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Mesenchymal Stem Cells Cultured in 3D System Inhibit Non-Small Cell Lung Cancer Cells through p38 MAPK and CXCR4/AKT Pathways by IL-24 Regulating

Abstract

Non-small cell lung cancer (NSCLC) is prevalent worldwide and has a high mortality rate. Even if mesenchymal stem cells (MSCs) are suggested as cancer treatment, the studies of their effects on NSCLC cells contradict each other, mainly due to utilization of two-dimensional (2D) culture system. Three-dimensional (3D) culture systems resemble tissue organization in vivo. Here we comprehensively explore the inhibitory effects of MSCs on NSCLC cells in a 3D culture system. We confirmed that the inhibitory effects of 3D-cultured MSCs (3D-MSCs) on the proliferation and migration of NSCLC cells are greater than that of the 2D-cultured MSCs. The expression of IL-24 in 3D-MSCs is higher than 2D-MSCs, which is the key factor to enhance the anti-tumor effect of MSCs. In these cells, IL-24 affects p38 MAPK and CXCR4/AKT pathways. Overall, this study provides the support for use of MSCs in tumor therapy.

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REFERENCES

  1. Siegel R.L., Miller K.D., Jemal A. 2019. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7‒34.

    PubMed  Google Scholar 

  2. Wu Z., Qiu X., Gao B., Lian C., Peng Y., Liang A., Xu C., Gao W., Zhang L., Su P., Rong L., Huang D. 2018. Melatonin-mediated miR-526b-3p and miR-590-5p upregulation promotes chondrogenic differentiation of human mesenchymal stem cells. J. Pineal. Res. 65, e12483.

    PubMed  Google Scholar 

  3. Camorani S., Hill B.S., Fontanella R., Greco A., Gramanzini M., Auletta L., Gargiulo S., Albanese S., Lucarelli E., Cerchia L., Zannetti A. 2017. Inhibition of bone marrow-derived mesenchymal stem cells homing towards triple-negative breast cancer microenvironment using an anti-PDGFRβ aptamer. Theranostics. 7, 3595‒3607.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kupcova Skalnikova H. 2013. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 95, 2196‒2211.

    CAS  PubMed  Google Scholar 

  5. 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, 143‒148.

    CAS  PubMed  Google Scholar 

  6. Jung P.Y., Ryu H., Rhee K.J., Hwang S., Lee C.G., Gwon S.Y., Kim J., Kim J., Yoo B.S., Baik S.K., Bae K.S., Eom Y.W. 2019. Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-β and TRAIL and suppress the growth of H460 human lung cancer cells. Cancer Lett. 440‒441, 202‒210.

    Google Scholar 

  7. Pan M., Hou L., Zhang J., Zhao D., Hua J., Wang Z., He J., Jiang H., Hu H., Zhang L. 2018. Inhibitory effect and molecular mechanism of mesenchymal stem cells on NSCLC cells. Mol. Cell. Biochem. 441, 63‒76.

    CAS  PubMed  Google Scholar 

  8. Fakiruddin K.S., Lim M.N., Nordin N., Rosli R., Zakaria Z., Abdullah S. 2019. Targeting of CD133+ cancer stem cells by mesenchymal stem cell expressing TRAIL reveals a prospective role of apoptotic gene regulation in non-small cell lung cancer. Cancers (Basel). 11, 1261.

    CAS  Google Scholar 

  9. Kim S.W., Lee Y.K., Hong J.H., Park J.Y., Choi Y.A., Lee D.U., Choi J., Sym S.J., Kim S.H., Khang D. 2018. Mutual destruction of deep lung tumor tissues by nanodrug-conjugated stealth mesenchymal stem cells. Adv. Sci. (Weinh). 5, 1700860.

    Google Scholar 

  10. Gazdic M., Simovic Markovic B., Jovicic N., Misirkic-Marjanovic M., Djonov V., Jakovljevic V., Arsenijevic N., Lukic M.L., Volarevic V. 2017. Mesenchymal stem cells promote metastasis of lung cancer cells by downregulating systemic antitumor immune response. Stem Cells Int. 2017, 6294717.

    PubMed  PubMed Central  Google Scholar 

  11. Wang S., Li X., Xu M., Wang J., Zhao R.C. 2017. Reduced adipogenesis after lung tumor exosomes priming in human mesenchymal stem cells via TGFβ signaling pathway. Mol. Cell. Biochem. 435, 59‒66.

    CAS  PubMed  Google Scholar 

  12. Luo D., Hu S., Tang C., Liu G. 2018. Mesenchymal stem cells promote cell invasion and migration and autophagy-induced epithelial-mesenchymal transition in A549 lung adenocarcinoma cells. Cell Biochem. Funct. 36, 88‒94.

    CAS  PubMed  Google Scholar 

  13. Fregni G., Quinodoz M., Moller E., Vuille J., Galland S., Fusco C., Martin P., Letovanec I., Provero P., Rivolta C., Riggi N., Stamenkovic I. 2018. Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis. EBioMedicine. 29, 128‒145.

    PubMed  PubMed Central  Google Scholar 

  14. Caliari S.R., Burdick J.A. 2016. A practical guide to hydrogels for cell culture. Nat. Methods. 13, 405‒414.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. DeVolder R., Kong H.J. 2012. Hydrogels for in vivo-like three-dimensional cellular studies. Wiley Interdisc. Rev. Syst. Biol. Med. 4, 351‒365.

    CAS  Google Scholar 

  16. Legant W.R., Chen C.S., Vogel V. 2012. Force-induced fibronectin assembly and matrix remodeling in a 3D microtissue model of tissue morphogenesis. Integr. Biol. (Camb.). 4, 1164‒1174.

    CAS  Google Scholar 

  17. Ravi M., Paramesh V., Kaviya S.R., Anuradha E., Solomon F.D. 2015. 3D cell culture systems: advantages and applications. J. Cell. Physiol. 230, 16‒26.

    CAS  PubMed  Google Scholar 

  18. Zhao D., Hou L., Pan M., Hua J., Wang Z., He J., Hu H. 2018. Inhibitory effect and mechanism of mesenchymal stem cells cultured in 3D system on hepatoma cells HepG2. Appl. Biochem. Biotechnol. 184, 212‒227.

    CAS  PubMed  Google Scholar 

  19. Chaudhuri O., Gu L., Klumpers D., Darnell M., Bencherif S.A., Weaver J.C., Huebsch N., Lee H.P., Lippens E., Duda G.N., Mooney D.J. 2016. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326‒334.

    CAS  PubMed  Google Scholar 

  20. Pradhan A.K., Bhoopathi P., Talukdar S., Scheunemann D., Sarkar D., Cavenee W.K., Das S.K., Emdad L., Fisher P.B. 2019. MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF. Proc. Natl. Acad. Sci. U. S. A. 116, 5687‒5692.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhutia S.K., Das S.K., Azab B., Menezes M.E., Dent P., Wang X.Y., Sarkar D., Fisher P.B. 2013. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24. Int. J. Cancer. 133, 2726‒2736.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sarkar D., Su Z.Z., Lebedeva I.V., Sauane M., Gopalkrishnan R.V., Valerie K., Dent P., Fisher P.B. 2002. mda-7 (IL-24) mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc. Natl. Acad. Sci. U. S. A. 99, 10054‒10059.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sauane M., Su Z.Z., Gupta P., Lebedeva I.V., Dent P., Sarkar D., Fisher P.B. 2008. Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis. Proc. Natl. Acad. Sci. U. S. A. 105, 9763‒9768.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet-Tieulent J., Jemal A. 2015. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87‒108.

    PubMed  Google Scholar 

  25. Kang S., Bhang S.H., Hwang S., Yoon J.K., Song J., Jang H.K., Kim S., Kim B.S. 2015. Mesenchymal stem cells aggregate and deliver gold nanoparticles to tumors for photothermal therapy. ACS Nano. 9, 9678‒9690.

    CAS  PubMed  Google Scholar 

  26. Shen W.C., Lai Y.C., Li L.H., Liao K., Lai H.C., Kao S.Y., Wang J., Chuong C.M., Hung S.C. 2019. Methylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis. Nat. Commun. 10, 2226.

    PubMed  PubMed Central  Google Scholar 

  27. Xu C., Lin L., Cao G., Chen Q., Shou P., Huang Y., Han Y., Wang Y., Shi Y. 2014. Interferon-α-secreting mesenchymal stem cells exert potent antitumor effect in vivo. Oncogene. 33, 5047‒5052.

    CAS  PubMed  Google Scholar 

  28. Ma Q., Jin B., Zhang Y., Shi Y., Zhang C., Luo D., Wang P., Duan C., Song H., Li X., Deng X., Chen Z., Wang Z., Jiang H., Liu Y. 2016. Secreted recombinant human IL-24 protein inhibits the proliferation of esophageal squamous cell carcinoma Eca-109 cells in vitro and in vivo. Oncol. Rep. 35, 2681‒2690.

    CAS  PubMed  Google Scholar 

  29. Chen J., Gao P., Yuan S., Li R., Ni A., Chu L., Ding L., Sun Y., Liu X.Y., Duan Y. 2016. Oncolytic adenovirus complexes coated with lipids and calcium phosphate for cancer gene therapy. ACS Nano. 10, 11548‒11560.

    CAS  PubMed  Google Scholar 

  30. Pradhan A.K., Talukdar S., Bhoopathi P., Shen X.N., Emdad L., Das S.K., Sarkar D., Fisher P.B. 2017. mda-7/IL-24 mediates cancer cell-specific death via regulation of miR-221 and the Beclin-1 axis. Cancer Res. 77, 949‒959.

    CAS  PubMed  Google Scholar 

  31. Dash R., Azab B., Quinn B.A., Shen X., Wang X.Y., Das S.K., Rahmani M., Wei J., Hedvat M., Dent P., Dmitriev I.P., Curiel D.T., Grant S., Wu B., Stebbins J.L., et al. 2011. Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc. Natl. Acad. Sci. U. S. A. 108, 8785‒8790.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao Y., Li Z., Sheng W., Miao J., Yang J. 2013. Radiosensitivity by ING4-IL-24 bicistronic adenovirus-mediated gene cotransfer on human breast cancer cells. Cancer Gene Ther. 20, 38‒45.

    CAS  PubMed  Google Scholar 

  33. Zhang J., Hou L., Zhao D., Pan M., Wang Z., Hu H., He J. 2017. Inhibitory effect and mechanism of mesenchymal stem cells on melanoma cells. Clin. Transl. Oncol. 19, 1358‒1374.

    CAS  PubMed  Google Scholar 

  34. Takahara K., Ii M., Inamoto T., Nakagawa T., Ibuki N., Yoshikawa Y., Tsujino T., Uchimoto T., Saito K., Takai T., Tanda N., Minami K., Uehara H., Komura K., Hirano H., et al. 2016. microRNA-145 mediates the inhibitory effect of adipose tissue-derived stromal cells on prostate cancer. Stem. Cells Dev. 25, 1290‒1298.

    CAS  PubMed  Google Scholar 

  35. Panneerselvam J., Jin J., Shanker M., Lauderdale J., Bates J., Wang Q., Zhao Y.D., Archibald S.J., Hubin T.J., Ramesh R. 2015. IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. PLoS One. 10, e0122439.

    PubMed  PubMed Central  Google Scholar 

  36. Moro M., Bertolini G., Pastorino U., Roz L., Sozzi G. 2015. Combination treatment with all-trans retinoic acid prevents cisplatin-induced enrichment of CD133+ tumor-initiating cells and reveals heterogeneity of cancer stem cell compartment in lung cancer. J. Thorac. Oncol. 10, 1027‒1036.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Teng F., Tian W.Y., Wang Y.M., Zhang Y.F., Guo F., Zhao J., Gao C., Xue F.X. 2016. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J. Hematol. Oncol. 9, 8.

    PubMed  PubMed Central  Google Scholar 

  38. Tsou L.K., Huang Y.H., Song J.S., Ke Y.Y., Huang J.K., Shia K.S. 2018. Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology. Med. Res. Rev. 38, 1188‒1234.

    CAS  PubMed  Google Scholar 

  39. Xu J., Liang J., Meng Y.M., Yan J., Yu X.J., Liu C.Q., Xu L., Zhuang S.M., Zheng L. 2017. Vascular CXCR4 expression promotes vessel sprouting and sensitivity to sorafenib treatment in hepatocellular carcinoma. Clin. Cancer Res. 23, 4482‒4492.

    CAS  PubMed  Google Scholar 

  40. Dash R., Bhoopathi P., Das S.K., Sarkar S., Emdad L., Dasgupta S., Sarkar D., Fisher P.B. 2014. Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res. 74, 563‒574.

    CAS  PubMed  Google Scholar 

  41. Fan S., Gao H., Ji W., Zhu F., Sun L., Liu Y., Zhang S., Xu Y., Yan Y., Gao Y. 2020. Umbilical cord-derived mesenchymal stromal/stem cells expressing IL-24 induce apoptosis in gliomas. J. Cell Physiol. 235, 1769‒1779.

    CAS  PubMed  Google Scholar 

  42. Ma M., Zhao L., Sun G., Zhang C., Liu L., Du Y., Yang X., Shan B. 2016. Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs. Oncol. Rep. 35, 3122‒3130.

    CAS  PubMed  Google Scholar 

  43. Ma Y.F., Ren Y., Wu C.J., Zhao X.H., Xu H., Wu D.Z., Xu J., Zhang X.L., Ji Y. 2016. Interleukin (IL)-24 transforms the tumor microenvironment and induces anticancer immunity in a murine model of colon cancer. Mol. Immunol. 75, 11‒20.

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81201762).

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Correspondence to L. Hou.

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The authors declare that they have no conflict of interest. This article does not contain any research involving humans or animals as subjects of research.

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Suo, F., Pan, M., Li, Y. et al. Mesenchymal Stem Cells Cultured in 3D System Inhibit Non-Small Cell Lung Cancer Cells through p38 MAPK and CXCR4/AKT Pathways by IL-24 Regulating. Mol Biol 55, 589–603 (2021). https://doi.org/10.1134/S0026893321030110

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  • DOI: https://doi.org/10.1134/S0026893321030110

Keywords:

  • mesenchymal stem cells
  • three-dimensional cell culture
  • interleukin-24
  • tumor inhibition
  • NSCLC