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Research Article| Volume 12, ISSUE 3, P408-417, 2010

Cytotherapy with naive rat umbilical cord matrix stem cells significantly attenuates growth of murine pancreatic cancer cells and increases survival in syngeneic mice

      Abstract

      Background aims

      Pancreatic cancer, sometimes called a ‘silent killer’, is one of the most aggressive human malignancies, with a very poor prognosis. It is the fourth leading cause of cancer-related morbidity and mortality in the USA.

      Methods

      A mouse peritoneal model was used to test the ability of unengineered rat umbilical cord matrix-derived stem cells (UCMSC) to control growth of pancreatic cancer. In vivo results were supported by various in vitro assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), direct cell count, [3H]thymidine uptake and soft agar colony assays.

      Results

      Co-culture of rat UCMSC with PAN02 murine pancreatic carcinoma cells (UCMSC:PAN02, 1:6 and 1:3) caused G0/G1 arrest and significantly attenuated the proliferation of PAN02 tumor cells, as monitored by MTT assay, direct cell counts and [3H]thymidine uptake assay. Rat UCMSC also significantly reduced PAN02 colony size and number, as measured by soft agar colony assay. The in vivo mouse studies showed that rat UCMSC treatment significantly decreased the peritoneal PAN02 tumor burden 3 weeks after tumor transplantation and increased mouse survival time. Histologic study revealed that intraperitoneally administered rat UCMSC survived for at least 3 weeks, and the majority were found near or inside the tumor.

      Conclusions

      These results indicate that naive rat UCMSC alone remarkably attenuate the growth of pancreatic carcinoma cells in vitro and in a mouse peritoneal model. This implies that UCMSC could be a potential tool for targeted cytotherapy for pancreatic cancer.

      Key Words

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      References

        • Jemal A.
        • Siegel R.
        • Ward E.
        • Hao Y.
        • Xu J.
        • Thun M.J.
        Cancer Statistics 2009.
        CA Cancer J Clin. 2009; 59: 225-249
        • Hezel A.F.
        • Kimmelman A.C.
        • Stanger B.Z.
        • Bardeesy N.
        • Depinho R.A.
        Genetics and biology of pancreatic ductal adenocarcinoma.
        Genes Dev. 2006; 20: 1218-1249
        • Warshaw A.L.
        • Fernandez-del Castillo C.
        Pancreatic carcinoma.
        N Engl J Med. 1992; 326: 455-465
        • Keleg S.
        • Buchler P.
        • Ludwig R.
        • Buchler M.W.
        • Friess H.
        Invasion and metastasis in pancreatic cancer.
        Mol Cancer. 2003; 2: 14-20
        • McKenna S.
        • Eatock M.
        The medical management of pancreatic cancer: a review.
        Oncologist. 2003; 8: 149-160
        • Li D.
        • Xie K.
        • Wolff R.
        • Abbruzzese J.L.
        Pancreatic cancer.
        Lancet. 2004; 363: 1049-1057
        • Corsten M.F.
        • Shah K.
        Therapeutic stem-cells for cancer treatment: hopes and hurdles in tactical warfare.
        Lancet Oncol. 2008; 9: 376-384
        • Aboody K.S.
        • Brown A.
        • Rainov N.G.
        • Bower K.A.
        • Liu S.
        • Yang W.
        • et al.
        Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.
        Proc Natl Acad Sci USA. 2000; 97: 12846-12851
        • Nakamizo A.
        • Marini F.
        • Amano T.
        • Khan A.
        • Studeny M.
        • Gumin J.
        • et al.
        Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.
        Cancer Res. 2005; 65: 3307-3318
        • Rachakatla R.S.
        • Marini F.
        • Weiss M.L.
        • Tamura M.
        • Troyer D.
        Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors.
        Cancer Gene Ther. 2007; 14: 828-835
        • Studeny M.
        • Marini F.C.
        • Champlin R.E.
        • Zompetta C.
        • Fidler I.J.
        • Andreeff M.
        Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.
        Cancer Res. 2002; 62: 3603-3608
        • Studeny M.
        • Marini F.C.
        • Dembinski J.L.
        • Zompetta C.
        • Cabreira-Hansen M.
        • Bekele B.N.
        • et al.
        Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.
        J Natl Cancer Inst. 2004; 96: 1593-1603
        • Aboody K.S.
        • Najbauer J.
        • Schmidt N.O.
        • Yang W.
        • Wu J.K.
        • Zhuge Y.
        • et al.
        Targeting of melanoma brain metastases using engineered neural stem/progenitor cells.
        Neuro Oncol. 2006; 8: 119-126
        • Kumar S.
        • Chanda D.
        • Ponnazhagan S.
        Therapeutic potential of genetically modified mesenchymal stem cells.
        Gene Ther. 2008; 15: 711-715
        • Mitchell K.E.
        • Weiss M.L.
        • Mitchell B.M.
        • Martin P.
        • Davis D.
        • Morales L.
        • et al.
        Matrix cells from Wharton's jelly form neurons and glia.
        Stem Cells. 2003; 21: 50-60
        • Ganta C.
        • Chiyo D.
        • Ayuzawa R.
        • Rachakatla R.
        • Pyle M.
        • Andrews G.
        • et al.
        Rat umbilical cord stem cells completely abolish rat mammary carcinomas with no evidence of metastasis or recurrence 100 days post-tumor cell inoculation.
        Cancer Res. 2009; 69: 1815-1820
        • Cho P.S.
        • Messina D.J.
        • Hirsh E.L.
        • Chi N.
        • Goldman S.N.
        • Lo D.P.
        • et al.
        Immunogenicity of umbilical cord tissue derived cells.
        Blood. 2008; 111: 430-438
        • Weiss M.L.
        • Anderson C.
        • Medicetty S.
        • Seshareddy K.B.
        • Weiss R.J.
        • VanderWerff I.
        • et al.
        Immune properties of human umbilical cord Wharton's jelly-derived cells.
        Stem Cells. 2008; 26: 2865-2874
        • Prowse K.R.
        • Greider C.W.
        Developmental and tissue-specific regulation of mouse telomerase and telomere length.
        Proc Natl Acad Sci USA. 1995; 92: 4818-4822
        • Yang L.
        • Hwang R.
        • Pandit L.
        • Gordon E.M.
        • Anderson W.F.
        • Parekh D.
        Gene therapy of metastatic pancreas cancer with intraperitoneal injections of concentrated retroviral herpes simplex thymidine kinase vector supernatant and ganciclovir.
        Ann Surg. 1996; 224 (discussion 14–7): 405-414
        • Khakoo A.Y.
        • Pati S.
        • Anderson S.A.
        • Reid W.
        • Elshal M.F.
        • Rovira I.I.
        • et al.
        Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma.
        J Exp Med. 2006; 203: 1235-1247
        • Friedman R.
        • Betancur M.
        • Boissel L.
        • Tuncer H.
        • Cetrulo C.
        • Klingemann H.
        Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation.
        Biol Blood Marrow Transplant. 2007; 13: 1477-1486
        • Aboody K.S.
        • Najbauer J.
        • Danks M.K.
        Stem and progenitor cell-mediated tumor selective gene therapy.
        Gene Ther. 2008; 15: 739-752
        • Hall B.
        • Andreeff M.
        • Marini F.
        The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles.
        Handb Exp Pharmacol. 2007; : 263-283
        • Muller A.
        • Homey B.
        • Soto H.
        • Ge N.
        • Catron D.
        • Buchanan M.E.
        • et al.
        Involvement of chemokine receptors in breast cancer metastasis.
        Nature. 2001; 410: 50-56
        • Lee B.C.
        • Lee T.H.
        • Avraham S.
        • Avraham H.K.
        Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells.
        Mol Cancer Res. 2004; 2: 327-338
        • Karnoub A.E.
        • Dash A.B.
        • Vo A.P.
        • Sullivan A.
        • Brooks M.W.
        • Bell G.W.
        • et al.
        Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
        Nature. 2007; 449: 557-563
        • Arbab A.S.
        • Janic B.
        • Knight R.A.
        • Anderson S.A.
        • Pawelczyk E.
        • Rad A.M.
        • et al.
        Detection of migration of locally implanted AC133+ stem cells by cellular magnetic resonance imaging with histological findings.
        FASEB J. 2008; 22: 3234-3246
        • Kang S.G.
        • Jeun S.S.
        • Lim J.Y.
        • Kim S.M.
        • Yang Y.S.
        • Oh W.I.
        • et al.
        Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells.
        Childs Nerv Syst. 2008; 24: 293-302
        • Larmonier N.
        • Ghiringhelli F.
        • Larmonier C.B.
        • Moutet M.
        • Fromentin A.
        • Baulot E.
        • et al.
        Freshly isolated bone marrow cells induce death of various carcinoma cell lines.
        Int J Cancer. 2003; 107: 747-756
        • Weiss M.L.
        • Medicetty S.
        • Bledsoe A.R.
        • Rachakatla R.S.
        • Choi M.
        • Merchav S.
        • et al.
        Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease.
        Stem Cells. 2006; 24: 781-792
        • Weiss M.L.
        • Troyer D.L.
        Stem cells in the umbilical cord.
        Stem Cell Rev. 2006; 2: 155-162