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Biophysics Reports 2019, 5(1): 10-18 https://doi.org/10.1007/s41048-018-0080-0
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Detection of cancer cells based on glycolytic-regulated surface electrical charges

Show Author's Information Wenjun Le1,  Bingdi Chen1,  Zheng Cui1,2,  Zhongmin Liu1( ),  Donglu Shi1,3( )
The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
Department of Pathology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA
Department of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA
Keywords:
Nanotechnology, Cancer cell, Circulating tumor cells, Cell surface charge
Cite this article:
Le W, Chen B, Cui Z, et al. Detection of cancer cells based on glycolytic-regulated surface electrical charges. Biophysics Reports, 2019, 5(1): 10-18. https://doi.org/10.1007/s41048-018-0080-0
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Abstract Full text About this article

Over the past decades, cell surface charge, although experimentally observed, has not been well understood particularly from the viewpoint of biophysics. Our recent studies have shown that all cancer cells exhibit negative surface charges that are directly proportional to the secreted lactic acid, a unique cancer metabolic characteristic: high rate of glycolysis. We have therefore designed and developed a set of electrically-charged, fluorescent, and super-paramagnetic nanoprobes, capable of sensitive detection of cancer cells based on the surface charges. These probes are utilized to bind onto cells via electrostatic reaction for capture and magnetic separation. In this fashion, we are able to characterize cell surface charges that are regulated by different metabolic patterns, therefore effectively distinguishing the cancer cells from the normal cells. All 22 cancer cells of different organs are found to be negatively-charged therefore bound strongly by the positively-charged nanoprobes, whereas the normal cells show insignificant binding to the nanoprobes of either charge signs (positive or negative). This finding suggests that all tested cancer cells are negatively-charged and normal cells are either charge-neutral or slightly positive. For diagnosis, cancer cells can be detected, electrostatically bound, and magnetically separated in blood by charged and super-paramagnetic nanoprobes. In therapeutics, circulating cancer cells (CTCs) can be filtered and removed in a continuous fashion to reduce the risk of cancer metastasis. If successful, this new nanotechnology will revolutionize early cancer diagnosis and potentially enable new therapeutics in clinical settings.


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About this article

Detection of cancer cells based on glycolytic-regulated surface electrical charges

Show Author's information Wenjun Le1, Bingdi Chen1, Zheng Cui1,2, Zhongmin Liu1( ), Donglu Shi1,3( )
The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University, Shanghai 200092, China
Department of Pathology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA
Department of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA

Abstract

Over the past decades, cell surface charge, although experimentally observed, has not been well understood particularly from the viewpoint of biophysics. Our recent studies have shown that all cancer cells exhibit negative surface charges that are directly proportional to the secreted lactic acid, a unique cancer metabolic characteristic: high rate of glycolysis. We have therefore designed and developed a set of electrically-charged, fluorescent, and super-paramagnetic nanoprobes, capable of sensitive detection of cancer cells based on the surface charges. These probes are utilized to bind onto cells via electrostatic reaction for capture and magnetic separation. In this fashion, we are able to characterize cell surface charges that are regulated by different metabolic patterns, therefore effectively distinguishing the cancer cells from the normal cells. All 22 cancer cells of different organs are found to be negatively-charged therefore bound strongly by the positively-charged nanoprobes, whereas the normal cells show insignificant binding to the nanoprobes of either charge signs (positive or negative). This finding suggests that all tested cancer cells are negatively-charged and normal cells are either charge-neutral or slightly positive. For diagnosis, cancer cells can be detected, electrostatically bound, and magnetically separated in blood by charged and super-paramagnetic nanoprobes. In therapeutics, circulating cancer cells (CTCs) can be filtered and removed in a continuous fashion to reduce the risk of cancer metastasis. If successful, this new nanotechnology will revolutionize early cancer diagnosis and potentially enable new therapeutics in clinical settings.

Keywords: Nanotechnology, Cancer cell, Circulating tumor cells, Cell surface charge

References(63)

Ambrose EJ, James AM, Lowick JHB, (1956) Differences between the electrical charge carried by normal and homologous tumour cells.Nature 177(4508):576
DOI Google Scholar

Ashworth TR, (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death.Aust Med J 14:146
Google Scholar

Blanks MJ, Stehle JR, Du W, Adams JM, Willingham MC, Allen GO, Hu JJ, Lovato J, Molnar I, Cui Z, (2011) Novel innate cancer killing activity in humans.Cancer Cell Int 11(1):26
DOI Google Scholar

Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M, (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab 24(5):657-671
DOI Google Scholar

Chaffer CL, Weinberg RA, (2011) A perspective on cancer cell metastasis.Science 331(6024):1559-1564
DOI Google Scholar

Chen B, Le W, Wang Y, Li Z, Wang D, Ren L, Lin L, Cui S, Hun JJ, Hu Y, Yang P, Ewing RC, Shi DL, Cui Z, (2016) Targeting negative surface charges of cancer cells by multifunctional nanoprobes.Theranostics 6(11):1887
DOI Google Scholar

Chikaishi Y, Yoneda K, Ohnaga T, Tanaka F, (2017) EpCAM-independent capture of circulating tumor cells with a ‘universal CTC-chip’.Oncol Rep 37(1):77-82
DOI Google Scholar

Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R, (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.Nature 513(7519):559
DOI Google Scholar
Copeland L , Turner JF (1980) The regulation of glycolysis and the pentose phosphate pathway. In: Davies DD (ed) Metabolism and respiration. Academic Press, New York, pp 279–316
DOI
Cui Z (2011) Granular cell anticancer therapy. Tsinghua UniversityPress, Beijing

Cui Z, Willingham MC, Hicks AM, Alexander-Miller MA, Howard TD, Hawkins GA, Miller MS, Weir HM, Du W, DeLong CJ, (2003) Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice.Proc Natl Acad Sci USA 100(11):6682-6687
DOI Google Scholar

De Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D, (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.Clin Cancer Res 14(19):6302-6309
DOI Google Scholar

den Toonder J, (2011) Circulating tumor cells: the grand challenge.Lab Chip 11(3):375-377
DOI Google Scholar

Dubyak GR, (2004) Ion homeostasis, channels, and transporters: an update on cellular mechanisms.Adv Physiol Educ 28(4):143-154
DOI Google Scholar

Fu D, Mitra K, Sengupta P, Jarnik M, Lippincott-Schwartz J, Arias IM, (2013) Coordinated elevation of mitochondrial oxidative phosphorylation and autophagy help drive hepatocyte polarization.Proc Natl Acad Sci USA 110(18):7288-7293
DOI Google Scholar

Gadsby DC, (2009) Ion channels versus ion pumps: the principal difference, in principle.Nat Rev Mol Cell Biol 10(5):344
DOI Google Scholar

Gadsby DC, Takeuchi A, Artigas P, Reyes N, (2009) Peering into an ATPase ion pump with single-channel recordings.Philos Trans R Soc B 364(1514):229-238
DOI Google Scholar

Ghossein RA, Rosai J, (1996) Polymerase chain reaction in the detection of micrometastases and circulating tumor cells.Cancer 78(1):10-16
DOI

Ghossein RA, Scher HI, Gerald WL, Kelly WK, Curley T, Amsterdam A, Zhang ZF, Rosai J, (1995) Detection of circulating tumor cells in patients with localized and metastatic prostatic carcinoma: clinical implications.J Clin Oncol 13(5):1195-1200
DOI Google Scholar

Gogichadze G, Gogichadze T, Misabishvili E, Kamkamidze G, (2014) Possible effect of variable membrane potential of a cancer cell on different carcinogenic processes.Georgian Med News 234:116-120
Google Scholar

Gorges TM, Tinhofer I, Drosch M, Röse L, Zollner M, Krahn T, von Ahsen O, (2012) Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition.BMC Cancer 12(1):178
DOI Google Scholar

Haber DA, Gray NS, Baselga J, (2011) The evolving war on cancer.Cell 145(1):19-24
DOI Google Scholar

Hanahan D, Weinberg RA, (2011) Hallmarks of cancer: the next generation.Cell 144(5):646-674
DOI Google Scholar

Hatt M, Majdoub M, Vallières M, Tixier F, Le Rest CC, Groheux D, Hindié E, Martineau A, Pradier O, Hustinx R, Perdrisot R, Guillevin R, Naqa IE, Visvikis D, (2015) 18F-FDG PET uptake characterization through texture analysis: investigating the complementary nature of heterogeneity and functional tumor volume in a multi–cancer site patient cohort.J Nucl Med 56(1):38-44
DOI Google Scholar

Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJ, Old LJ, Cui Z, (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice.Proc Natl Acad Sci USA 103(20):7753-7758
DOI Google Scholar

Hosokawa M, Hayata T, Fukuda Y, Arakaki A, Yoshino T, Tanaka T, Matsunaga T, (2010) Size-selective microcavity array for rapid and efficient detection of circulating tumor cells.Anal Chem 82(15):6629-6635
DOI Google Scholar

Hsu PP, Sabatini DM, (2008) Cancer cell metabolism: Warburg and beyond.Cell 134(5):703-707
DOI Google Scholar

Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J, Buus S, Keiding S, D’Amore F, Boesen A, Berthelsen AK, Lena Specht, (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma.Blood 107(1):52-59
DOI Google Scholar

Kim TH, Lim M, Park J, Oh JM, Kim H, Jeong H, Lee SJ, Park HC, Jung S, Kim BC, Lee K, Kim MH, Park DY, Kim GH, Cho YK, (2016) FAST: size-selective, clog-free isolation of rare cancer cells from whole blood at a liquid-liquid interface.Anal Chem 89(2):1155-1162
DOI Google Scholar

Kuismanen E, Saraste J, (1989) Low temperature-induced transport blocks as tools to manipulate membrane traffic.Methods Cell Biol 3:257-274
DOI Google Scholar

Lehrer RI, Lichtenstein AK, Ganz T, (1993) Defensins: antimicrobial and cytotoxic peptides of mammalian cells.Annu Rev Immunol 11(1):105-128
DOI Google Scholar

Li P, Mao Z, Peng Z, Zhou L, Chen Y, Huang PH, Truica CI, Drabick JJ, El-Deiry WS, Dao M, Suresh S, Huang TJ, (2015) Acoustic separation of circulating tumor cells.Proc Natl Acad Sci USA 112(16):4970-4975
DOI Google Scholar

Lu J, Tan M, Cai Q, (2015) The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.Cancer Lett 356(2):156-164
DOI Google Scholar

McLaughlin PJ, (1954) A history of the theories of aether and electricity.Philos Stud 4:118-119
DOI Google Scholar

Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A, (2016) Cancer treatment and survivorship statistics.CA: A Cancer J Clin 66(4):271-289
DOI Google Scholar

Moon HS, Kwon K, Kim SI, Han H, Sohn J, Lee S, Jung HI, (2011) Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP).Lab Chip 11(6):1118-1125
DOI Google Scholar

Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Simth MR, Kwak EL, Diagumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkin RG, Haber DA, Toner M, (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology.Nature 450(7173):1235
DOI Google Scholar

Osaka T, Nakanishi T, Shanmugam S, Takahama S, Zhang H, (2009) Effect of surface charge of magnetite nanoparticles on their internalization into breast cancer and umbilical vein endothelial cells.Colloids Surf, B 71(2):325-330
DOI Google Scholar

Pestonjamasp VK, Mehta NG, (1995) Erythrocytes from Yoshida ascites sarcoma-bearing rats have reduced surface charge: the effect of tumor products.Cancer Biochem Biophys 15(1):19-23
Google Scholar

Plaks V, Koopman CD, Werb Z, (2013) Circulating tumor cells.Science 341(6151):1186-1188
DOI Google Scholar

Pore M, Meijer C, de Bock GH, Boersma-van Ek W, Terstappen LW, Groen HJ, Timens W, Kruyt FAE, Hiltermann TJN, (2016) Cancer stem cells, epithelial to mesenchymal markers, and circulating tumor cells in small cell lung cancer.Clin Lung Cancer 17(6):535-542
DOI Google Scholar

Purdom L, Ambrose EJ, Klein G, (1958) A correlation between electrical surface charge and some biological characteristics during the stepwise progression of a mouse sarcoma.Nature 181(4623):1586
DOI Google Scholar

Racila E, Euhus D, Weiss AJ, Rao C, McConnell J, Terstappen LW, Uhr JW, (1998) Detection and characterization of carcinoma cells in the blood.Proc Natl Acad Sci USA 95(8):4589-4594
DOI Google Scholar

Radovic-Moreno AF, Lu TK, Puscasu VA, Yoon CJ, Langer R, Farokhzad OC, (2012) Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics.ACS Nano 6(5):4279-4287
DOI Google Scholar

Riedlinger G, Adams J, Stehle JR, Blanks MJ, Sanders AM, Hicks AM, Willingham MC, Cui Z, (2010) The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction.BMC Cancer 10(1):179
DOI Google Scholar

Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, DeBeradinis RJ, Rutter J, (2014) A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.Mol Cell 56(3):400-413
DOI Google Scholar

Siegel RL, Miller KD, Jemal A, (2017) Cancer statistics, 2017.CA: A Cancer J Clin 67:7-30
DOI Google Scholar

Siegel RL, Miller KD, Jemal A, (2018) Cancer statistics, 2008.Ca: A Cancer J Clin 68:5-29
DOI Google Scholar

Sonders MS, Amara SG, (1996) Channels in transporters.Curr Opin Neurobiol 6(3):294-302
DOI Google Scholar
Stewart B, Wild CP (2014) World cancer report 2014
DOI

Tellez-Gabriel M, Brown HK, Young R, Heymann MF, Heymann D, (2016) The challenges of detecting circulating tumor cells in sarcoma.Front Oncol 6:202
DOI Google Scholar

Vander Heiden MG, Cantley LC, Thompson CB, (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science 324(5930):1029-1033
DOI Google Scholar

Vassar PS, (1963) Electrophoretic mobility of human tumour cells.Nature 197(4873):1215-1216
DOI Google Scholar

Vyas S, Zaganjor E, Haigis MC, (2016) Mitochondria and cancer.Cell 166(3):555-566
DOI Google Scholar

Warburg O, (1924) Über den stoffwechsel der carcinomzelle.Naturwissenschaften 12(50):1131-1137
DOI Google Scholar

Warburg O, (1956) On the origin of cancer cells.Science 123(3191):309-314
DOI Google Scholar

Yoon HJ, Kim TH, Zhang Z, Azizi E, Pham TM, Paoletti C, Lin J, Ramnath N, Wicha MS, Hayes DF, Simeone DM, Nagrath S, (2013) Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets.Nat Nanotechnol 8(10):735
DOI Google Scholar

Yoshii T, Geng Y, Peyton S, Mercurio AM, Rotello VM, (2016) Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine.Drug Discov Today 21(9):1489-1494
DOI Google Scholar

You JS, Jones PA, (2012) Cancer genetics and epigenetics: two sides of the same coin?.Cancer Cell 22(1):9-20
DOI Google Scholar

Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Concannon KF, (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition.Science 339:580-584
DOI Google Scholar

Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z, Wittner BS, Petar Stojanov, Brachtel E, Sgroi D, Kapur R, Shioda T, Ting DT, Ramaswamy S, Getz G, Iafrate AJ, Benes C, Toner M, Maheswaran S, Harber D, (2014) Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.Science 345(6193):216-220
DOI Google Scholar

Zink D, Fischer AH, Nickerson JA, (2004) Nuclear structure in cancer cells.Nat Rev Cancer 4(9):677
DOI Google Scholar

Williams SCP, (2013) Circulating tumor cells.Proc Natl Acad Sci USA 110(13):4861-4861
DOI Google Scholar
Publication history
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Publication history

Received: 29 May 2018
Accepted: 27 August 2018
Published: 01 March 2019
Issue date: February 2019

Copyright

© The Author(s) 2019

Acknowledgements

Acknowledgement

This study was supported by National Natural Science Foundation of China (31671029, 81772285), Shanghai Natural Science Foundation (16ZR1400700), National Postdoctoral Program for Innovation Talents (BX201700173), and China Postdoctoral Science Foundation (2017M621534).

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