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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

  • MOLECULAR CELL BIOLOGY
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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.

    Article  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.

    Article  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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.

    Article  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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Authors and Affiliations

  1. College of Life Sciences and Bioengineering, Beijing Jiaotong University, 100044, Beijing, PR China

    F. Suo, M. Pan, Y. Li, Q. Yan, H. Hu & L. Hou

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Correspondence to L. Hou.

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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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