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Differential effects of mesenchymal stem cells on a heterogeneous cell population within lung cancer cell lines

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Abstract

Although mesenchymal stem cells (MSCs) promote lung cancer growth in vivo, in vitro studies indicate that they inhibit the proliferation of lung cancer cells. Because malignant tumors contain a heterogeneous cell population with variable capacity for self-renewal, the aim of this study was to determine whether the inconsistencies between in vitro and in vivo studies are a result of differential effects of MSCs on the heterogeneous cell population within lung cancer cell lines. Human MSCs were isolated from the bone marrow, and their cell surface antigen expression and multi-lineage differentiation capacity was examined at passage 10. CD133+ cells were isolated from A549 and H446 cell lines using immunomagnetic separation. The effects of MSCs on the growth and microsphere formation of heterogeneous cell populations within two lung cancer cell lines (A549 and H446) were compared. MSCs inhibited the in vitro proliferation of both cell lines, but significantly accelerated tumor formation and stimulated tumor growth in vivo (P < 0.05). In CD133+ cells isolated from both A549 and H446 cells, co-culture with MSCs for 1–3 days significantly increased their proliferation (P < 0.05). MSCs also significantly increased microsphere formation in both cell lines (P < 0.05). Selective stimulation of CD133+ cell growth may account for the discrepant effects of MSCs on lung cancer progression.

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References

  1. Pittenger MF, Mosca JD, McIntosh KR (2000) Human mesenchymal stem cells: progenitor cells for cartilage, bone, fat and stroma. Curr Top Microbiol Immunol 251:3–11

    Article  PubMed  CAS  Google Scholar 

  2. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumor stroma promote breast cancer metastasis. Nature 449:557–563

    Article  PubMed  CAS  Google Scholar 

  3. Knoop K, Kolokythas M, Klutz K, Willhauck MJ, Wunderlich N, Draganovici D, Zach C, Gildehaus FJ, Boning G, Goke B et al (2011) Image-guided, tumor stroma-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated NIS gene delivery. Mol Ther 19:1704–1713

    Article  PubMed  CAS  Google Scholar 

  4. Tian LLH, Chen Z, Yue W, Li S, Li W (2011) Inhibition of lung cancer cell proliferation mediated by human mesenchymal stem cells. Acta Biochim Biophys Sin (Shanghai) 43:143–148

    Article  Google Scholar 

  5. Tian LLH, Yue W, Zhu F, Li S, Li W (2011) Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol 226:1860–1867

    Article  PubMed  Google Scholar 

  6. Roorda BD, Elst A, Boer TG, Kamps WA, de Bont ES (2010) Mesenchymal stem cells contribute to tumor cell proliferation by direct cell–cell contact interactions. Cancer Invest 28:526–534

    Article  PubMed  CAS  Google Scholar 

  7. Li GC, Ye QH, Xue YH, Sun HJ, Zhou HJ, Ren N, Jia HL, Shi J, Wu JC, Dai C, Dong QZ, Qin LX (2010) Human mesenchymal stem cells inhibit metastasis of a hepatocellular carcinoma model using the MHCC97-H cell line. Cancer Sci 101:2546–2553

    Article  PubMed  CAS  Google Scholar 

  8. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumor initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  9. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323

    Article  PubMed  CAS  Google Scholar 

  10. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15:504–514

    Article  PubMed  CAS  Google Scholar 

  11. Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE (2008) Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One 3:e3077

    Article  PubMed  Google Scholar 

  12. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumor stem cells. Nat Rev Cancer 6:425–436

    Article  PubMed  CAS  Google Scholar 

  13. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S, Sesterhenn IA, McLeod DG, Srivastava S, Rhim JS (2007) 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 67:3153–3161

    Article  PubMed  CAS  Google Scholar 

  14. Wakitani S, Saito T, Caplan AI (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417–1426

    Article  PubMed  CAS  Google Scholar 

  15. Ishiyama M, Miyazono Y, Sasamoto K, Ohkura Y, Ueno K (1997) A highly water-soluble disulfonated tetrazolium salt as a chromogenic indicator for NADH as well as cell viability. Talanta 44:1299–1305

    Article  PubMed  CAS  Google Scholar 

  16. Qiu X, Wang Z, Li Y, Miao Y, Ren Y, Luan Y (2012) Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446. Cancer Lett 323:161–170

    Article  PubMed  CAS  Google Scholar 

  17. Li F, Zeng H, Ying K (2011) The combination of stem cell markers CD133 and ABCG2 predicts relapse in stage I non-small cell lung carcinomas. Med Oncol 28:1458–1462

    Article  PubMed  CAS  Google Scholar 

  18. Teng Y, Wang X, Wang Y, Ma D (2010) Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 392:373–379

    Article  PubMed  CAS  Google Scholar 

  19. Wang B, Yang H, Huang YZ, Yan RH, Liu FJ, Zhang JN (2010) Biologic characteristics of the side population of human small cell lung cancer cell line H446. Chin J Cancer 29:254–260

    Article  PubMed  Google Scholar 

  20. Meng X, Li M, Wang X, Wang Y, Ma D (2009) Both CD133+ and CD133− subpopulations of A549 and H446 cells contain cancer-initiating cells. Cancer Sci 100:1040–1046

    Article  PubMed  CAS  Google Scholar 

  21. Levina V, Marrangoni A, Wang T, Parikh S, Su Y, Herberman R, Lokshin A, Gorelik E (2010) Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res 70:338–346

    Article  PubMed  CAS  Google Scholar 

  22. Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S et al (2009) Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA 106:16281–16286

    Article  PubMed  CAS  Google Scholar 

  23. Bertolini G, Gatti L, Roz L (2010) The “stem” of chemoresistance. Cell Cycle 9:628–629

    Article  PubMed  CAS  Google Scholar 

  24. Dittmer A, Hohlfeld K, Lutzkendorf J, Muller LP, Dittmer J (2009) Human mesenchymal stem cells induce e-cadherin degradation in breast carcinoma spheroids by activating ADAM10. Cell Mol Life Sci 66:3053–3065

    Article  PubMed  CAS  Google Scholar 

  25. Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC, Ye L, Zhang X (2008) Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res 18:500–507

    Article  PubMed  CAS  Google Scholar 

  26. Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB (2008) Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells 26:99–107

    Article  PubMed  CAS  Google Scholar 

  27. Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, Korkaya H, Heath A, Dutcher J, Kleer CG et al (2011) Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 71:614–624

    Article  PubMed  CAS  Google Scholar 

  28. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed  CAS  Google Scholar 

  29. Wong CC, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO et al (2011) Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA 108:16369–16374

    Article  PubMed  CAS  Google Scholar 

  30. Peng Q, Liu M, Song SM, Li XH, Du YH, Zhi Y, Wang MY (2010) The recruitment of exogenous endothelial progenitor cells in lung tumor model of nude mice. Chin J Cancer 29(11):952–958

    Google Scholar 

  31. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603

    Article  PubMed  CAS  Google Scholar 

  32. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J et al (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318

    PubMed  CAS  Google Scholar 

  33. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 62:3603–3608

    PubMed  CAS  Google Scholar 

  34. Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, Li J, Yan X, Liu Y, Shao C, Zhao RC (2009) Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 23:925–933

    Article  PubMed  CAS  Google Scholar 

  35. Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G et al (2006) Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med 203:1235–1247

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (30871123, 81071728).

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The authors declare that they have no competing interests.

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Correspondence to Guoxiang Liu.

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Luo, D., Yan, X., Liu, D. et al. Differential effects of mesenchymal stem cells on a heterogeneous cell population within lung cancer cell lines. Mol Cell Biochem 378, 107–116 (2013). https://doi.org/10.1007/s11010-013-1600-3

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  • DOI: https://doi.org/10.1007/s11010-013-1600-3

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