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Open Access 01-12-2011 | Research

Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors

Authors: Xi Xia, Teng Ji, Pingbo Chen, Xiao Li, Yong Fang, Qinglei Gao, Shujie Liao, Lanying You, Hongbin Xu, Quanfu Ma, Peng Wu, Wencheng Hu, Mingfu Wu, Li Cao, Kezhen Li, Yanjie Weng, Zhiqiang Han, Junchen Wei, Ronghua Liu, Shixuan Wang, Gang Xu, Daowen Wang, Jianfeng Zhou, Ding Ma

Published in: Molecular Cancer | Issue 1/2011

Abstract

Background

Mesenchymal stem cells (MSCs) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern, kinetic delivery of adenovirus, and therapeutic efficacy of the MSC loading of E1A mutant conditionally replicative adenovirus Adv-Stat3(-) which selectively replicated and expressed high levels of anti-sense Stat3 complementary DNA in breast cancer and melanoma cells.

Methods

We assessed the release ability of conditionally replicative adenovirus (CRAd) from MSC using crystal violet staining, TCID₅₀ assay, and quantitative PCR. In vitro killing competence of MSCs carrying Adv-Stat3(-) toward breast cancer and melanoma was performed using co-culture system of transwell plates. We examined tumor tropism of MSC by Prussian blue staining and immunofluorescence. In vivo killing competence of MSCs carrying Adv-Stat3(-) toward breast tumor was analyzed by comparison of tumor volumes and survival periods.

Results

Adv-Stat3(-) amplified in MSCs and were released 4 days after infection. MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines. In vivo experiments confirmed the preferential localization of MSCs in the tumor periphery 24 hours after tail vein injection, and this localization was mainly detected in the tumor parenchyma after 72 hours. Intravenous injection of MSCs carrying Adv-Stat3(-) suppressed the Stat3 pathway, down-regulated Ki67 expression, and recruited CD11b-positive cells in the local tumor, inhibiting tumor growth and increasing the survival of tumor-bearing mice.

Conclusions

These results indicate that MSCs migrate to the tumor site in a time-dependent manner and could be an effective platform for the targeted delivery of CRAd and the amplification of tumor killing effects.

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Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics. CA Cancer J Clin. 2007, 57: 43-66. 10.3322/canjclin.57.1.43CrossRefPubMed

Saad ED, Katz A, Buyse M: Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010, 28: 1958-1962. 10.1200/JCO.2009.25.5414CrossRefPubMed

Hartman M, Loy EY, Ku CS, Chia KS: Molecular epidemiology and its current clinical use in cancer management. Lancet Oncol. 2010, 11: 383-390. 10.1016/S1470-2045(10)70005-XCrossRefPubMed

Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L: Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther. 2006, 5: 755-766. 10.1158/1535-7163.MCT-05-0334CrossRefPubMed

Chiocca EA: Oncolytic viruses. Nat Rev Cancer. 2002, 2: 938-950. 10.1038/nrc948CrossRefPubMed

Vile R, Ando D, Kirn D: The oncolytic virotherapy treatment platform for cancer: unique biological and biosafety points to consider. Cancer Gene Ther. 2002, 9: 1062-1067. 10.1038/sj.cgt.7700548CrossRefPubMed

Ries SJ, Brandts CH: Oncolytic viruses for the treatment of cancer: current strategies and clinical trials. Drug Discov Today. 2004, 9: 759-768. 10.1016/S1359-6446(04)03221-0CrossRefPubMed

Heise C, Hermiston T, Johnson L, Brooks G, Sampson-Johannes A, Williams A, Hawkins L, Kirn D: An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med. 2000, 6: 1134-1139. 10.1038/80474CrossRefPubMed

Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, Gore M, Ironside J, MacDougall RH, Heise C, Randlev B, Gillenwater AM, Bruso P, Kaye SB, Hong WK, Kirn DH: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med. 2000, 6: 879-885. 10.1038/78638CrossRefPubMed

10.

Gao Q, Zhou J, Huang X, Chen G, Ye F, Lu Y, Li K, Zhuang L, Huang M, Xu G, Wang S, Ma D: Selective targeting of checkpoint kinase 1 in tumor cells with a novel potent oncolytic adenovirus. Mol Ther. 2006, 13: 928-937. 10.1016/j.ymthe.2005.12.009CrossRefPubMed

11.

Zhou J, Gao Q, Chen G, Huang X, Lu Y, Li K, Xie D, Zhuang L, Deng J, Ma D: Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability. Clin Cancer Res. 2005, 11: 8431-8440. 10.1158/1078-0432.CCR-05-1085CrossRefPubMed

12.

Han Z, Hong Z, Chen C, Gao Q, Luo D, Fang Y, Cao Y, Zhu T, Jiang X, Ma Q, Li W, Han L, Wang D, Xu G, Wang S, Meng L, Zhou J, Ma D: A novel oncolytic adenovirus selectively silences the expression of tumor-associated Stat3 and exhibits potent antitumoral activity. Carcinogenesis. 2009, 30: 2014-2022. 10.1093/carcin/bgp249CrossRefPubMed

13.

Johnson M, Huyn S, Burton J, Sato M, Wu L: Differential biodistribution of adenoviral vector in vivo as monitored by bioluminescence imaging and quantitative polymerase chain reaction. Hum Gene Ther. 2006, 17: 1262-1269. 10.1089/hum.2006.17.1262CrossRefPubMed

14.

Tao N, Gao GP, Parr M, Johnston J, Baradet T, Wilson JM, Barsoum J, Fawell SE: Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther. 2001, 3: 28-35. 10.1006/mthe.2000.0227CrossRefPubMed

15.

Martin K, Brie A, Saulnier P, Perricaudet M, Yeh P, Vigne E: Simultaneous CAR- and alpha V integrin-binding ablation fails to reduce Ad5 liver tropism. Mol Ther. 2003, 8: 485-494. 10.1016/S1525-0016(03)00182-5CrossRefPubMed

16.

Mathis JM, Stoff-Khalili MA, Curiel DT: Oncolytic adenoviruses-selective retargeting to tumor cells. Oncogene. 2005, 24: 7775-7791. 10.1038/sj.onc.1209044CrossRefPubMed

17.

Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003, 21: 2508-2018. 10.1200/JCO.2003.11.138CrossRefPubMed

18.

Alemany R, Suzuki K, Curiel DT: Blood clearance rates of adenovirus type 5 in mice. J Gen Virol. 2000, 81: 2605-2609.CrossRefPubMed

19.

Kirn D: Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?. Gene Ther. 2001, 8: 89-98. 10.1038/sj.gt.3301377CrossRefPubMed

20.

Hamada K, Desaki J, Nakagawa K, Zhang T, Shirakawa T, Gotoh A, Tagawa M: Carrier cell-mediated delivery of a replication-competent adenovirus for cancer gene therapy. Mol Ther. 2007, 15: 1121-1128.PubMed

21.

Kreppel F, Gackowski J, Schmidt E, Kochanek S: Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of adenovirus vectors. Mol Ther. 2005, 12: 107-117. 10.1016/j.ymthe.2005.03.006CrossRefPubMed

22.

Kühnel F, Schulte B, Wirth T, Woller N, Schäfers S, Zender L, Manns M, Kubicka S: Protein transduction domains fused to virus receptors improve cellular virus uptake and enhance oncolysis by tumor-specific replicating vectors. J Virol. 2004, 78: 13743-13754. 10.1128/JVI.78.24.13743-13754.2004PubMedCentralCrossRefPubMed

23.

Glasgow JN, Everts M, Curiel DT: Transductional targeting of adenovirus vectors for gene therapy. Cancer Gene Ther. 2006, 13: 830-844. 10.1038/sj.cgt.7700928PubMedCentralCrossRefPubMed

24.

Serfozo P, Schlarman MS, Pierret C, Maria BL, Kirk MD: Selective migration of neuralized embryonic stem cells to stem cell factor and media conditioned by glioma cell lines. Cancer Cell Int. 2006, 6: 1- 10.1186/1475-2867-6-1PubMedCentralCrossRefPubMed

25.

Ziu M, Schmidt NO, Cargioli TG, Aboody KS, Black PM, Carroll RS: Glioma-produced extracellular matrix influences brain tumor tropism of human neural stem cells. J Neurooncol. 2006, 79: 125-133. 10.1007/s11060-006-9121-5CrossRefPubMed

26.

Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS: Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells. 2008, 26: 831-841. 10.1634/stemcells.2007-0758CrossRefPubMed

27.

Loebinger MR, Eddaoudi A, Davies D, Janes SM: Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res. 2009, 69: 4134-4142.PubMedCentralCrossRefPubMed

28.

Stoff-Khalili MA, Rivera AA, Mathis JM, Banerjee NS, Moon AS, Hess A, Rocconi RP, Numnum TM, Everts M, Chow LT, Douglas JT, Siegal GP, Zhu ZB, Bender HG, Dall P, Stoff A, Pereboeva L, Curiel DT: Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat. 2007, 105: 157-167. 10.1007/s10549-006-9449-8CrossRefPubMed

29.

Uccelli A, Moretta L, Pistoia V: Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008, 8: 726-736. 10.1038/nri2395CrossRefPubMed

30.

Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R, Shah K: Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA. 2009, 106: 822-827.CrossRef

31.

Karp JM, Leng Teo GS: Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009, 4: 206-216. 10.1016/j.stem.2009.02.001CrossRefPubMed

32.

Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, Bogler O, Andreeff M, Lang FF: Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res. 2009, 69: 8932-8940. 10.1158/0008-5472.CAN-08-3873PubMedCentralCrossRefPubMed

33.

Magin AS, Körfer NR, Partenheimer H, Lange C, Zander A, Noll T: Primary cells as feeder cells for coculture expansion of human hematopoietic stem cells from umbilical cord blood--a comparative study. Stem Cells Dev. 2009, 18: 173-186. 10.1089/scd.2007.0273CrossRefPubMed

34.

Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD: MDA-MB-435 cells are derived from M14 melanoma cells--a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat. 2007, 104: 13-9. 10.1007/s10549-006-9392-8CrossRefPubMed

35.

Huang X, Bai X, Cao Y, Wu J, Huang M, Tang D, Tao S, Zhu T, Liu Y, Yang Y, Zhou X, Zhao Y, Wu M, Wei J, Wang D, Xu G, Wang S, Ma D, Zhou J: Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J Exp Med. 2010, 207: 505-520. 10.1084/jem.20090397PubMedCentralCrossRefPubMed

36.

Huang X, Zhuang L, Cao Y, Gao Q, Han Z, Tang D, Xing H, Wang W, Lu Y, Xu G, Wang S, Zhou J, Ma D: Biodistribution and kinetics of the novel selective oncolytic adenovirus M1 after systemic administration. Mol Cancer Ther. 2008, 7: 1624-1632. 10.1158/1535-7163.MCT-07-2134CrossRefPubMed

37.

Bianco P, Robey PG, Simmons PJ: Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2008, 2: 313-319. 10.1016/j.stem.2008.03.002PubMedCentralCrossRefPubMed

38.

Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005, 65: 3307-3318.PubMed

39.

Knaän-Shanzer S, van de Watering MJ, van der Velde I, Gonçalves MA, Valerio D, de Vries AA: Endowing human adenovirus serotype 5 vectors with fiber domains of species B greatly enhances gene transfer into human mesenchymal stem cells. Stem Cells. 2005, 23: 1598-1607. 10.1634/stemcells.2005-0016CrossRefPubMed

40.

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: 1235-1247. 10.1084/jem.20051921PubMedCentralCrossRefPubMed

41.

Qiao L, Xu ZL, Zhao TJ, Ye LH, Zhang XD: Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008, 269: 67-77. 10.1016/j.canlet.2008.04.032CrossRefPubMed

42.

Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007, 449: 557-563. 10.1038/nature06188CrossRefPubMed

43.

Burdelya L, Kujawski M, Niu G, Zhong B, Wang T, Zhang S, Kortylewski M, Shain K, Kay H, Djeu J, Dalton W, Pardoll D, Wei S, Yu H: Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J Immunol. 2005, 174: 3925-31.PubMedCentralCrossRefPubMed

44.

Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004, 10: 48-54. 10.1038/nm976CrossRefPubMed

45.

Bingle L, Brown NJ, Lewis CE: The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002, 196: 254-65. 10.1002/path.1027CrossRefPubMed

46.

Piras F, Colombari R, Minerba L, Murtas D, Floris C, Maxia C, Corbu A, Perra MT, Sirigu P: The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer. 2005, 104: 1246-54. 10.1002/cncr.21283CrossRefPubMed

47.

Fujiwara T, Fukushi J, Yamamoto S, Matsumoto Y, Setsu N, Oda Y, Yamada H, Okada S, Watari K, Ono M, Kuwano M, Kamura S, Iida K, Okada Y, Koga M, Iwamoto Y: Macrophage infiltration predicts a poor prognosis for human ewing sarcoma. Am J Pathol. 2011, 179: 1157-70. 10.1016/j.ajpath.2011.05.034PubMedCentralCrossRefPubMed

Title: Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors
Authors: Xi Xia
Teng Ji
Pingbo Chen
Xiao Li
Yong Fang
Qinglei Gao
Shujie Liao
Lanying You
Hongbin Xu
Quanfu Ma
Peng Wu
Wencheng Hu
Mingfu Wu
Li Cao
Kezhen Li
Yanjie Weng
Zhiqiang Han
Junchen Wei
Ronghua Liu
Shixuan Wang
Gang Xu
Daowen Wang
Jianfeng Zhou
Ding Ma
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2011
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-10-134

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Abstract

Background

Methods

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Conclusions

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