Dual effects of human adipose tissue-derived mesenchymal stem cells in human lung adenocarcinoma A549 xenografts and colorectal adenocarcinoma HT-29 xenografts in mice

Rhyu,Jung Joo; Yun,Jun-Won; Kwon,Euna; Che,Jeong-Hwan; Kang,Byeong-Cheol

doi:10.3892/or.2015.4185

Dual effects of human adipose tissue-derived mesenchymal stem cells in human lung adenocarcinoma A549 xenografts and colorectal adenocarcinoma HT-29 xenografts in mice

Authors:
- Jung Joo Rhyu
- Jun-Won Yun
- Euna Kwon
- Jeong-Hwan Che
- Byeong-Cheol Kang
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Affiliations: Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea, Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea, Biomedical Center for Animal Resource and Development, N-BIO, Seoul National University, Seoul, Republic of Korea
Published online on: August 7, 2015 https://doi.org/10.3892/or.2015.4185
Pages: 1733-1744

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Abstract

Human adipose tissue-derived mesenchymal stem cells (hATMSCs) have great potential as a therapy for various diseases. However, emerging evidence shows that there are conflicting results concerning effects of hATMSCs on tumor progression. Our objective was to determine whether and how hATMSCs modulate tumor growth. After cancer cell lines were subcutaneously inoculated into BALB/c-nude and hairless severe combined immunodeficient mice, hATMSCs were intratumorally injected into the mice. The growth of the A549 tumors was inhibited by hATMSCs, yet that of the HT-29 tumors was significantly promoted by hATMSCs in the in vivo xenograft models. In vitro study using a co-culture system of cancer cells and hATMSCs was consistent with the in vivo experiments. To reveal the molecular events induced by hATMSCs in the xenograft models, global gene expression profiles of the A549 and HT-29 tumors in the absence or presence of hATMSCs were determined. Significant numbers of genes involved in biological processes were altered in the hATMSC-treated A549 tumors, whereas no biological process was regulated by treatment with hATMSCs in the HT-29 tumors, reflecting the different effects of hATMSCs in the different types of cancer. Notably, histone cluster 1, H2aj and neuropeptide Y receptor Y4 were found to be expressed in direct or inverse proportion to tumor size in both xenograft models. In addition, nuclear factor κB (NF-κB) p65 was differentially phosphorylated by the hATMSCs dependent on the source of the cancer cells. In conclusion, the identified gene profiling and NF-κB signaling provide molecular evidence to explain the conflicting findings in tumor‑MSC studies, although further study is needed to confirm these findings using various types of cancer.

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1	Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
2	Dong J, Uemura T, Shirasaki Y and Tateishi T: Promotion of bone formation using highly pure porous beta-TCP combined with bone marrow-derived osteoprogenitor cells. Biomaterials. 23:4493–4502. 2002. View Article : Google Scholar : PubMed/NCBI
3	Choi HJ, Kim JM, Kwon E, Che JH, Lee JI, Cho SR, Kang SK, Ra JC and Kang BC: Establishment of efficacy and safety assessment of human adipose tissue-derived mesenchymal stem cells (hATMSCs) in a nude rat femoral segmental defect model. J Korean Med Sci. 26:482–491. 2011. View Article : Google Scholar : PubMed/NCBI
4	Toyoshima KE, Asakawa K, Ishibashi N, Toki H, Ogawa M, Hasegawa T, Irié T, Tachikawa T, Sato A, Takeda A, et al: Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat Commun. 3:7842012. View Article : Google Scholar : PubMed/NCBI
5	Seo KW, Sohn SY, Bhang DH, Nam MJ, Lee HW and Youn HY: Therapeutic effects of hepatocyte growth factor-overexpressing human umbilical cord blood-derived mesenchymal stem cells on liver fibrosis in rats. Cell Biol Int. 38:106–116. 2014. View Article : Google Scholar
6	Perez-Basterrechea M, Obaya AJ, Meana A, Otero J and Esteban MM: Cooperation by fibroblasts and bone marrow-mesenchymal stem cells to improve pancreatic rat-to-mouse islet xenotransplantation. PLoS One. 8:e735262013. View Article : Google Scholar : PubMed/NCBI
7	Bas E, Van De Water TR, Lumbreras V, Rajguru S, Goss G, Hare JM and Goldstein BJ: Adult human nasal mesenchymal-like stem cells restore cochlear spiral ganglion neurons after experimental lesion. Stem Cells Dev. 23:502–514. 2014. View Article : Google Scholar :
8	Tian LL, Yue W, Zhu F, Li S and Li W: Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol. 226:1860–1867. 2011. View Article : Google Scholar : PubMed/NCBI
9	Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, et al: Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 20:1297–1308. 2011. View Article : Google Scholar : PubMed/NCBI
10	MacIsaac ZM, Shang H, Agrawal H, Yang N, Parker A and Katz AJ: Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells. Exp Cell Res. 318:416–423. 2012. View Article : Google Scholar :
11	Klopp AH, Gupta A, Spaeth E, Andreeff M and Marini F III: Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 29:11–19. 2011. View Article : Google Scholar : PubMed/NCBI
12	Maestroni GJ, Hertens E and Galli P: Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cell Mol Life Sci. 55:663–667. 1999. View Article : Google Scholar : PubMed/NCBI
13	Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G, et al: Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med. 203:1235–1247. 2006. View Article : Google Scholar : PubMed/NCBI
14	Li L, Tian H, Chen Z, Yue W, Li S and Li W: Inhibition of lung cancer cell proliferation mediated by human mesenchymal stem cells. Acta Biochim Biophys Sin. 43:143–148. 2011. View Article : Google Scholar : PubMed/NCBI
15	Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C and Chen Y: Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 80:267–274. 2006. View Article : Google Scholar
16	Xu WT, Bian ZY, Fan QM, Li G and Tang TT: Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett. 281:32–41. 2009. View Article : Google Scholar : PubMed/NCBI
17	Tsai KS, Yang SH, Lei YP, Tsai CC, Chen HW, Hsu CY, Chen LL, Wang HW, Miller SA, Chiou SH, et al: Mesenchymal stem cells promote formation of colorectal tumors in mice. Gastroenterology. 141:1046–1056. 2011. View Article : Google Scholar : PubMed/NCBI
18	Roorda BD, ter Elst A, Kamps WA and de Bont ES: Bone marrow-derived cells and tumor growth: Contribution of bone marrow-derived cells to tumor microenvironments with special focus on mesenchymal stem cells. Crit Rev Oncol Hematol. 69:187–198. 2009. View Article : Google Scholar
19	Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW and Banerjee D: Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 68:4331–4339. 2008. View Article : Google Scholar : PubMed/NCBI
20	Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC and Favrot MC: Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia. 19:1597–1604. 2005. View Article : Google Scholar : PubMed/NCBI
21	Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R and Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
22	Lu YR, Yuan Y, Wang XJ, Wei LL, Chen YN, Cong C, Li SF, Long D, Tan WD, Mao YQ, et al: The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther. 7:245–251. 2008. View Article : Google Scholar
23	Otsu K, Das S, Houser SD, Quadri SK, Bhattacharya S and Bhattacharya J: Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood. 113:4197–4205. 2009. View Article : Google Scholar :
24	Qiao L, Xu ZL, Zhao TJ, Ye LH and Zhang XD: Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 269:67–77. 2008. View Article : Google Scholar : PubMed/NCBI
25	Kubota T, Yamaguchi H, Watanabe M, Yamamoto T, Takahara T, Takeuchi T, Furukawa T, Kase S, Kodaira S, Ishibiki K, et al: Growth of human tumor xenografts in nude mice and mice with severe combined immunodeficiency (SCID). Surg Today. 23:375–377. 1993. View Article : Google Scholar : PubMed/NCBI
26	Denicolaï E, Baeza-Kallee N, Tchoghandjian A, Carré M, Colin C, Jiglaire CJ, Mercurio S, Beclin C and Figarella-Branger D: Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo. Oncotarget. 5:10934–10948. 2014.PubMed/NCBI
27	Yun JW, Lee TR, Kim CW, Park YH, Chung JH, Lee YS, Kang KS and Lim KM: Predose blood gene expression profiles might identify the individuals susceptible to carbon tetrachloride-induced hepatotoxicity. Toxicol Sci. 115:12–21. 2010. View Article : Google Scholar : PubMed/NCBI
28	Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG and Lee JS: Prediction of cancer incidence and mortality in Korea, 2013. Cancer Res Treat. 45:15–21. 2013. View Article : Google Scholar : PubMed/NCBI
29	Paine-Murrieta GD, Taylor CW, Curtis RA, Lopez MH, Dorr RT, Johnson CS, Funk CY, Thompson F and Hersh EM: Human tumor models in the severe combined immune deficient (scid) mouse. Cancer Chemother Pharmacol. 40:209–214. 1997. View Article : Google Scholar : PubMed/NCBI
30	Hao Y, Huang W, Liao M, Zhu Y, Liu H, Hao C, Liu G, Zhang G, Feng H, Ning X, et al: The inhibition of resveratrol to human skin squamous cell carcinoma A431 xenografts in nude mice. Fitoterapia. 86:84–91. 2013. View Article : Google Scholar : PubMed/NCBI
31	Ansari D, Bauden MP, Sasor A, Gundewar C and Andersson R: Analysis of MUC4 expression in human pancreatic cancer xenografts in immunodeficient mice. Anticancer Res. 34:3905–3910. 2014.PubMed/NCBI
32	Uchibori R, Tsukahara T, Mizuguchi H, Saga Y, Urabe M, Mizukami H, Kume A and Ozawa K: NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites. Cancer Res. 73:364–372. 2013. View Article : Google Scholar
33	Kéramidas M, de Fraipont F, Karageorgis A, Moisan A, Persoons V, Richard MJ, Coll JL and Rome C: The dual effect of mesenchymal stem cells on tumour growth and tumour angiogenesis. Stem Cell Res Ther. 4:412013. View Article : Google Scholar : PubMed/NCBI
34	Fierro FA, Sierralta WD, Epuñan MJ and Minguell JJ: Marrow-derived mesenchymal stem cells: Role in epithelial tumor cell determination. Clin Exp Metastasis. 21:313–319. 2004. View Article : Google Scholar : PubMed/NCBI
35	Potapova IA, Gaudette GR, Brink PR, Robinson RB, Rosen MR, Cohen IS and Doronin SV: Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cells. 25:1761–1768. 2007. View Article : Google Scholar : PubMed/NCBI
36	Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC, Ye L and Zhang X: Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 18:500–507. 2008. View Article : Google Scholar : PubMed/NCBI
37	Abdel aziz MT, El Asmar MF, Atta HM, Mahfouz S, Fouad HH, Roshdy NK, Rashed LA, Sabry D, Hassouna AA and Taha FM: Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: Possible role of Wnt signaling. J Exp Clin Cancer Res. 30:492011. View Article : Google Scholar : PubMed/NCBI
38	Kim BY, Lee J, Park SJ, Bang OS and Kim NS: Gene expression profile of the A549 human non-small cell lung carcinoma cell line following treatment with the seeds of Descurainia sophia, a potential anticancer drug. Evid Based Complement Alternat Med. 2013:5846042013.PubMed/NCBI
39	Creighton C, Kuick R, Misek DE, Rickman DS, Brichory FM, Rouillard JM, Omenn GS and Hanash S: Profiling of pathway-specific changes in gene expression following growth of human cancer cell lines transplanted into mice. Genome Biol. 4:R462003. View Article : Google Scholar : PubMed/NCBI
40	Lu C, Xiong M, Luo Y, Li J, Zhang Y, Dong Y, Zhu Y, Niu T, Wang Z and Duan L: Genome-wide transcriptional analysis of apoptosis-related genes and pathways regulated by H2AX in lung cancer A549 cells. Apoptosis. 18:1039–1047. 2013. View Article : Google Scholar : PubMed/NCBI
41	Lo FY, Chang JW, Chang IS, Chen YJ, Hsu HS, Huang SF, Tsai FY, Jiang SS, Kanteti R, Nandi S, et al: The database of chromosome imbalance regions and genes resided in lung cancer from Asian and Caucasian identified by array-comparative genomic hybridization. BMC Cancer. 12:2352012. View Article : Google Scholar : PubMed/NCBI
42	Yang B, Zhang J, Yin Y and Zhang Y: Network-based inference framework for identifying cancer genes from gene expression data. BioMed Res Int. 2013:4016492013. View Article : Google Scholar : PubMed/NCBI
43	Kavak E, Unlü M, Nistér M and Koman A: Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumor associated regions of co-regulation. Nucleic Acids Res. 38:7008–7021. 2010. View Article : Google Scholar : PubMed/NCBI
44	Herzog H: Neuropeptide Y and energy homeostasis: Insights from Y receptor knockout models. Eur J Pharmacol. 480:21–29. 2003. View Article : Google Scholar : PubMed/NCBI
45	Renshaw D and Batterham RL: Peptide YY: A potential therapy for obesity. Curr Drug Targets. 6:171–179. 2005. View Article : Google Scholar : PubMed/NCBI
46	Huda MS, Wilding JP and Pinkney JH: Gut peptides and the regulation of appetite. Obes Rev. 7:163–182. 2006. View Article : Google Scholar : PubMed/NCBI
47	Zhang L, Bijker MS and Herzog H: The neuropeptide Y system: Pathophysiological and therapeutic implications in obesity and cancer. Pharmacol Ther. 131:91–113. 2011. View Article : Google Scholar : PubMed/NCBI
48	Ma Y, Hao X, Zhang S and Zhang J: The in vitro and in vivo effects of human umbilical cord mesenchymal stem cells on the growth of breast cancer cells. Breast Cancer Res Treat. 133:473–485. 2012. View Article : Google Scholar
49	Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A and Zamora A: The transcription factor nuclear factor-kappa B and cancer. Clin Oncol. 19:154–161. 2007. View Article : Google Scholar
50	Pikarsky E and Ben-Neriah Y: NF-kappaB inhibition: A double-edged sword in cancer? Eur J Cancer. 42:779–784. 2006. View Article : Google Scholar : PubMed/NCBI
51	Zhang J, Xu YJ, Xiong WN, Zhang ZX, Du CL, Qiao LF, Ni W and Chen SX: Inhibition of NF-kappaB through IkappaBalpha transfection affects invasion of human lung cancer cell line A549. Ai Zheng. 27:710–715. 2008.In Chinese. PubMed/NCBI
52	Kuliková L, Mikeš J, Hýžďalová M, Palumbo G and Fedoročko P: NF-κB is not directly responsible for photoresistance induced by fractionated light delivery in HT-29 colon adenocarcinoma cells. Photochem Photobiol. 86:1285–1293. 2010. View Article : Google Scholar