Molecular and Cellular Biochemistry

, Volume 441, Issue 1–2, pp 63–76 | Cite as

Inhibitory effect and molecular mechanism of mesenchymal stem cells on NSCLC cells

  • Mengwu Pan
  • Lingling HouEmail author
  • Jingsi Zhang
  • Diandian Zhao
  • Jilei Hua
  • Ziling Wang
  • Jinsheng He
  • Hong Jiang
  • Honggang Hu
  • Lishu Zhang


Non-small-cell lung cancer (NSCLC) is still the main threat of cancer-associated death. Current treatment of NSCLC has limited effectiveness, and unfortunately, the prognosis of NSCLC remains poor. Therefore, a novel strategy for cancer therapy is urgently needed. Stem cell therapy has significant potential for cancer treatment. Mesenchymal stem cells (MSCs) with capacity for self-renewal and differentiation into various cells types exhibit the feature of homing to tumor site and immunosuppression, have been explored as a new treatment for various cancers. Studies revealed that the broad repertoire of trophic factors secreted by MSCs extensively involved in the interplay between MSCs and tumor cells. In this study, we confirmed that MSCs do have the paracrine effect on proliferation and migration of NSCLC cells (A549, NCI-H460, and SK-MES-1). Co-culture system and conditioned medium experiments results showed that soluble factors secreted by MSCs inhibited the proliferation of NSCLC cells in vitro. The scratch assay showed that conditioned medium of MSCs could suppress the migration of NSCLC cells in vitro. Western blot results showed that the expression of proteins relevant to cell proliferation, anti-apoptosis, and migration was remarkably decreased via MAPK/eIF4E signaling pathway. We speculated that soluble factors secreted by MSCs might be responsible for inhibitory mechanism of NSCLC cells. By Human Gene Expression Microarray Assay and recombinant Vascular Endothelial Growth Factor 165 (VEGF165) neutralizing experiment, we verified that VEGF might be responsible for the down-regulation of proteins related to cell proliferation, anti-apoptosis, and migration by suppressing translation initiation factor eIF4E via MAPK signaling pathway. Taken together, our study demonstrated that a possible trophic factor secreted by MSCs could manipulate translation initiation of NSCLC cells via MAPK signaling pathway, and significantly affect the fate of tumor cells, which will be a new strategy for cancer therapy.


NSCLC MSCs MAPK Inhibition Mechanism 



This work was supported by the National Natural Science Foundation of China (81201762, 31371194). The authors thank Dr. Juan Du (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet) for critical reading of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Jemal A, Siegel R, Xu J et al (2010) Cancer statistics, 2010. CA Cancer J Clin 60:227–300CrossRefGoogle Scholar
  2. 2.
    Bunn PA, Shepherd FA, Sandler A, Le Chevalier T, Belani CP, Kosmidis PA et al (2003) Ongoing and future trials of biologic therapies in lung cancer. Lung Cancer 41:175–186CrossRefGoogle Scholar
  3. 3.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMedGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E et al (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130CrossRefPubMedGoogle Scholar
  5. 5.
    Abengozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M, Olmeda D et al (2012) Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119:4565–4576CrossRefPubMedGoogle Scholar
  6. 6.
    Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN et al (2012) Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21:82–91CrossRefPubMedGoogle Scholar
  7. 7.
    Conley SJ, Gheordunescu E, Kakarala P et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 109:2784–2789CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhang XX, Zhang LL, Yang HL, Wang XW (2016) Mechanism of Wnt/beta-catenin signaling pathway in enhanced malignant phenotype of non-small cell lung cancer induced by anti-angiogenesis therapy. Asian Pac J Trop Med 9:58–62CrossRefPubMedGoogle Scholar
  9. 9.
    Kerbel RS, Guerin E, Francia G, Xu P, Lee CR, Ebos JM et al (2013) Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis. Breast 22(Suppl 2):S57–S65CrossRefPubMedGoogle Scholar
  10. 10.
    Tanoue LT (2008) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. Yearb Pulm Dis 2008:146–148CrossRefGoogle Scholar
  11. 11.
    Ribatti D (2016) Tumor refractoriness to anti-VEGF therapy. Oncotarget 2:46668–46677Google Scholar
  12. 12.
    Lazarus HM, Haynesworth SE, Gerson SL et al (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells) implications for therapeutic use. Bone Marrow Transpl 16:557–564Google Scholar
  13. 13.
    Ramdasi S, Sarang S, Viswanathan C (2015) Potential of mesenchymal stem cell based application in cancer. Int J Hematol Oncol Stem Cell Res 9:95–103PubMedPubMedCentralGoogle Scholar
  14. 14.
    Hou L, Wang X, Zhou Y, Ma H, Wang Z, He J et al (2014) Inhibitory effect and mechanism of mesenchymal stem cells on liver cancer cells. Tumour Biol 35:1239–1250CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang J, Hou L, Zhao D, Pan M et al (2017) Inhibitory effect and mechanism of Mesenchymal stem cells on melanoma cells. Clin Transl Oncol. doi: 10.1007/s12094-12017-11677-12093 PubMedCentralGoogle Scholar
  16. 16.
    Maestroni GJ, Hertens E, Galli P (1999) Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cell Mol Life Sci 55:663–667CrossRefPubMedGoogle Scholar
  17. 17.
    Pelagalli A, Nardelli A, Fontanella R, Zannetti A (2016) Inhibition of AQP1 hampers osteosarcoma and hepatocellular carcinoma progression mediated by bone marrow-derived mesenchymal stem cells. Int J Mol Sci. doi: 10.3390/ijms17071102 Google Scholar
  18. 18.
    Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK et al (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE 8:e84256CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cho JA, Park H, Kim HK, Lim EH, Seo SW, Choi JS et al (2009) Hyperthermia-treated mesenchymal stem cells exert antitumor effects on human carcinoma cell line. Cancer 115:311–323CrossRefPubMedGoogle Scholar
  20. 20.
    Cavarretta IT, Altanerova V, Matuskova M, Kucerova L, Culig Z, Altaner C (2010) Adipose tissue-derived mesenchymal stem cells expressing prodrug-converting enzyme inhibit human prostate tumor growth. Mol Ther 18:223–231CrossRefPubMedGoogle Scholar
  21. 21.
    Ryu H, Oh JE, Rhee KJ, Baik SK, Kim J, Kang SJ et al (2014) Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-beta and suppress the growth of MCF-7 human breast cancer cells. Cancer Lett 352:220–227CrossRefPubMedGoogle Scholar
  22. 22.
    Chao KC, Yang HT, Chen MW (2012) Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization. J Cell Mol Med 16:1803–1815CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Asakura A, Yamahara K, Harada K, Ohshima M, Ishikane S, Ohnishi S et al (2014) Comparison of angiogenic, cytoprotective, and immunosuppressive properties of human amnion- and chorion-derived mesenchymal stem cells. PLoS ONE. doi: 10.1371/journal.pone.0088319 Google Scholar
  24. 24.
    Moodley Y, Vaghjiani V, Chan J (2013) Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study. PLoS ONE. doi: 10.1371/journal.pone.0069299 Google Scholar
  25. 25.
    Tian LL, 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 226:1860–1867CrossRefPubMedGoogle Scholar
  26. 26.
    Waterman RS, Henkle SL, Betancourt AM (2012) Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis. PLoS ONE 7:e45590CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang ML, Pan CM, Chiou SH, Chen WH, Chang HY, Lee OK et al (2012) Oncostatin m modulates the mesenchymal-epithelial transition of lung adenocarcinoma cells by a mesenchymal stem cell-mediated paracrine effect. Cancer Res 72:6051–6064CrossRefPubMedGoogle Scholar
  28. 28.
    Walter M, Liang S, Ghosh S, Hornsby PJ, Li R (2009) Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene 28:2745–2755CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ (2007) CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 9:556–562CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yu JM, Jun ES, Bae YC, Jung JS (2008) Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev 17:463–474CrossRefPubMedGoogle Scholar
  31. 31.
    Kang SG, Jeun SS, Lim JY, Kim SM, Yang YS, Oh WI et al (2008) Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells. Childs Nerv Syst 24:293–302CrossRefPubMedGoogle Scholar
  32. 32.
    Li Y, Fan S, Koo J, Yue P, Chen ZG, Owonikoko TK et al (2012) Elevated expression of eukaryotic translation initiation factor 4E is associated with proliferation, invasion and acquired resistance to erlotinib in lung cancer. Cancer Biol Ther 13:272–280CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Thornton S, Anand N, Purcell D, Lee J (2003) Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis. J Mol Med (Berl) 81:536–548CrossRefGoogle Scholar
  34. 34.
    Wendel HG, Silva RL, Malina A, Mills JR, Zhu H, Ueda T et al (2007) Dissecting eIF4E action in tumorigenesis. Genes Dev 21:3232–3237CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Joshi S, Platanias LC (2014) Mnk kinase pathway: cellular functions and biological outcomes. World J Biol Chem 5:321–333CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Waskiewicz AJ, Johnson JC, Penn B et al (1999) Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase MNK1 in vivo. Mol Cell Biol 19:1871–1880CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Boomsma RA, Geenen DL (2012) Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS ONE 7:e35685CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Tao H, Chen Z-W, Yang J-J, Shi K-H (2016) MicroRNA-29a suppresses cardiac fibroblasts proliferation via targeting VEGF-A/MAPK signal pathway. Int J Biol Macromol 88:414–423CrossRefPubMedGoogle Scholar
  39. 39.
    Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R (2016) The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy 18:13–24CrossRefPubMedGoogle Scholar
  40. 40.
    Shi S, Lee J-K, Park S-R, Jung B-K, Jeon Y-K, Lee Y-S et al (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE 8:e84256CrossRefGoogle Scholar
  41. 41.
    Zhang MH, Hu YD, Xu Y, Xiao Y, Luo Y, Song ZC et al (2013) Human mesenchymal stem cells enhance autophagy of lung carcinoma cells against apoptosis during serum deprivation. Int J Oncol 42:1390–1398CrossRefPubMedGoogle Scholar
  42. 42.
    Jeon ES, Lee IH, Heo SC, Shin SH, Choi YJ, Park JH et al (2010) Mesenchymal stem cells stimulate angiogenesis in a murine xenograft model of A549 human adenocarcinoma through an LPA1 receptor-dependent mechanism. Biochim Biophys Acta 1801:1205–1213CrossRefPubMedGoogle Scholar
  43. 43.
    Li L, Tian H, 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) 43:143–148CrossRefGoogle Scholar
  44. 44.
    Roger M, Clavreul A, Venier-Julienne MC, Passirani C, Sindji L, Schiller P et al (2010) Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31:8393–8401CrossRefPubMedGoogle Scholar
  45. 45.
    Porada CD, Almeida-Porada G (2010) Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev 62:1156–1166CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Doucette T, Rao G, Yang Y, Gumin J, Shinojima N, Bekele BN et al (2011) Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv—a glioma model. Neoplasia 13:716–725CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kim D, Kim S, Koh H et al (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 15:1953–1962CrossRefPubMedGoogle Scholar
  48. 48.
    Bryan BC, Simon MC (2007) Taking aim at translation for tumor therapy. J Clin Investig 117:2385–2388CrossRefGoogle Scholar
  49. 49.
    Thumma SC, Kratzke RA (2007) Translational control: a target for cancer therapy. Cancer Lett 258:1–8CrossRefPubMedGoogle Scholar
  50. 50.
    Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors, effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963CrossRefPubMedGoogle Scholar
  51. 51.
    Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127CrossRefPubMedGoogle Scholar
  52. 52.
    Cameron D (2008) Bevacizumab in the first-line treatment of metastatic breast cancer. Eur J Cancer Suppl 6:21–28CrossRefGoogle Scholar
  53. 53.
    Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Dobbin ZC, Landen CN (2013) The importance of the PI3 K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 14:8213–8227CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR et al (2010) Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17:249–261CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ (2008) eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol 181:293–307CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ferrari G, Pintucci G, Seghezzi G, Hyman K, Galloway AC, Mignatti P (2006) VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis. Proc Natl Acad Sci USA 103:17260–17265CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Mengwu Pan
    • 1
  • Lingling Hou
    • 1
    Email author
  • Jingsi Zhang
    • 1
  • Diandian Zhao
    • 1
  • Jilei Hua
    • 1
  • Ziling Wang
    • 1
  • Jinsheng He
    • 1
  • Hong Jiang
    • 1
  • Honggang Hu
    • 1
  • Lishu Zhang
    • 1
  1. 1.College of Life Sciences and BioengineeringBeijing Jiaotong UniversityBeijingPeople’s Republic of China

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