Human mesenchymal stem cells enhance autophagy of lung carcinoma cells against apoptosis during serum deprivation

Zhang,Ming-Hui; Hu,Yi-De; Xu,Yu; Xiao,Yu; Luo,Yan; Song,Zong‑Chang; Zhou,Jing

doi:10.3892/ijo.2013.1810

Human mesenchymal stem cells enhance autophagy of lung carcinoma cells against apoptosis during serum deprivation

Authors:
- Ming-Hui Zhang
- Yi-De Hu
- Yu Xu
- Yu Xiao
- Yan Luo
- Zong‑Chang Song
- Jing Zhou
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Affiliations: The Third Department of Oncology, PLA Cancer Research Institute of the Second Affiliated Hospital, The Third Military Medical University, Chongqing 400037, P.R. China
Published online on: February 6, 2013 https://doi.org/10.3892/ijo.2013.1810
Pages: 1390-1398

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Abstract

Currently, some evidence suggests that human multipotential mesenchymal stems cells (hMSCs) aid tumor growth and metastasis. Nutrient deprivation and oxygen deficiency are representative characteristics of solid tumor microenvironment during the cancer development. Because the effects of hMSCs on tumors under stressful conditions have not been determined, we investigated the survival mechanisms used by stressed stromal cells on A549 and SPC-1 lung carcinoma cell lines in vitro and in vivo. An indirect culture system was used to investigate the effects of hMSCs on viability and apoptosis in starved carcinoma cells and focused on the role of autophagy in regulating the survival of carcinoma cells. The results showed that A549 and SPC-1 cells had higher viability when co-cultured with hMSCs and that this was mainly attributed to decreased apoptosis. Autophagosomes were analyzed using GFP-LC3 and electron microscopy, which showed that autophagy was significantly activated in the starved co-culture groups. However, the inhibition of autophagy by the autophagic inhibitor 3-MA significantly abrogated the apoptosis reduction in either single groups or co-culture groups under serum deprivation, which implied that the hMSCs protected against apoptosis by enhancing autophagy in lung carcinoma cells in vitro. We also observed that hMSCs promoted tumor initiation and growth in vivo. In conclusion, our study demonstrates that hMSCs can protect carcinoma cells from nutrient deprivation-induced apoptosis and promote tumor initiation and growth, and, interestingly, autophagy plays an important role in the survival of cancer cells.

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1	Siegel R, Desantis C, Virgo K, et al: Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 62:220–241. 2012. View Article : Google Scholar : PubMed/NCBI
2	Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 276:71–74. 1997. View Article : Google Scholar : PubMed/NCBI
3	Young HE, Steele TA, Bray RA, et al: Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec (Hoboken). 264:51–62. 2001. View Article : Google Scholar
4	Pittenger MF, Mackay AM, Beck SC, et al: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
5	Young HE, Duplaa C, Young TM, et al: Clonogenic analysis reveals reserve stem cells in postnatal mammals: I. Pluripotent mesenchymal stem cells. Anat Rec (Hoboken). 263:350–360. 2001. View Article : Google Scholar : PubMed/NCBI
6	Fox JM, Chamberlain G, Ashton BA and Middleton J: Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol. 137:491–502. 2007. View Article : Google Scholar : PubMed/NCBI
7	Karnoub AE, Dash AB, Vo AP, et al: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
8	Mishra PJ, Humeniuk R, Medina DJ, et al: Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 68:4331–4339. 2008. View Article : Google Scholar : PubMed/NCBI
9	Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ and Andreeff M: Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 62:3603–3608. 2002.PubMed/NCBI
10	Xin H, Kanehira M, Mizuguchi H, et al: Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells. 25:1618–1626. 2007. View Article : Google Scholar : PubMed/NCBI
11	Stagg J: Mesenchymal stem cells in cancer. Stem Cell Rev. 4:119–124. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zhang W: Mesenchymal stem cells in cancer: friends or foes. Cancer Biol Ther. 7:252–254. 2008. View Article : Google Scholar : PubMed/NCBI
13	Bian ZY, Fan QM, Li G, Xu WT and Tang TT: Human mesenchymal stem cells promote growth of osteosarcoma: involvement of interleukin-6 in the interaction between human mesenchymal stem cells and Saos-2. Cancer Sci. 101:2554–2560. 2010. View Article : Google Scholar : PubMed/NCBI
14	Bagley RG, Weber W, Rouleau C, et al: Human mesenchymal stem cells from bone marrow express tumor endothelial and stromal markers. Int J Oncol. 34:619–627. 2009. View Article : Google Scholar : PubMed/NCBI
15	Kato K, Ogura T, Kishimoto A, et al: Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene. 21:6082–6090. 2002. View Article : Google Scholar : PubMed/NCBI
16	Li Y, Iglehart JD, Richardson AL and Wang ZC: The amplified cancer gene LAPTM4B promotes tumor growth and tolerance to stress through the induction of autophagy. Autophagy. 8:273–274. 2012. View Article : Google Scholar : PubMed/NCBI
17	Kelekar A: Introduction to the review series Autophagy in Higher Eukaryotes--a matter of survival or death. Autophagy. 4:555–556. 2008. View Article : Google Scholar : PubMed/NCBI
18	Yin L, Kharbanda S and Kufe D: MUC1 oncoprotein promotes autophagy in a survival response to glucose deprivation. Int J Oncol. 34:1691–1699. 2009.PubMed/NCBI
19	Carew JS, Medina EC, Esquivel JA II, et al: Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med. 14:2448–2459. 2010. View Article : Google Scholar
20	Kang C, You YJ and Avery L: Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev. 21:2161–2171. 2007. View Article : Google Scholar : PubMed/NCBI
21	Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Nature reviews Cancer. 7:961–967. 2007. View Article : Google Scholar
22	Fujii S, Mitsunaga S, Yamazaki M, et al: Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci. 99:1813–1819. 2008.PubMed/NCBI
23	Dominici M, Le Blanc K, Mueller I, et al: 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
24	Rhodes LV, Muir SE, Elliott S, et al: Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. Breast Cancer Res Treat. 121:293–300. 2010. View Article : Google Scholar : PubMed/NCBI
25	Klionsky DJ, Abeliovich H, Agostinis P, et al: Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 4:151–175. 2008. View Article : Google Scholar
26	Seglen PO and Gordon PB: 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA. 79:1889–1892. 1982. View Article : Google Scholar : PubMed/NCBI
27	Sanchez CG, Penfornis P, Oskowitz AZ, et al: Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis. 32:964–972. 2011. View Article : Google Scholar : PubMed/NCBI
28	Degenhardt K, Mathew R, Beaudoin B, et al: Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 10:51–64. 2006. View Article : Google Scholar : PubMed/NCBI
29	Karantza-Wadsworth V and White E: Role of autophagy in breast cancer. Autophagy. 3:610–613. 2007. View Article : Google Scholar
30	Lum JJ, Bauer DE, Kong M, et al: Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 120:237–248. 2005. View Article : Google Scholar : PubMed/NCBI
31	Karantza-Wadsworth V, Patel S, Kravchuk O, et al: Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21:1621–1635. 2007. View Article : Google Scholar : PubMed/NCBI
32	Boya P, Gonzalez-Polo RA, Casares N, et al: Inhibition of macro-autophagy triggers apoptosis. Mol Cell Biol. 25:1025–1040. 2005. View Article : Google Scholar : PubMed/NCBI
33	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 micro-environments with special focus on mesenchymal stem cells. Crit Rev Oncol Hematol. 69:187–198. 2009. View Article : Google Scholar : PubMed/NCBI
34	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
35	Sinha S and Levine B: The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene. 27(Suppl 1): S137–S148. 2008. View Article : Google Scholar : PubMed/NCBI
36	Maiuri MC, Criollo A, Tasdemir E, et al: BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy. 3:374–376. 2007. View Article : Google Scholar
37	Pattingre S, Tassa A, Qu X, et al: Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 122:927–939. 2005. View Article : Google Scholar : PubMed/NCBI
38	Chang NC, Nguyen M, Germain M and Shore GC: Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1. EMBO J. 29:606–618. 2010. View Article : Google Scholar : PubMed/NCBI
39	Lian J, Wu X, He F, et al: A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ. 18:60–71. 2011. View Article : Google Scholar : PubMed/NCBI