Suppression of tumor cell proliferation and migration by human umbilical cord mesenchymal stem cells: A possible role for apoptosis and Wnt signaling

Yuan,Yin; Zhou,Chang; Chen,Xuan; Tao,Changli; Cheng,Huiqing; Lu,Xin

doi:10.3892/ol.2018.8368

Suppression of tumor cell proliferation and migration by human umbilical cord mesenchymal stem cells: A possible role for apoptosis and Wnt signaling

Authors:
- Yin Yuan
- Chang Zhou
- Xuan Chen
- Changli Tao
- Huiqing Cheng
- Xin Lu
View Affiliations

Affiliations: School of Life Science and Biopharmacology, School of Anatomy and Histology, Guangdong Provincial Key Laboratory of Biotechnology Candidate Drug Research, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China, School of Life Science, South China Normal University, Guangzhou, Guangdong 510631, P.R. China
Published online on: March 28, 2018 https://doi.org/10.3892/ol.2018.8368
Pages: 8536-8544
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Human umbilical cord‑derived mesenchymal stem cells (hUCMSCs) represent potential therapeutic tools for solid tumors. However, there are numerous inconsistent results regarding the effects of hUCMSCs on tumors, and the mechanisms underlying this remain poorly understood. The present study further examined this controversial issue by analyzing the molecular mechanisms of the inhibitory effects of hUCMSCs on the proliferation and migration of the human lung cancer A549 cell line and the human hepatocellular carcinoma (HCC) BEL7402 cell line in vitro. Flow cytometric analysis demonstrated that hUCMSCs arrested tumor cells in specific phases of the cell cycle and induced the apoptosis of tumor cells by using the hUCMSC‑conditioned medium (hUCMSC‑CM). The hUCMSC‑CM also attenuated the migratory abilities of the two tumor cell types. Furthermore, the expression of B‑cell lymphoma 2 (Bcl‑2), the pro‑form of caspase‑7 (pro‑caspase‑7), β‑catenin and c‑Myc was downregulated, while that of ephrin receptor (EphA5), a biomarker of cancer cell dormancy, was slightly increased in these two tumor cell lines treated with hUCMSC‑CM. Specifically, when co‑cultured via direct cell‑to‑cell contact, hUCMSCs were able to spontaneously fuse with any of the two types of solid tumor cells. These observations suggested that hUCMSCs may be a promising candidate for the biological therapy of lung cancer and HCC. Future studies should focus on detailed evidence for cell fusion, as well as other mechanisms proposed in the present study, by introducing additional experimental approaches and models.

View Figures

View References

1	Wang W, Zhang L, Liu L, Zheng Y, Zhang Y, Yang S, Shi R and Wang S: Chemosensitizing effect of shRNA-mediated ERCC1 silencing on a Xuanwei lung adenocarcinoma cell line and its clinical significance. Oncol Rep. 37:1989–1997. 2017. View Article : Google Scholar : PubMed/NCBI
2	Rojas A, Zhang P, Wang Y, Foo WC, Muñoz NM, Xiao L, Wang J, Gores GJ, Hung MC and Blechacz B: A positive TGF-β/c-KIT feedback loop drives tumor progression in advanced primary liver cancer. Neoplasia. 18:371–386. 2016. View Article : Google Scholar : PubMed/NCBI
3	Baskar R, Yap SP, Chua KL and Itahana K: The diverse and complex roles of radiation on cancer treatment: Therapeutic target and genome maintenance. Am J Cancer Res. 2:372–382. 2012.PubMed/NCBI
4	Lee DH, Ahn Y, Kim SU, Wang KC, Cho BK, Phi JH, Park IH, Black PM, Carroll RS, Lee J and Kim SK: Targeting rat brainstem glioma using human neural stem cells and human mesenchymal stem cells. Clin Cancer Res. 15:4925–4934. 2009. View Article : Google Scholar : PubMed/NCBI
5	Ciavarella S, Dominici M, Dammacco F and Silvestris F: Mesenchymal stem cells: A new promise in anticancer therapy. Stem Cells Dev. 20:1–10. 2011. View Article : Google Scholar : PubMed/NCBI
6	Yang J, Miao Y, Chang Y, Zhang F, Wang Y and Zheng S: Condition medium of HepG-2 cells induces the transdifferentiation of human umbilical cord mesenchymal stem cells into cancerous mesenchymal stem cells. Am J Transl Res. 8:3429–3438. 2016.PubMed/NCBI
7	Liao W, Zhong J, Yu J, Xie J, Liu Y, Du L, Yang S, Liu P, Xu J, Wang J, et al: Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: Implications of anti-inflammation and angiogenesis. Cell Physiol Biochem. 24:307–316. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zhong YS, Lin N, Deng MH, Zhang FC, Tang ZF and Xu RY: Deficient proliferation of bone marrow-derived mesenchymal stem cells in patients with chronic hepatitis B viral infections and cirrhosis of the liver. Dig Dis Sci. 55:438–445. 2010. View Article : Google Scholar : PubMed/NCBI
9	Bieback K, Kem S, Kluter H and Eichler H: Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells. 22:625–634. 2004. View Article : Google Scholar : PubMed/NCBI
10	Shen CJ, Chan TF, Chen CC, Hsu YC, Long CY and Lai CS: Human umbilical cord matrix-derived stem cells expressing interferon-β gene inhibit breast cancer cells via apoptosis. Oncotarget. 7:34172–34179. 2016. View Article : Google Scholar : PubMed/NCBI
11	Ma S, Liang S, Jiao H, Chi L, Shi X, Tian Y, Yang B and Guan F: Human umbilical cord mesenchymal stem cells inhibit C6 glioma growth via secretion of dickkopf-1 (DKK1). Mol Cell Biochem. 385:277–286. 2014. View Article : Google Scholar : PubMed/NCBI
12	Yang C, Lei D, Ouyang W, Ren J, Li H, Hu J and Huang S: Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. Biomed Res Int. 2014:1093892014. View Article : Google Scholar : PubMed/NCBI
13	Wang M, Cai J, Huang F, Zhu M, Zhang Q, Yang T, Zhang X, Qian H and Xu W: Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells. Int J Mol Med. 35:367–375. 2015. View Article : Google Scholar : PubMed/NCBI
14	Yang X, Li Z, Ma Y, Gao J, Liu S, Gao Y and Wang G: Human umbilical cord mesenchymal stem cells promote carcinoma growth and lymph node metastasis when co-injected with esophageal carcinoma cells in nude mice. Cancer Cell Int. 14:932014. View Article : Google Scholar : PubMed/NCBI
15	Yuan Y, Lu X, Chen X, Shao H and Huang S: Jagged1 contributes to the drug resistance of Jurkat cells in contact with human umbilical cord-derived mesenchymal stem cells. Oncol Lett. 6:1000–1006. 2013. View Article : Google Scholar : PubMed/NCBI
16	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
17	Ba Q, Li J, Huang C, Qiu H, Li J, Chu R, Zhang W, Xie D, Wu Y and Wang H: Effects of benzo [a]pyrene exposure on human hepatocellular carcinoma cell angiogenesis, metastasis and NF-κB signaling. Environ Health Perspect. 123:246–254. 2015.PubMed/NCBI
18	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
19	Wei HJ, Nickoloff JA, Chen WH, Liu HY, Lo WC, Chang YT, Yang PC, Wu CW, Williams DF, Gelovani JG and Deng WP: FOXF1 mediates mesenchymal stem cell fusion-induced reprogramming of lung cancer cells. Oncotarget. 5:9514–9529. 2014. View Article : Google Scholar : PubMed/NCBI
20	Wang Y, Fan H, Zhou B, Ju Z, Yu L, Guo L, Han J and Lu S: Fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells. Int J Oncol. 40:370–377. 2012.PubMed/NCBI
21	Di GH, Jiang S, Li FQ, Sun JZ, Wu CT, Hu X and Duan HF: Human umbilical cord mesenchymal stromal cells mitigate chemotherapy-associated tissue injury in a pre-clinical mouse model. Cytotherapy. 14:412–422. 2012. View Article : Google Scholar : PubMed/NCBI
22	Zhang C, Yang SJ, Wen Q, Zhong JF, Chen XL, Stucky A, Press MF and Zhang X: Human-derived normal mesenchymal stem/stromal cells in anticancer therapies. J Cancer. 8:85–96. 2017. View Article : Google Scholar : PubMed/NCBI
23	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 : PubMed/NCBI
24	Zhang Y, Wang J, Ren M, Li M, Chen D, Chen J, Shi F, Wang X and Dou J: Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice. J Ovarian Res. 7:82014. View Article : Google Scholar : PubMed/NCBI
25	Subramanian A, Shu-Uin G, Kae-Siang N, Gauthaman K, Biswas A, Choolani M, Bongso A and Chui-Yee F: Human umbilical cord wharton's jelly mesenchymal stem cells do not transform to tumor-associated fibroblasts in the presence of breast and ovarian cancer cells unlike bone marrow mesenchymal stem cells. J Cell Biochem. 113:1886–1895. 2012. View Article : Google Scholar : PubMed/NCBI
26	Cohen GM: Caspases: The executioners of apoptosis. Biochem J. 326:1–16. 1997. View Article : Google Scholar : PubMed/NCBI
27	Ghoshal A and Ghosh SS: Antagonizing canonical Wnt signaling pathway by recombinant human sFRP4 purified from E. coli and its implications in cancer therapy. Mol Cell Biochem. 418:119–135. 2016. View Article : Google Scholar : PubMed/NCBI
28	Wei Y, Shen N, Wang Z, Yang G, Yi B, Yang N, Qiu Y and Lu J: Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling. Mol Cell Biochem. 381:139–144. 2013. View Article : Google Scholar : PubMed/NCBI
29	Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW and Rosenfeld MG: Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc Natl Acad Sci USA. 100:3245–3250. 2003. View Article : Google Scholar : PubMed/NCBI
30	Liu J, Han G, Liu H and Qin C: Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: A possible role of Wnt and Akt signaling. PLoS One. 8:e628442013. View Article : Google Scholar : PubMed/NCBI
31	Caplan AI and Correa D: The MSC: An injury drugstore. Cell Stem Cell. 9:11–15. 2011. View Article : Google Scholar : PubMed/NCBI
32	Aguirre-Ghiso JA: Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 7:834–846. 2007. View Article : Google Scholar : PubMed/NCBI
33	Barkan D, El Touny LH, Michalowski AM, Smith JA, Chu I, Davis AS, Webster JD, Hoover S, Simpson RM, Gauldie J and Green JE: Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 70:5706–5716. 2010. View Article : Google Scholar : PubMed/NCBI
34	Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J and Abdollahi A: Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 69:836–844. 2009. View Article : Google Scholar : PubMed/NCBI
35	Glick AB and Yuspa SH: Tissue homeostasis and the control of the neoplastic phenotype in epithelial cancers. Semin Cancer Biol. 15:75–83. 2005. View Article : Google Scholar : PubMed/NCBI
36	Alt-Holland A, Zhang W, Margulis A and Garlick JA: Microenvironmental control of premalignant disease: The role of intercellular adhesion in the progression of squamous cell carcinoma. Semin Cancer Biol. 15:84–96. 2005. View Article : Google Scholar : PubMed/NCBI
37	David DM and Goodridge HS: Information processing during phagocytosis. Nat Rev Immuno. 12:492–502. 2012. View Article : Google Scholar
38	Lavoie JR and Rosu-Myles M: Uncovering the secretes of mesenchymal stem cells. Biochimie. 95:2212–2221. 2013. View Article : Google Scholar : PubMed/NCBI
39	Jacobsen BM, Harrell JC, Jedlicka P, Borges VF, Varella-Garcia M and Horwitz KB: Spontaneous fusion with and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res. 66:8274–8279. 2006. View Article : Google Scholar : PubMed/NCBI
40	Mortensen K, Lichtenberg J, Thomsen PD and Larsson LI: Spontaneous fusion between cancer cells and endothelial cells. Cell Mol Life Sci. 61:2125–2131. 2004. View Article : Google Scholar : PubMed/NCBI