Abstract 3356: A controversial study on well reported liver cancer stem cell marker
Ching-Huai KoHsiang‐Wen TsengTing-Shou ChenWei‐Hsin WangMai-Wei LinChin-Pen LaiChun-Chung WangChung-Yuan SunShih‐Heng TsengJen-Ming LiTing-Yu ChouLing-Mei Wang
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Abstract Recent studies suggest that the presence of cancer stem cells (CSC) could be linked with patients’ survival. The ability of cancers to grow indefinitely has fueled the idea that cancer and stem cells may have common underlying mechanisms. It has been suggested that tumors are initiated from cancer stem cells (CSCs) with proliferation potential drives the growth of cancer. CSCs are resistant to chemotherapy and radiation. However, the suggested cancer stem cell markers in human hepatocellular carcinoma cells are variable and confused. In this study, we profiled some of the most reported CSC markers, including CD133, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH), CD90, CD24, c-kit, global-H and stemness genes in eight human hepatocellular carcinoma cell lines. Through specific marker expressed cell sorting by FACs aria or magnetic beads, the CSC associated drug resistance and tumorigenicity were further evaluated. However, there is no obvious difference among parental group, marker-positive group and marker-negative group in these CSC characteristics evaluated. It seems no good correlation between reported markers in liver cancer stem cells. Therefore, presence of markers alone should be taken with caution as single prognostic parameters. Through harsh culture condition, spheroid cell grew and had been isolated, which perform CSC-like properties. Moreover, forced activation of an ESC-like gene expression program can reprogram HCC cells into CSC-like cells and achieve pathologic self-renewal. The ability to create induced cancer stem cells (iCSC) may provide opportunities to better define the biology of cancer stem cells in order to trace or eliminate them in human patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3356.Keywords:
CD90
Stem cell marker
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// Marketa Svobodova 1, 2, 3 , Martina Raudenska 1, 3 , Jaromir Gumulec 1, 3 , Jan Balvan 1 , Michaela Fojtu 1 , Monika Kratochvilova 1, 3 , Hana Polanska 1, 2, 3 , Zuzana Horakova 4 , Rom Kostrica 4 , Petr Babula 1 , Zbynek Heger 3, 5 and Michal Masarik 1, 2 1 Department of Physiology, Faculty of Medicine, Masaryk University, CZ-62500 Brno, Czech Republic 2 Department of Pathological Physiology, Faculty of Medicine, Masaryk University, CZ-62500 Brno, Czech Republic 3 Central European Institute of Technology, Brno University of Technology, CZ-61600 Brno, Czech Republic 4 Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne's Faculty Hospital, CZ-65691 Brno, Czech Republic 5 Department of Chemistry and Biochemistry, Mendel University in Brno, CZ-61300 Brno, Czech Republic Correspondence to: Michal Masarik, email: masarik@med.muni.cz Keywords: head and neck neoplasms, coculture techniques, cell line, tumor, carcinoma Received: May 24, 2017 Accepted: June 28, 2017 Published: August 03, 2017 ABSTRACT In this study, we describe the establishment of the human papillomavirus 18-positive, stage II, grade 1, T2N0M0 head and neck tumor primary cell line derived from oral squamous cell carcinoma of a non-smoking patient by using two different protocols. Furthermore, a preparation of subpopulations derived from this primary cell line according to the cluster of differentiation molecules CD44/CD90 status using magnetic bead-based separation and their characterization was performed. Impedance-based real-time cell analysis, enzyme-linked immunsorbant assay (ELISA), wound-healing assay, flow-cytometry, gene expression analysis, and MTT assay were used to characterize these four subpopulations (CD44 + /CD90 − , CD44 − /CD90 − , CD44 + /CD90 + , CD44 − /CD90 − ). We optimised methodics for establishement of primary cell lines derived from oral squamous cell carcinoma tissue samples and subsequent separation of mesenchymal (CD90 + ) and epithelial (CD90 − ) types of tumorous cells. Primary cell line prepared by using trypsin proteolysis was more viable than the one prepared by using collagenase. According to our results, CD90 separation is a necessary step in preparation of permanent tumor-tissue derived cell lines. Based on the wound-healing assay, CD44 + cells exhibited stronger migratory capacity than CD44 − subpopulations. CD44 + subpopulations had also significantly higher expression of BIRC5 and SOX2 , lower expression of FLT1 and IL6 , and higher levels of basal autophagy compared to CD44 − subpopulations. Furthermore, co-cultivation experiments revealed that CD44 − /CD90 + cells supported growth of epithelial tumor cells (CD44 + /CD90 − ). On the contrary, factors released by CD44 + /CD90 + type of cells seem to have rather inhibiting effect. The most cisplatin-resistant subpopulation with the shortest doubling time was CD44 − /CD90 + , but this subpopulation had a low migratory capacity.
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Cancer Stem Cells (CSCs) have been recently identified and their role in carcinogenesis has been ascertained. CSCs have been correlated with high relapse in certain cancers, multiple drug resistance against chemotherapy and metastasis. Several markers such as CD133, CD24, CD44, EpCAM, and CD26 have been identified to isolate and characterize CSCs. None of these markers or their combinations are universal in nature and can be used to isolate CSCs from all types of cancer. CD90 is one such marker whose expression has been extensively studied in recent years. CD90+ cells have been isolated from several types of tumors and shown to exhibit cardinal properties of CSCs such as proliferation, differentiation, spheroid formation, metastasis and ability to form tumor xenograft in immunodeficient mice. It is also found to be co-expressed with several other CSC markers. CD90 is therefore, suggested as a candidate marker as well as a potential therapeutic target for elimination of CSCs.
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Objective:To study the expression of CD90 and CD44 in human hepatocelluar carcinoma(HCC) tissues,and to explore the relationship between their expression and recurrence of HCC.Methods: We collected tissue samples of 20 HCC patients,who had been followed up for more than one year,including 10 cases with recurrence and 10 cases without recurrence.Specimens were embedded in paraffin,and then 3 pieces were cut from each specimen in the thickness of 1μm.The first piece was routinely HE stained for pathological diagnosis.The other two consecutive pieces were used to detect CD90 and CD44 by immunohistochemistry.The expression of CD90 and CD44 in recurrence group and recurrence-free group was compared.Results: The expression of CD90 and CD44 in human HCC tissues was from 0.13% to 4.10%.The expression of CD90 and CD44 had a relationship with HCC recurrence and prognosis.The expression of CD90 in the recurrent group was significantly higher than that in the recurrent-free group.Most of CD90 or CD44 positive cells were closed to vessels in recurrence group.Conclusions: Liver cancer stem cells exist in HCC tumor tissues with significant heterogeneity,and they express a variety of cancer stem cell markers such as CD90 and CD44.The expression of liver cancer stem cell markers is correlated with recurrence of HCC.
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The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial-mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44-CD90- populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.
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Objective To evaluate the expression of several CD cell markers and investigate their significance in hepatocellular carcinoma cell lines with different metastatic potential. Methods Three human hepatocellular cell lines,HepG2,MHCC-97H and SK-HEP-1 were cultivated by routine method.Single cell suspension was achieved by digestion with trypsin.After CD133,CD90,CD44, CD34 and CD24 antibody labeling,cells were analyzed by flow cytometry. Results CD133+ cells represented only a very small subpopulation in three hepatocellular carcinoma cell lines(0.1%~0.4%).In addition,CD90+,CD44+ and CD90+CD44+cells were detected in the three cell lines and the percentage increased with the development of metastatic potential(P﹤0.05).The expression rates of CD44+CD24+ cells in HepG2,MHCC-97H and SK-HEP-1 were 0.05%,10.3% and 0.3%,respectively(P﹤0.05).Furthermore,no CD34+ or CD133+CD90+ expression was observed in the three cell lines. Conclusion CD90 and CD44 are significantly correlated with the metastatic potential of hepatocellular carcinoma cells and may be prospective markers for hepatocellular carcinoma stem cells.
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Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures.We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo.All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones.Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.
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Although the cancer stem cell (CSC) hypothesis has been around for many years, the reliability of cell-surface markers to classify CSCs has remained debatable. The finding that cancerous cells are significantly more deformable than healthy ones has provided motivation to consider mechanical properties as a possible biomarker for stemness. In this study, using the micropipette aspiration technique, mechanical properties of multiple breast cancer cell lines were investigated and correlated with breast cancer stem cell (BCSC) marker, CD44+/CD24-/ALDH1+. The results indicated that Hs578T and MDA-MB-231 cell lines with CD44+/CD24-/ALDH1+ phenotype were significantly more deformable than the MDA-MB-468 cell line, which did not express the BCSC marker. The BT-20 cell line with intermediate deformability did not express any CD44+/CD24- phenotype, but it expressed aldehyde dehydrogenase-1 activity. In addition, more-deformable cell lines were found to roll with shear-independent velocities on E-selectin-coated substrates in a parallel-plate flow chamber, which might be a mediating factor for firm adhesion of CSCs to endothelium during metastasis. Our results indicate that rheological properties can be considered as a biomechanical marker in addition to, or as a complement of, surface markers to find more-definitive evidence of CSC characteristics within tumors.-Mohammadalipour, A., Burdick, M. M., Tees, D. F. J. Deformability of breast cancer cells in correlation with surface markers and cell rolling.
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