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Cancer Stem Cell Markers in Glioblastoma – an Update

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Cancer Stem Cell Markers in Glioblastoma – an Update European Review for Medical and Pharmacological Sciences 2017; 21: 3207-3211 Cancer stem cell markers in glioblastoma – an update H.-S. XU1, X.-L. QIN2, H.-L. ZONG1, X.-G. HE, L. CAO1 1Department of Neurosurgery, Affiliated Xuzhou Hospital of Southeast University, Xuzhou, Jiangsu Province, China 2Department of Neurology, Affiliated Xuzhou Hospital of Southeast University, Xuzhou, Jiangsu Province, China Hongsheng Xu and Xiaoling Qin contributed equally to this work Abstract. – The glioblastoma includes brain prospective isolation and study of such cells. Ini- tumors, which are very aggressive in nature and tial studies of the surface marker PROM1 (CD133/ are among the most common brain tumors in AC133/Prominin-1) suggested that PROM1+ cells adults. Latest therapeutic avenues involve com- were responsible for repopulating tumors, while bination approach. However, the observed medi- 3 an survival is still no more than 15 months. More- PROM1-cells did not have this capacity . However, over, there is a scarcity of accurate pre-clinical this proved to be less reliable as subsequently stu- model systems, which in turn resulted in limit- dies showed that both PROM1+ and PROM1-po- ed treatment options for this disease. Cancer pulations were able to generate tumors following stem cells are attractive avenues in anticancer transplantation into mice4. Also, this has been the research against glioblastoma. Most of the re- case for other markers described in the literature. cent studies are focused towards the identifica- Despite the absence of a single defining biomar- tion of novel markers for cancer stem cells. The present review article is focused on two import- ker, there is a high expression of a large number ant markers in current research viz. Prominin-1 of stem cell associated genes (e.g. NESTIN, GFAP, and NPM1 in glioblastoma. SOX2, A2B5, NANOG, OKT4, CD44 and KLF4) in glioblastomas5. Several of these are transcription Key Words: factors linked to embryonic development and stem/ Glioblastoma, NPM1, Cancer stem cells, Prominin-1. progenitor cells suggesting an activity of stem/pro- genitor cell associated transcriptional networks in glioblastoma. Genetically engineered mouse mo- Introduction dels (GEMMs) have also provided extra support to CSCs residing in the tumors giving rise to transient Glioblastoma cancer stem cells (CSCs) are the amplifying cells and differentiated progeny in a fa- population of cells with the potency to form neu- shion similar to NSCs6. However, it remains uncle- rospheres, when cultured under NSC conditions, ar the exact mechanism of differentiation pathways showing multi lineage (neuronal-, astrocytic- and such as progenitor and terminally differentiated oligodendroglial-like) differentiation1. Even thou- cell states. To add more complexity to the stem cell gh the term CSCs has been accepted for variants markers, a new research has shown that many of of leukemia, there is still a debate regarding CSCs them are context dependent acting together with in solid tumors. Stem cells, whether it comes to other factors to exert their final function; for exam- cancer or normal stem cells, are functionally defi- ple GFAP is expressed in stem cells as well as in ned as cells with the capacity of self-renewal and differentiated astrocytes, potentially serving diffe- multi-potency. Stem cells continuously self-renew rent functions7. throughout our life span and would, thereby, be more likely to accumulate mutations. Even if the Glioblastoma cell of Origin origin of CSCs is not defined, cancer cells with The glioblastoma cell of origin has long been stem cell properties are found in various types of debated. Theories about identification of CSCs in cancers including glioblastoma2. An ongoing chal- glioblastoma have certainly refueled this question. lenge with glioblastoma CSCs has been to identify Reviewing the literature with regards to glioma a robust defining biomarker that could be used for models and GEMMs, it is more likely that gliobla- Corresponding Author: Hongsheng Xu, MD; e-mail: [email protected] 3207 H.-S. Xu, X.-L. Qin, H.-L. Zong, X.-G. He, L. Cao stomas arise from transformed neural stem/proge- teins actual function and its expression across the nitor cells than from differentiated neural cells. differentiation spectrum of cells. GEMMs utilizing stem/progenitor-associated ge- nes, such as GFAP and NESTIN for cell targeting, Prominin-1 in Glioblastoma illustrated that cells expressing these genes could Prominin-1 has been observed to identify tu- be transformed into glioblastomas8. This transfor- mor-initiating cancer stem cells in numerous mation process more readily occurs in stem cell cancers including leukemia, breast and gliobla- niches of the adult brain, such as the SVZ, and stoma19. The cancer stem cell hypothesis sugge- could be induced by some glioblastoma associa- sted that only a minor subpopulation of the tumor ted genetic events9. Mouse glioma cells have also cells have indefinite ability to self-renew in order been shown to be dependent on OLIG2 function to promote tumor growth and invasion. Based on similarly to normal oligodendrocyte lineage cel- flow cytometry analysis, PROM1+ cells in glio- ls, that in turn has raised the possibility that glio- blastoma have been described as tumor initiating blastoma arisen from this lineage10. In addition to cells and have been observed to propagate tumor niche progenitors, the fact that NG2+/OLIG2+ growth in immune-deficient NOD/SCID mice progenitor cells are the most abundant dividing xenograft models along with radio resistance20. cells in the brain, suggested that these might be However, glioblastoma PROM1-cells could also source of glioblastoma. Even though GEMMs are contribute to tumor propagation21. This raises the not as prone to form glioblastomas when differen- possibility that Prominin-1 might not be as closely tiated cells are targeted under more physiological related to tumor initiation in normal cells or can- conditions, it is possible to transform neurons into cer cells as previously proposed. Recent studies of glioblastoma cells11. PROM1 have used alternatives to flow cytometry, which allow more direct in situ visualization of its Prominin-1 (PROM1/Cd133) expression. These studies have also increasingly Prominin-1 was the first 5-transmembrane (5- highlighted Prominin-1 non-stem cell functions in TM) protein identified in the prominin family12. the hematopoietic, retinal and prostate systems22. Since its discovery, several research groups have Also, expression of PROM1 has been seen to be described prominin-1 as a stem cell marker, al- controlled by hypoxia, supporting the possibility though evidence in the normal nervous system is that PROM1 may be a dynamically regulated pro- very limited and surpassed by the interest in the tein not necessarily associated with cell lineage cancer stem cell community13. PROM1 is a sin- or stem cell phenotypes23. Multiple studies have gle-chain polypeptide of 865 amino acids with shown neurosphere formation or PROM1 antigen 5-TM regions, extracellular N-terminus and cyto- expression to be associated with shorter survival plasmic C-terminus. It has two extracellular loops in patients and in mice transplanted with such tu- with eight sites each for N-linked glycosylation. mor cells24. This would imply that PROM1 could PROM1 was first discovered in human hemato- serve as a prognostic marker; however, the biolo- poietic progenitor cells, but it was later described gy behind this has not been explained. in mouse tissue14. Mouse PROM1 has only 60% amino acid identity with the human PROM1. On Npm1 (Nucleophosmin/B23) the other hand it has a very similar protein structu- Cancer cells, including glioma cells, display in- re. Prominin-1 has been detected in many diffe- creasing nucleolar prominence and number alon- rent tissue types: brain, intestine, kidney, bone gside coarsening and dispersion of chromatin25. marrow, heart, liver, lung, pancreas, placenta, Given this, the nucleolus and nucleolar proteins skeletal muscle, and testis, either through mRNA hold a potential interesting role in cancer. NPM1 or antibody15. At least two splice variants exist is a non-ribosomal nucleolar protein that has been for human PROM1 and 8 are available for mouse related to cancer26. PROM116. Evidence suggested that Prominin-1 in- teracts with micro domains known as lipid rafts in The Nucleolus and Nucleolar Stress the plasma. Mutations in PROM1 have also been Nucleoli are dynamic nuclear compartments observed to cause retinal degeneration17. PROM1 rich in protein and RNA, where the cell’s ribosome has been associated with CSCs in a wide number biogenesis takes place27. The nucleolus is the mir- of cancers, particularly in the CNS18. Even though ror of a series of metabolic changes in cancer cel- researchers have shown great interest in studying ls, and human tumors with nucleolar hypertrophy PROM1, there is limited knowledge about pro- have a worse prognosis28. The recent finding re- 3208 Cancer stem cell markers in glioblastoma – an update garding hTERT promoter mutation is of interest is not the only nucleolar protein capable of media- in glioblastoma, and the nucleolus is the assembly ting p53 stabilization following nucleolar stress41. place for the telomerase complex29,30. Furthermo- Furthermore, NPM1 interacts with proteins invol- re, TP53 mutations and RB loss, also common in ved in maintaining nucleolar structure. One such glioblastoma, are related to higher degree of nu- protein is CTCF, a sequence-specific DNA
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