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| 1 | Circulating cancer stem cells:the importance to select显示文摘It has been demonstrated that even localized tumors without clinically apparent metastasis give rise to circulating tumor cells(CTCs).A growing number of technically diverse platforms are being developed for detecting/isolating CTCs in the circulating blood.Despite the technical challenges of isolating rare CTCs from blood,recent studies have already shown the predictive value of CTCs enumeration.Thus,it is becoming increasingly accepted that CTC numbers are linked to patients' outcome and may also be used to monitor treatment response and disease relapse,respectively.Further CTCs provide a non-invasive source for tumor material,'liquid biopsy',which is particularly important for patients,where no biopsy material can be obtained or where serial biopsies of the tumor,e.g.,following treatment,are practically impossible.On the other hand the molecular and biological characterization of CTCs has still remained at a rather experimental stage.Future studies are necessary to define CTC heterogeneity to establish the crucial role of circulating cancer stem cells for driving metastasis,which represent a distinct subpopulation of CTCs that bear metastasis-initiating capabilities based on their stemness properties and invasiveness and thus are critical for the patients' clinical outcome.As compared to non-tumorigenic/metastatic bulk CTCs,circulating cancer stem cells may not only be capable of evading from the primary tumor,but also escape from immune surveillance,survive in the circulating blood and subsequently form metastases in distant organs.Thus,circulating cancer stem cells represent a subset of exclusively tumorigenic cancer stem cells characterized by their invasive characteristics and are potential therapeutic targets for preventing disease progression.To date,only a few original reports and reviews have been published focusing on circulating cancer stem cells.This review discusses the potential importance of isolating and characterizing these circulating cancer stem cells,but also highlights current technological limitations. | Ming-Hsin Yang Ahmet Imrali Christopher Heeschen | 2015 | Chinese Journal of Cancer Research2015，27，5： | 9 |
| 2 | Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer显示文摘 | Patrick C. Hermann Stephan L. Huber Tanja Herrler Alexandra Aicher Joachim W. Ellwart Markus Guba Christiane J. Bruns Christopher Heeschen | 2007 | Cell Stem Cell2007，，3： | 5 |
| 3 | Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells显示文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance. | Petra Jagust Sonia Alcala Bruno Sainz Jr Christopher Heeschen Patricia Sancho | 2020 | World Journal of Stem Cells2020，12，11： | 2 |
| 4 | lnterleukin--10 serum levels and systemic endothelial vasoreactivity in patients with coronary artery disease显示文摘 | IFichtlscherer S Brener S Heeschen C | 2004 | J Am Coil Cardiol2004，44，1： | 1 |
| 5 | Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident pro- genitor cells 显示文摘 | Urbich C Aicher A Heeschen C | 2005 | J Mol Cell Cardiol2005，39，： | 1 |
| 6 | Second hand smoke stimulates tumor angiogenesis and growth显示文摘 | Zhu BQ Heeschen C Sievers RE | 2003 | Cancer Cell2003，4，3： | 1 |
| 7 | Soluble CD40 ligand in Acute Coronary Syndromes显示文摘 | Heeschen G Dimmeler S Hamm CW | 2003 | N Engl J Med2003，348，12： | 1 |
| 8 | N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes显示文摘 | Heeschen C Hamm CW Mitrovic V | 2004 | Circulation2004，110，20： | 1 |
| 9 | Serum level of the anti- inflammatory cytokine interleukin - 10 is an important prognostic determinant in patients with acute coronary syndromes 显示文摘 | Heeschen C Dimmeler S Harem CW | 2003 | Circulation2003，107，16： | 1 |
| 10 | Statins have biphasic effects on angiogenesis显示文摘 | WEIS M HEESCHEN C GLASSFORD A J | 2002 | Circulation2002，105，6： | 1 |
| 11 | Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis 显示文摘 | Heeschen C Jang JJ Weis M | 2001 | Nat Med2001，7，7： | 1 |
| 12 | Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization显示文摘 | Heeschen C Aicher A Lehmann R | 2003 | Blood2003，102，： | 1 |
| 13 | Withdrawal of statins increases event rates in patients with acute coronary syndromes显示文摘 | HEESCHEN C HAMM CW LAUFS U | 2002 | Circulation2002，105，12： | 1 |
| 14 | N-terminal pro B- type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes显示文摘 | Heeschen C Hamm C W Mitrovie V | 2004 | Circulation2004，110，20： | 1 |
| 15 | Statins have biphasic effects on angiogenesis显示文摘 | Weis M Heeschen C Glassford AJ | | 0，，： | 1 |
| 16 | Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells 显示文摘 | Aicher A Heeschen C Mildner-Rihm C | 2003 | Nat Med2003，9，： | 1 |
| 17 | Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels, c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina ( CAPTURE ) Study Investigators 显示文摘 | Hamm C W Heeschen C Goldmann B | 1999 | N Engl J Med1999，340，： | 1 |
| 18 | Improvement of postnatal neovascularization by human adipose tissue-derived stem cells 显示文摘 | Miranville A Heeschen C Sengenes C | 2004 | Circulation2004，10，3： | 1 |
| 19 | Analyticl and diagnostic performance of troponin assays in patients suspicious for acute coronary syndromes显示文摘 | Heeschen C Deu A Langenbrink L | 2000 | Clin Biochem2000，33，5： | 1 |
| 20 | Essential role of endo thelial nitric oxide synthase for mobilization of stem and progenitor cells显示文摘 | Aicher A Heeschen C Mildner-Rihm C | 2003 | Nat Med2003，9，11： | 1 |
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