Top

Published in:

Open Access 01-12-2015 | Research article

Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness

Authors: Jianguo Xue, Yuan Zhu, Zixuan Sun, Runbi Ji, Xu Zhang, Wenrong Xu, Xiao Yuan, Bin Zhang, Yongmin Yan, Lei Yin, Huijuan Xu, Leilei Zhang, Wei Zhu, Hui Qian

Published in: BMC Cancer | Issue 1/2015

Abstract

Background

Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer.

Methods

We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting、cell colony formation and transwell assays. The proteins and genes related to epithelial- mesenchymal transition and stemness were tested by western blot、immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids.

Results

The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo.

Conclusions

Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer.

Available only for authorised users

Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9. doi:10.1038/nature00870.CrossRefPubMed

Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.CrossRefPubMed

Gomes CM. The dual role of mesenchymal stem cells in tumor progression. Stem Cell Res Ther. 2013;4(2):42. doi:10.1186/scrt189.CrossRefPubMedPubMedCentral

Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 2006;80(3):267–74. doi:10.1016/j.yexmp.2005.07.004.

Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012;315(1):28–37. doi:10.1016/j.canlet.2011.10.002.

Zhu W, Huang L, Li Y, Qian H, Shan X, Yan Y, et al. Mesenchymal stem cell-secreted soluble signaling molecules potentiate tumor growth. Cell Cycle. 2011;10(18):3198–207.CrossRefPubMed

Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol. 2005;6(7):567–75. doi:10.1038/nrm1678.CrossRefPubMed

Chakraborty AK, Sodi S, Rachkovsky M, Kolesnikova N, Platt JT, Bolognia JL, et al. A spontaneous murine melanoma lung metastasis comprised of host x tumor hybrids. Cancer Res. 2000;60(9):2512–9.PubMed

Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res. 2009;69(22):8536–9. doi:10.1158/0008-5472.CAN-09-2159.CrossRefPubMedPubMedCentral

10.

Lu X, Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc Natl Acad Sci U S A. 2009;106(23):9385–90. doi:10.1073/pnas.0900108106.CrossRefPubMedPubMedCentral

11.

Pawelek JM. Tumour cell hybridization and metastasis revisited. Melanoma Res. 2000;10(6):507–14.CrossRefPubMed

12.

Vignery A. Macrophage fusion: the making of osteoclasts and giant cells. J Exp Med. 2005;202(3):337–40. doi:10.1084/jem.20051123.CrossRefPubMedPubMedCentral

13.

Busund LT, Killie MK, Bartnes K, Seljelid R. Spontaneously formed tumorigenic hybrids of Meth A sarcoma cells and macrophages in vivo. Int J Cancer. 2003;106(2):153–9. doi:10.1002/ijc.11210.

14.

Ding J, Jin W, Chen C, Shao Z, Wu J. Tumor associated macrophage x cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PLoS One. 2012;7(7):e41942. doi:10.1371/journal.pone.0041942.CrossRefPubMedPubMedCentral

15.

Rappa G, Mercapide J, Lorico A. Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity. Am J Pathol. 2012;180(6):2504–15. doi:10.1016/j.ajpath.2012.02.020.CrossRefPubMedPubMedCentral

16.

Duelli D, Lazebnik Y. Cell fusion: a hidden enemy? Cancer Cell. 2003;3(5):445–8.CrossRefPubMed

17.

Clawson GA. Cancer. Fusion for moving. Science. 2013;342(6159):699–700. doi:10.1126/science.1244270.CrossRefPubMed

18.

Wei HJ, Nickoloff JA, Chen WH, Liu HY, Lo WC, Chang YT, et al. FOXF1 mediates mesenchymal stem cell fusion-induced reprogramming of lung cancer cells. Oncotarget. 2014;5(19):9514–29.CrossRefPubMedPubMedCentral

19.

He X, Tsang TC, Pipes BL, Ablin RJ, Harris DT. A stem cell fusion model of carcinogenesis. J Exp Ther Oncol. 2005;5(2):101–9.PubMed

20.

Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci U S A. 2006;103(16):6321–5. doi:10.1073/pnas.0508593103.CrossRefPubMedPubMedCentral

21.

Schichor C, Albrecht V, Korte B, Buchner A, Riesenberg R, Mysliwietz J, et al. Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro. Exp Neurol. 2012;234(1):208–19. doi:10.1016/j.expneurol.2011.12.033.

22.

Xu MH, Gao X, Luo D, Zhou XD, Xiong W, Liu GX. EMT and acquisition of stem cell-like properties are involved in spontaneous formation of tumorigenic hybrids between lung cancer and bone marrow-derived mesenchymal stem cells. PLoS One. 2014;9(2):e87893. doi:10.1371/journal.pone.0087893.CrossRefPubMedPubMedCentral

23.

Li H, Feng Z, Tsang TC, Tang T, Jia X, He X, et al. Fusion of HepG2 cells with mesenchymal stem cells increases cancerassociated and malignant properties: an in vivo metastasis model. Oncol Rep. 2014;32(2):539–47. doi:10.3892/or.2014.3264.

24.

Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol. 2009;472:467–77. doi:10.1007/978-1-60327-492-0_23.CrossRefPubMed

25.

Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, et al. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-beta/Smad pathway. PLoS One. 2012;7(12):e52465. doi:10.1371/journal.pone.0052465.CrossRefPubMedPubMedCentral

26.

Yang T, Zhang X, Wang M, Zhang J, Huang F, Cai J, et al. Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-kappaB pathway. PLoS One. 2014;9(5):e97569. doi:10.1371/journal.pone.0097569.CrossRefPubMedPubMedCentral

27.

Qiao C, Xu W, Zhu W, Hu J, Qian H, Yin Q, et al. Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int. 2008;32(1):8–15. doi:10.1016/j.cellbi.2007.08.002.CrossRefPubMed

28.

Pawelek JM. Cancer-cell fusion with migratory bone-marrow-derived cells as an explanation for metastasis: new therapeutic paradigms. Future Oncol. 2008;4(4):449–52. doi:10.2217/14796694.4.4.449.CrossRefPubMed

29.

Pawelek JM, Chakraborty AK. Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 2008;8(5):377–86. doi:10.1038/nrc2371.CrossRefPubMed

30.

Lazova R, Laberge GS, Duvall E, Spoelstra N, Klump V, Sznol M, et al. A Melanoma Brain Metastasis with a Donor-Patient Hybrid Genome following Bone Marrow Transplantation: First Evidence for Fusion in Human Cancer. PLoS One. 2013;8(6):e66731. doi:10.1371/journal.pone.0066731.CrossRefPubMedPubMedCentral

31.

Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306(5701):1568–71. doi:10.1126/science.1099513.CrossRefPubMed

32.

He X, Li B, Shao Y, Zhao N, Hsu Y, Zhang Z, et al. Cell fusion between gastric epithelial cells and mesenchymal stem cells results in epithelial-to-mesenchymal transition and malignant transformation. BMC Cancer. 2015;15(1):24. doi:10.1186/s12885-015-1027-1.CrossRefPubMedPubMedCentral

33.

NatureWang Y, Fan H, Zhou B, Ju Z, Yu L, Guo L, et al. Fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells. Int J Oncol. 2012;40(2):370–7. doi:10.3892/ijo.2011.1232.

34.

Cuyas E, Corominas-Faja B, Menendez JA. The nutritional phenome of EMT-induced cancer stem-like cells. Oncotarget. 2014;5(12):3970–82.CrossRefPubMedPubMedCentral

35.

Lu X, Kang Y. Cell fusion hypothesis of the cancer stem cell. Adv Exp Med Biol. 2011;714:129–40. doi:10.1007/978-94-007-0782-5_6.CrossRefPubMed

36.

Nagler C, Zanker KS, Dittmar T. Cell Fusion, Drug Resistance and Recurrence CSCs. Adv Exp Med Biol. 2011;714:173–82. doi:10.1007/978-94-007-0782-5_9.CrossRefPubMed

37.

Dittmar T, Nagler C, Schwitalla S, Reith G, Niggemann B, Zanker KS. Recurrence cancer stem cells--made by cell fusion? Med Hypotheses. 2009;73(4):542–7. doi:10.1016/j.mehy.2009.05.044.CrossRefPubMed

38.

Fan H, Lu S. Fusion of human bone hemopoietic stem cell with esophageal carcinoma cells didn’t generate esophageal cancer stem cell. Neoplasma. 2014;61(5):540–5. doi:10.4149/neo_2014_066.CrossRefPubMed

39.

Berndt B, Zanker KS, Dittmar T. Cell fusion is a potent inducer of aneuploidy and drug resistance in tumor cell/ normal cell hybrids. Crit Rev Oncog. 2013;18(1–2):97–113.CrossRefPubMed

Title: Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness
Authors: Jianguo Xue
Yuan Zhu
Zixuan Sun
Runbi Ji
Xu Zhang
Wenrong Xu
Xiao Yuan
Bin Zhang
Yongmin Yan
Lei Yin
Huijuan Xu
Leilei Zhang
Wei Zhu
Hui Qian
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-015-1780-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study)

Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer

Fractal analysis of nuclear histology integrates tumor and stromal features into a single prognostic factor of the oral cancer microenvironment

Difficulty of predicting the presence of lymph node metastases in patients with clinical early stage gastric cancer: a case control study

Nuclear expression of p65 (RelA) in patients receiving post-operative radiotherapy for locally advanced squamous cell carcinoma of the head and neck

Metaplastic breast cancer: a comparison between the most common histologies with poor immunohistochemistry factors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer