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 International

Gengyin Wang¹  Yuhua Gao¹  Surui Liu¹  Jun Gao¹  Yintu Ma¹  Zhu Li¹  Xiaoya Yang¹ 

[1] Blood Transfusion Department, The Bethune International Peace Hospital, Shijiazhuang 050082, Hebei, P R. China

关键词: Tumor growth;    Metastasis;    Esophageal carcinoma;    Mesenchymal stem cells;    Umbilical cord;   

Others  :  1121656
DOI  :  10.1186/s12935-014-0093-9

 received in 2014-01-23, accepted in 2014-09-05,  发布年份 2014

【 摘 要 】

Background

Human umbilical cord blood derived-mesenchymal stem cells (hUCMSCs) offer an attractive alternative to bone marrow-derived MSCs (BMMSCs) for cell-based therapy as it is a less invasive source of biological material. However, limited studies have been conducted with hUCMSCs as compared to BMMSCs. The present study was conducted to evaluate the effects of hUCMSCs in esophageal carcinoma (EC).

Methods

hUCMSCs together with EC cells were transplanted subcutaneously into BALB/c nude mice to observe the effects of hUCMSCs on tumor establishment. hUCMSCs injected through the caudal vein to the mice with pre-established EC to observe the effects of hUCMSCs on tumor outgrowth. In order to elucidate the underlying mechanisms, we also performed in vitro experiments including directly co-culture, transwell assay, proliferation assay and western blotting analysis.

Results

hUCMSCs promoted EC formation in nude mice. In the in vivo model of pre-established EC, intravenously injected hUCMSCs potently promoted tumor growth. When in vitro co-cultured with hUCMSCs, EC cells proliferation increased. After co-cultured with hUCMSCs through transwell system, EC cells showed increased proliferation. Through transwell assay, we also observed that EC cells recruited MSCs, and MSCs promoted EC cells migration and invasion. Western blotting data showed that the expressions of proliferation related proteins Bcl-2, survivin and metastasis related proteins MMP-2 and MMP-9 were up-regulated in the EC cells transwell co-cultured with hUCMSCs.

Conclusions

Our results indicated that hUCMSCs could favor tumor growth in vivo and in vitro. Thus, the exploitation of hUCMSCs in new therapeutic strategies should be cautious under the malignant conditions.

【 授权许可】

   
2014 Yang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Friedenstein AJ, Gorskaja JF, Kulagina NN: Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976, 4(5):267-274.
• [2]Bianco P, Robey PG, Simmons PJ: Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008, 2(4):313-319.
• [3]Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001, 7(2):211-228.
• [4]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284(5411):143-147.
• [5]Barry FP, Murphy JM: Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol 2004, 36(4):568-584.
• [6]Sensebe L, Krampera M, Schrezenmeier H, Bourin P, Giordano R: Mesenchymal stem cells for clinical application. Vox Sang 2009, 98(2):93-107.
• [7]Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ: Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 2012, 7(10):e47559.
• [8]Dvorak HF: Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986, 315(26):1650-1659.
• [9]Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004, 96(21):1593-1603.
• [10]Chen X, Lin X, Zhao J, Shi W, Zhang H, Wang Y, Kan B, Du L, Wang B, Wei Y, Liu Y, Zhao X: A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs. Mol Ther 2008, 16(4):749-756.
• [11]Goldstein RH, Reagan MR, Anderson K, Kaplan DL, Rosenblatt M: Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res 2010, 70(24):10044-10050.
• [12]Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M, Higashi Y, Tanaka S, Yasui W, Chayama K: Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 2010, 127(10):2323-2333.
• [13]Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G, Zhang J, Raffeld M, Rogers TB, Stetler-Stevenson W, Frank JA, Reitz M, Finkel T: Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med 2006, 203(5):1235-1247.
• [14]Otsu K, Das S, Houser SD, Quadri SK, Bhattacharya S, Bhattacharya J: Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood 2009, 113(18):4197-4205.
• [15]Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC: Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 2004, 22(7):1330-1337.
• [16]Nagano M, Kimura K, Yamashita T, Ohneda K, Nozawa D, Hamada H, Yoshikawa H, Ochiai N, Ohneda O: Hypoxia responsive mesenchymal stem cells derived from human umbilical cord blood are effective for bone repair. Stem Cells Dev 2010, 19(8):1195-1210.
• [17]Bieback K, Kern S, Kluter H, Eichler H: Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004, 22(4):625-634.
• [18]Ciavarella S, Dominici M, Dammacco F, Silvestris F: Mesenchymal stem cells: a new promise in anticancer therapy. Stem Cells Dev 2011, 20(1):1-10.
• [19]Fong CY, Chak LL, Biswas A, Tan JH, Gauthaman K, Chan WK, Bongso A: Human Wharton’s jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev 2011, 7(1):1-16.
• [20]Zhao P, Dai M, Chen W, Li N: Cancer trends in China. Jpn J Clin Oncol 2010, 40(4):281-285.
• [21]He Z, Zhao Y, Guo C, Liu Y, Sun M, Liu F, Wang X, Guo F, Chen K, Gao L, Ning T, Pan Y, Li Y, Zhang S, Lu C, Wang Z, Cai H, Ke Y: Prevalence and risk factors for esophageal squamous cell cancer and precursor lesions in Anyang, China: a population-based endoscopic survey. Br J Cancer 2010, 103(7):1085-1088.
• [22]Manochantr S, Up Y, Kheolamai P, Rojphisan S, Chayosumrit M, Tantrawatpan C, Supokawej A, Issaragrisil S: Immunosuppressive properties of mesenchymal stromal cells derived from amnion, placenta, Wharton’s jelly and umbilical cord. Intern Med J 2013, 43(4):430-439.
• [23]Kim DW, Staples M, Shinozuka K, Pantcheva P, Kang SD, Borlongan CV: Wharton’s jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications. Int J Mol Sci 2013, 14(6):11692-11712.
• [24]Papetti M, Herman IM: Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 2002, 282(5):C947-C970.
• [25]Hsieh JY, Wang HW, Chang SJ, Liao KH, Lee IH, Lin WS, Wu CH, Lin WY, Cheng SM: Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One 2013, 8(8):e72604.
• [26]Groblewska M, Siewko M, Mroczko B, Szmitkowski M: The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol 2012, 50(1):12-19.
• [27]Li J, Lau GK, Chen L, Dong SS, Lan HY, Huang XR, Li Y, Luk JM, Yuan YF, Guan XY: Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression. PLoS One 2011, 6(7):e21816.
• [28]Tian LL, Yue W, Zhu F, Li S, Li W: Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol 2011, 226(7):1860-1867.
• [29]Akimoto K, Kimura K, Nagano M, Takano S, To’a Salazar G, Yamashita T, Ohneda O: Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev 2013, 22(9):1370-1386.
• [30]Naito S, von Eschenbach AC, Giavazzi R, Fidler IJ: Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Res 1986, 46(8):4109-4115.