma, M.; Sakashita, H.; Matsuzaki, S.; Tanaka, F.; Mimori, K.; Kamohara, Y.; Inoue, H.; Mori, M. CD133+CD44+ population efficiently enriches colon cancer initiating cells. Ann. Surg. Oncol. 2008, 15, 2927–2933.
  41. Su, C.Y.; Huang, G.C.; Chang, Y.C.; Chen, Y.J.; Fang, H.W. Analyzing the Expression of Biomarkers in Prostate Cancer Cell Lines. In Vivo 2021, 35, 1545–1548.
  42. Fargeas, C.A.; Huttner, W.B.; Corbeil, D. Nomenclature of prominin-1 (CD133) splice variants—An update. Tissue Antigens 2007, 69, 602–606.
  43. Baba, T.; Convery, P.A.; Matsumura, N.; Whitaker, R.S.; Kondoh, E.; Perry, T.; Huang, Z.; Bentley, R.C.; Mori, S.; Fujii, S.; et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 2009, 28, 209–218.
  44. Yi, J.M.; Tsai, H.C.; Glockner, S.C.; Lin, S.; Ohm, J.E.; Easwaran, H.; James, C.D.; Costello, J.F.; Riggins, G.; Eberhart, C.G.; et al. Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res. 2008, 68, 8094–8103.
  45. Shmelkov, S.V.; Jun, L.; St Clair, R.; McGarrigle, D.; Derderian, C.A.; Usenko, J.K.; Costa, C.; Zhang, F.; Guo, X.; Rafii, S. Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 2004, 103, 2055–2061.
  46. Tabu, K.; Sasai, K.; Kimura, T.; Wang, L.; Aoyanagi, E.; Kohsaka, S.; Tanino, M.; Nishihara, H.; Tanaka, S. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res. 2008, 18, 1037–1046.
  47. Uchida, N.; Buck, D.W.; He, D.; Reitsma, M.J.; Masek, M.; Phan, T.V.; Tsukamoto, A.S.; Gage, F.H.; Weissman, I.L. Direct isolation of human central nervous system stem cells. Proc. Natl. Acad. Sci. USA 2000, 97, 14720–14725.
  48. Lee, A.; Kessler, J.D.; Read, T.A.; Kaiser, C.; Corbeil, D.; Huttner, W.B.; Johnson, J.E.; Wechsler-Reya, R.J. Isolation of neural stem cells from the postnatal cerebellum. Nat. NeuroSci. 2005, 8, 723–729.
  49. Richardson, G.D.; Robson, C.N.; Lang, S.H.; Neal, D.E.; Maitland, N.J.; Collins, A.T. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 2004, 117, 3539–3545.
  50. Kordes, C.; Sawitza, I.; Muller-Marbach, A.; Ale-Agha, N.; Keitel, V.; Klonowski-Stumpe, H.; Haussinger, D. CD133+ hepatic stellate cells are progenitor cells. Biochem. Biophys. Res. Commun. 2007, 352, 410–417.
  51. Pellacani, D.; Packer, R.J.; Frame, F.M.; Oldridge, E.E.; Berry, P.A.; Labarthe, M.C.; Stower, M.J.; Simms, M.S.; Collins, A.T.; Maitland, N.J. Regulation of the stem cell marker CD133 is independent of promoter hypermethylation in human epithelial differentiation and cancer. Mol. Cancer 2011, 10, 94.
  52. Mak, A.B.; Nixon, A.M.; Moffat, J. The mixed lineage leukemia (MLL) fusion-associated gene AF4 promotes CD133 transcription. Cancer Res. 2012, 72, 1929–1934.
  53. Kim, I.; Saunders, T.L.; Morrison, S.J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 2007, 130, 470–483.
  54. Fukamachi, H.; Shimada, S.; Ito, K.; Ito, Y.; Yuasa, Y. CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation. Cancer Sci. 2011, 102, 1313–1321.
  55. Tabu, K.; Kimura, T.; Sasai, K.; Wang, L.; Bizen, N.; Nishihara, H.; Taga, T.; Tanaka, S. Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks. Mol. Cancer 2010, 9, 39.
  56. Zacchigna, S.; Oh, H.; Wilsch-Brauninger, M.; Missol-Kolka, E.; Jaszai, J.; Jansen, S.; Tanimoto, N.; Tonagel, F.; Seeliger, M.; Huttner, W.B.; et al. Loss of the cholesterol-binding protein prominin-1/CD133 causes disk dysmorphogenesis and photoreceptor degeneration. J. NeuroSci. 2009, 29, 2297–2308.
  57. Maw, M.A.; Corbeil, D.; Koch, J.; Hellwig, A.; Wilson-Wheeler, J.C.; Bridges, R.J.; Kumaramanickavel, G.; John, S.; Nancarrow, D.; Roper, K.; et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol. Genet. 2000, 9, 27–34.
  58. Sohn, H.M.; Kim, B.; Park, M.; Ko, Y.J.; Moon, Y.H.; Sun, J.M.; Jeong, B.C.; Kim, Y.W.; Lim, W. Effect of CD133 overexpression on bone metastasis in prostate cancer cell line LNCaP. Oncol. Lett. 2019, 18, 1189–1198.
  59. Vander Griend, D.J.; Karthaus, W.L.; Dalrymple, S.; Meeker, A.; DeMarzo, A.M.; Isaacs, J.T. The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 2008, 68, 9703–9711.
  60. Wei, Y.; Jiang, Y.; Zou, F.; Liu, Y.; Wang, S.; Xu, N.; Xu, W.; Cui, C.; Xing, Y.; Liu, Y.; et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc. Natl. Acad. Sci. USA 2013, 110, 6829–6834.
  61. Manoranjan, B.; Chokshi, C.; Venugopal, C.; Subapanditha, M.; Savage, N.; Tatari, N.; Provias, J.P.; Murty, N.K.; Moffat, J.; Doble, B.W.; et al. A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells. Oncogene 2020, 39, 1590–1599.
  62. Bisson, I.; Prowse, D.M. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009, 19, 683–697.
  63. Murillo-Garzon, V.; Kypta, R. WNT signalling in prostate cancer. Nat. Rev. Urol. 2017, 14, 683–696.
  64. Soeda, A.; Park, M.; Lee, D.; Mintz, A.; Androutsellis-Theotokis, A.; McKay, R.D.; Engh, J.; Iwama, T.; Kunisada, T.; Kassam, A.B.; et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 2009, 28, 3949–3959.
  65. Matsumoto, K.; Arao, T.; Tanaka, K.; Kaneda, H.; Kudo, K.; Fujita, Y.; Tamura, D.; Aomatsu, K.; Tamura, T.; Yamada, Y.; et al. mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res. 2009, 69, 7160–7164.
  66. Ma, Y.; Liang, D.; Liu, J.; Axcrona, K.; Kvalheim, G.; Stokke, T.; Nesland, J.M.; Suo, Z. Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. PLoS ONE 2011, 6, e29170.
  67. Griguer, C.E.; Oliva, C.R.; Gobin, E.; Marcorelles, P.; Benos, D.J.; Lancaster, J.R., Jr.; Gillespie, G.Y. CD133 is a marker of bioenergetic stress in human glioma. PLoS ONE 2008, 3, e3655.
  68. Ye, X.Q.; Li, Q.; Wang, G.H.; Sun, F.F.; Huang, G.J.; Bian, X.W.; Yu, S.C.; Qian, G.S. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int. J. Cancer 2011, 129, 820–831.
  69. Kim, Y.S.; Kang, M.J.; Cho, Y.M. Low production of reactive oxygen species and high DNA repair: Mechanism of radioresistance of prostate cancer stem cells. Anticancer Res. 2013, 33, 4469–4474.
  70. Gupta, G.P.; Massague, J. Cancer metastasis: Building a framework. Cell 2006, 127, 679–695.
  71. Bubendorf, L.; Schopfer, A.; Wagner, U.; Sauter, G.; Moch, H.; Willi, N.; Gasser, T.C.; Mihatsch, M.J. Metastatic patterns of prostate cancer: An autopsy study of 1,589 patients. Hum. Pathol. 2000, 31, 578–583.
  72. Ricci, E.; Mattei, E.; Dumontet, C.; Eaton, C.L.; Hamdy, F.; van der Pluije, G.; Cecchini, M.; Thalmann, G.; Clezardin, P.; Colombel, M. Increased expression of putative cancer stem cell markers in the bone marrow of prostate cancer patients is associated with bone metastasis progression. Prostate 2013, 73, 1738–1746.
  73. Yao, D.; Dai, C.; Peng, S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 2011, 9, 1608–1620.
  74. Gunasinghe, N.P.; Wells, A.; Thompson, E.W.; Hugo, H.J. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012, 31, 469–478.
  75. Mehra, N.; Penning, M.; Maas, J.; Beerepoot, L.V.; van Daal, N.; van Gils, C.H.; Giles, R.H.; Voest, E.E. Progenitor marker CD133 mRNA is elevated in peripheral blood of cancer patients with bone metastases. Clin. Cancer Res. 2006, 12, 4859–4866.
  76. Horst, D.; Kriegl, L.; Engel, J.; Kirchner, T.; Jung, A. CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br. J. Cancer 2008, 99, 1285–1289.
  77. Shin, J.H.; Lee, Y.S.; Hong, Y.K.; Kang, C.S. Correlation between the prognostic value and the expression of the stem cell marker CD133 and isocitrate dehydrogenase1 in glioblastomas. J. NeuroOncol. 2013, 115, 333–341.
  78. Ishigami, S.; Ueno, S.; Arigami, T.; Uchikado, Y.; Setoyama, T.; Arima, H.; Kita, Y.; Kurahara, H.; Okumura, H.; Matsumoto, M.; et al. Prognostic impact of CD133 expression in gastric carcinoma. Anticancer Res. 2010, 30, 2453–2457.
  79. Silva, I.A.; Bai, S.; McLean, K.; Yang, K.; Griffith, K.; Thomas, D.; Ginestier, C.; Johnston, C.; Kueck, A.; Reynolds, R.K.; et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011, 71, 3991–4001.
  80. Nakamura, M.; Kyo, S.; Zhang, B.; Zhang, X.; Mizumoto, Y.; Takakura, M.; Maida, Y.; Mori, N.; Hashimoto, M.; Ohno, S.; et al. Prognostic impact of CD133 expression as a tumor-initiating cell marker in endometrial cancer. Hum. Pathol. 2010, 41, 1516–1529.
  81. Reyes, E.E.; Gillard, M.; Duggan, R.; Wroblewski, K.; Kregel, S.; Isikbay, M.; Kach, J.; Brechka, H.; Weele, D.J.; Szmulewitz, R.Z.; et al. Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J. Transl. Sci. 2015, 1.
  82. Yang, Y.; Liu, Z.; Wang, Q.; Chang, K.; Zhang, J.; Ye, D.; Kong, Y.; Dai, B. Presence of CD133-positive circulating tumor cells predicts worse progression-free survival in patients with metastatic castration-sensitive prostate cancer. Int. J. Urol. 2022, 29, 383–389.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback