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Subcutaneous injection of multipotent mesenchymal stromal cells admixed with melanoma cells in mice favors tumor incidence and growth: a systematic review and meta-analysis

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Abstract

Multipotent mesenchymal stem/stromal cells (MSCs) have strong tropism towards cancer cells, thus being tested as tools for the targeted delivery of therapeutic substances for the treatment of melanoma. However, different experimental approaches for melanoma induction and MSC treatment can have a direct impact on the outcomes. Systematic search was carried out in three databases (PubMed, Scopus, and Web of Science) to include all studies, where stem cells were used as intervention for animal models for melanoma. Selected articles were classified according to SYRCLE’s risk of bias tool for animals’ studies. Experimental variables and published data for tumor incidence and growth were extracted from the eligible articles and standardized using Hedge’s G for random effects meta-analysis and meta-regression. From 627 entries, 11 articles were eligible for meta-analysis. All studies tested the effects of a single injection of mesenchymal stem/stromal cells (MSCs) (from bone marrow or adipose tissue) admixed with B16 mouse melanoma cells (B16–F0 or B16–F10) or with human melanoma cells (A375 or M4Beu) in mice. Mean SYRCLE score was 3.09 out of 10. Results from random effects meta-analysis indicate that MSCs favored both tumor incidence and tumor growth (p = 0.001) in melanoma. Our results show that MSCs are protumorigenic in co-injection mice models for melanoma, increasing both tumor incidence and growth.

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References

  1. Akay I, Oxmann D, Helfenstein A, Mentlein R, Schünke M, Hassenpflug J, Kurz B (2010) Tumor risk by tissue engineering: cartilaginous differentiation of mesenchymal stem cells reduces tumor growth. Osteoarthritis Cartilage 18:389–396. https://doi.org/10.1016/j.joca.2009.10.015

    Article  CAS  PubMed  Google Scholar 

  2. Atkinson V (2015) Medical management of malignant melanoma. Aust Prescr 38:74–78. https://doi.org/10.18773/austprescr.2015.028

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bahrambeigi V, Ahmadi N, Salehi R, Javanmard SH (2015) Genetically modified murine adipose-derived mesenchymal stem cells producing interleukin-2 favor B16F10 melanoma cell proliferation. Immunol Invest 44:216–236. https://doi.org/10.3109/08820139.2014.988719

    Article  CAS  PubMed  Google Scholar 

  4. Boukerche H, Benchaibi M, Berthier-Vergnes O, Lizard G, Bailly M, Bailly M, McGregor JL (1994) Two human melanoma cell-line variants with enhanced in vivo tumor growth and metastatic capacity do not express the beta 3 integrin subunit. Eur J Biochem 220:485–491

    Article  CAS  PubMed  Google Scholar 

  5. Briquet A, Dubois S, Bekaert S, Dolhet M, Beguin Y, Gothot A (2010) Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages. Haematologica 95:47–56. https://doi.org/10.3324/haematol.2009.008524

    Article  PubMed  Google Scholar 

  6. Chapman SWK, Metzger N, Grest P, Feige K, von Rechenberg B, Auer JA, Hottiger MO (2009) Isolation, establishment, and characterization of ex vivo equine melanoma cell cultures. In Vitro Cell Dev Biol Anim 45:152–162. https://doi.org/10.1007/s11626-008-9156-3

    Article  CAS  PubMed  Google Scholar 

  7. Chen X, Lin X, Zhao J, Shi W, Zhang H, Wang Y, Kan B, Du L, Wang B, Wei Y, Liu Y, Zhao X (2008) A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs. Mol Ther 16:749–756. https://doi.org/10.1038/mt.2008.3

    Article  CAS  PubMed  Google Scholar 

  8. Clark EA, Golub TR, Lander ES, Hynes RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406:532–535. https://doi.org/10.1038/35020106

    Article  CAS  PubMed  Google Scholar 

  9. Cornfield J (1951) A method of estimating comparative rates from clinical data; applications to cancer of the lung, breast, and cervix. J Natl Cancer Inst 11:1269–1275

    CAS  PubMed  Google Scholar 

  10. Das M, Sundell IB, Koka PS (2013) Adult mesenchymal stem cells and their potency in the cell-based therapy. J Stem Cells 8:1–16

    PubMed  Google Scholar 

  11. Di Battista JA, Shebaby W, Kizilay O, Hamade E, Abou Merhi R, Mebarek S, Abdallah D, Badran B, Saad F, K Abdalla E, Faour WH (2014) Proliferation and differentiation of human adipose-derived mesenchymal stem cells (ASCs) into osteoblastic lineage are passage dependent. Inflamm Res Off J Eur Histamine Res Soc Al 63:907–917. https://doi.org/10.1007/s00011-014-0764-y

    Google Scholar 

  12. Edge SB, American Joint Committee on Cancer (2010) AJCC cancer staging manual, 7th edn. Springer, New York

    Google Scholar 

  13. Eliopoulos N, Francois M, Boivin M-N, Martineau D, Galipeau J (2008) Neo-organoid of marrow mesenchymal stromal cells secreting interleukin-12 for breast cancer therapy. Cancer Res 68:4810–4818. https://doi.org/10.1158/0008-5472.CAN-08-0160

    Article  CAS  PubMed  Google Scholar 

  14. Fidler IJ (1973) Selection of successive tumour lines for metastasis. Nature New Biol 242:148–149

    Article  CAS  PubMed  Google Scholar 

  15. Flower A, McKenna JW, Upreti G (2015) Validity and reliability of GraphClick and DataThief III for data extraction. Behav Modif. https://doi.org/10.1177/0145445515616105

    Google Scholar 

  16. Gallagher RP, Lee TK, Bajdik CD, Borugian M (2010) Ultraviolet radiation. Chronic Dis Can 29(Suppl 1):51–68

    PubMed  Google Scholar 

  17. Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP (1973) In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst 51:1417–1423

    Article  CAS  PubMed  Google Scholar 

  18. Green A, Shilkaitis A, Bratescu L, Amoss MS, Beattie CW (1992) Establishment and characterization of four Sinclair swine cutaneous malignant melanoma cell lines. Cancer Genet Cytogenet 61:77–92

    Article  CAS  PubMed  Google Scholar 

  19. Han Z, Tian Z, Lv G, Zhang L, Jiang G, Sun K, Wang C, Bu X, Li R, Shi Y, Wu M, Wei L (2011) Immunosuppressive effect of bone marrow-derived mesenchymal stem cells in inflammatory microenvironment favours the growth of B16 melanoma cells. J Cell Mol Med 15:2343–2352. https://doi.org/10.1111/j.1582-4934.2010.01215.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Harbord RM, Higgins JPT (2008) Meta-regression in Stata. Stata J 8:493–519

    Google Scholar 

  21. Hedges LV, Olkin I (1985) Statistical methods for meta-analysis. Academic Press, Orlando

    Google Scholar 

  22. Herlyn M, Fukunaga-Kalabis M (2010) What is a good model for melanoma? J Invest Dermatol 130:911–912. https://doi.org/10.1038/jid.2009.441

    Article  CAS  PubMed  Google Scholar 

  23. Holman C, Piper SK, Grittner U, Diamantaras AA, Kimmelman J, Siegerink B, Dirnagl U (2016) Where have all the rodents gone? The effects of attrition in experimental research on cancer and stroke. PLoS Biol 14:e1002331. https://doi.org/10.1371/journal.pbio.1002331

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hong I-S, Lee H-Y, Kang K-S (2014) Mesenchymal stem cells and cancer: friends or enemies? Mutat Res 768:98–106. https://doi.org/10.1016/j.mrfmmm.2014.01.006

    Article  CAS  PubMed  Google Scholar 

  25. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:43. https://doi.org/10.1186/1471-2288-14-43

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M (2010) Enhancing search efficiency by means of a search filter for finding all studies on animal experimentation in PubMed. Lab Anim 44:170–175. https://doi.org/10.1258/la.2010.009117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang Y, Yu P, Li W, Ren G, Roberts AI, Cao W, Zhang X, Su J, Chen X, Chen Q, Shou P, Xu C, Du L, Lin L, Xie N, Zhang L, Wang Y, Shi Y (2014) p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation. Oncogene 33:3830–3838. https://doi.org/10.1038/onc.2013.355

    Article  CAS  PubMed  Google Scholar 

  28. Hutchinson L, Kirk R (2011) High drug attrition rates—where are we going wrong? Nat Rev Clin Oncol 8:189–190. https://doi.org/10.1038/nrclinonc.2011.34

    Article  PubMed  Google Scholar 

  29. Inoue K, Ohashi E, Kadosawa T, Hong S-H, Matsunaga S, Mochizuki M, Nishimura R, Sasaki N (2004) Establishment and characterization of four canine melanoma cell lines. J Vet Med Sci Jpn Soc Vet Sci 66:1437–1440

    Article  Google Scholar 

  30. Jazedje T, Ribeiro AL, Pellati M, de Siqueira Bueno HM, Nagata G, Trierveiler M, Rodrigues EG, Zatz M (2015) Human mesenchymal stromal cells transplantation may enhance or inhibit 4T1 murine breast adenocarcinoma through different approaches. Stem Cells Int 2015:796215. https://doi.org/10.1155/2015/796215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived-but they can be improved. Cancer Biol Ther 2:S134-139

    Google Scholar 

  32. Kidd S, Spaeth E, Klopp A, Andreeff M, Hall B, Marini F (2008) The (in) auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy 10:657–667. https://doi.org/10.1080/14653240802486517

    Article  CAS  PubMed  Google Scholar 

  33. Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F (2011) Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29:11–19. https://doi.org/10.1002/stem.559

    Article  CAS  PubMed  Google Scholar 

  34. Kucerova L, Matuskova M, Hlubinova K, Altanerova V, Altaner C (2010) Tumor cell behaviour modulation by mesenchymal stromal cells. Mol Cancer 9:129. https://doi.org/10.1186/1476-4598-9-129

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kucerova L, Zmajkovic J, Toro L, Skolekova S, Demkova L, Matuskova M (2015) Tumor-driven molecular changes in human mesenchymal stromal cells. Cancer Microenviron Off J Int Cancer Microenviron Soc 8:1–14. https://doi.org/10.1007/s12307-014-0151-9

    Article  CAS  Google Scholar 

  36. Kuzu OF, Nguyen FD, Noory MA, Sharma A (2015) Current state of animal (mouse) modeling in melanoma research. Cancer Growth Metastasis 8:81–94. https://doi.org/10.4137/CGM.S21214

    PubMed  PubMed Central  Google Scholar 

  37. Leenaars M, Hooijmans CR, van Veggel N, ter Riet G, Leeflang M, Hooft L, van der Wilt GJ, Tillema A, Ritskes-Hoitinga M (2012) A step-by-step guide to systematically identify all relevant animal studies. Lab Anim 46:24–31. https://doi.org/10.1258/la.2011.011087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li L, Tian H, Yue W, Zhu F, Li S, Li W (2011) Human mesenchymal stem cells play a dual role on tumor cell growth in vitro and in vivo. J Cell Physiol 226:1860–1867. https://doi.org/10.1002/jcp.22511

    Article  CAS  PubMed  Google Scholar 

  39. Linares MA, Zakaria A, Nizran P (2015) Skin cancer. Prim Care Clin Off Pract 42:645–659. https://doi.org/10.1016/j.pop.2015.07.006

    Article  Google Scholar 

  40. Liu Y, Zhang Z, Zhang C, Deng W, Lv Q, Chen X, Huang T, Pan L (2016) Adipose-derived stem cells undergo spontaneous osteogenic differentiation in vitro when passaged serially or seeded at low density. Biotech Histochem Off Publ Biol Stain Comm 91:369–376. https://doi.org/10.1080/10520295.2016.1175026

    Article  CAS  Google Scholar 

  41. Maestroni GJ, Hertens E, Galli P (1999) Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cell Mol Life Sci CMLS 55:663–667

    Article  CAS  PubMed  Google Scholar 

  42. Meirelles L, Chagastelles S, Nardi PC NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213. https://doi.org/10.1242/jcs.02932

    Article  CAS  Google Scholar 

  43. Melnikova VO, Bolshakov SV, Walker C, Ananthaswamy HN (2004) Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines. Oncogene 23:2347. https://doi.org/10.1038/sj.onc.1207405

    Article  CAS  PubMed  Google Scholar 

  44. Merlino G, Flaherty K, Acquavella N, Day C-P, Aplin A, Holmen S, Topalian S, Van Dyke T, Herlyn M (2013) Meeting report: The future of preclinical mouse models in melanoma treatment is now. Pigment Cell Melanoma Res 26:E8–E14. https://doi.org/10.1111/pcmr.12099

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pendleton C, Li Q, Chesler DA, Yuan K, Guerrero-Cazares H, Quinones-Hinojosa A (2013) Mesenchymal stem cells derived from adipose tissue vs bone marrow: in vitro comparison of their tropism towards gliomas. PloS One 8:e58198. https://doi.org/10.1371/journal.pone.0058198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pessina A, Bonomi A, Coccè V, Invernici G, Navone S, Cavicchini L, Sisto F, Ferrari M, Viganò L, Locatelli A, Ciusani E, Cappelletti G, Cartelli D, Arnaldo C, Parati E, Marfia G, Pallini R, Falchetti ML, Alessandri G (2011) Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy. PLoS One 6:e28321. https://doi.org/10.1371/journal.pone.0028321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ren G, Zhao X, Wang Y, Zhang X, Chen X, Xu C, Yuan Z, Roberts AI, Zhang L, Zheng B, Wen T, Han Y, Rabson AB, Tischfield JA, Shao C, Shi Y (2012) CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα. Cell Stem Cell 11:812–824. https://doi.org/10.1016/j.stem.2012.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schadendorf D, Hauschild A (2014) Melanoma in 2013: melanoma—the run of success continues. Nat Rev Clin Oncol 11:75–76. https://doi.org/10.1038/nrclinonc.2013.246

    Article  CAS  PubMed  Google Scholar 

  49. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019

    Article  CAS  PubMed  Google Scholar 

  50. Seltenhammer MH, Sundström E, Meisslitzer-Ruppitsch C, Cejka P, Kosiuk J, Neumüller J, Almeder M, Majdic O, Steinberger P, Losert UM, Stöckl J, Andersson L, Sölkner J, Vetterlein M, Golovko A (2014) Establishment and characterization of a primary and a metastatic melanoma cell line from Grey horses. In Vitro Cell Dev Biol Anim 50:56–65. https://doi.org/10.1007/s11626-013-9678-1

    Article  CAS  PubMed  Google Scholar 

  51. Seo SH, Kim KS, Park SH, Suh YS, Kim SJ, Jeun S-S, Sung YC (2011) The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity. Gene Ther 18:488–495. https://doi.org/10.1038/gt.2010.170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shadish WR, Brasil ICC, Illingworth DA, White KD, Galindo R, Nagler ED, Rindskopf DM (2009) Using UnGraph to extract data from image files: verification of reliability and validity. Behav Res Methods 41:177–183. https://doi.org/10.3758/BRM.41.1.177

    Article  PubMed  Google Scholar 

  53. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F (2008) Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15:730–738. https://doi.org/10.1038/gt.2008.39

    Article  CAS  PubMed  Google Scholar 

  54. Stagg J, Lejeune L, Paquin A, Galipeau J (2004) Marrow stromal cells for interleukin-2 delivery in cancer immunotherapy. Hum Gene Ther 15:597–608

    Article  CAS  PubMed  Google Scholar 

  55. StataCorp (2013) Stata statistical software: Release 13. StataCorp LP, College Station, TX

    Google Scholar 

  56. Sterne JAC, Harbord RM (2004) Funnel plots in meta-analysis. Stata J 4:127–141

    Google Scholar 

  57. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-β delivery into tumors. Cancer Res 62:3603–3608

    CAS  PubMed  Google Scholar 

  58. Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA (2009) Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy. Mol Cancer Ther 8:1292–1304. https://doi.org/10.1158/1535-7163.MCT-08-1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Suzuki K, Sun R, Origuchi M, Kanehira M, Takahata T, Itoh J, Umezawa A, Kijima H, Fukuda S, Saijo Y (2011) Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med 17:579–587. https://doi.org/10.2119/molmed.2010.00157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Szebeni GJ, Kriston-Pál É, Blazsó P, Katona RL, Novák J, Szabó E, Czibula Á, Fajka-Boja R, Hegyi B, Uher F, Krenács L, Joó G, Monostori É (2012) Identification of galectin-1 as a critical factor in function of mouse mesenchymal stromal cell-mediated tumor promotion. PLoS One. https://doi.org/10.1371/journal.pone.0041372

    PubMed  PubMed Central  Google Scholar 

  61. Thomasset N, Quash G, Doré JF (1982) Diamine oxidase activity in human melanoma cell lines with different tumorigenicity in nude mice. Br J Cancer 46:58–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tyciakova S, Matuskova M, Bohovic R, Polakova K, Toro L, Skolekova S, Kucerova L (2015) Genetically engineered mesenchymal stromal cells producing TNFα have tumour suppressing effect on human melanoma xenograft: AT-MSC/hTNFα in treatment of A375 xenografts. J Gene Med 17:54–67. https://doi.org/10.1002/jgm.2823

    Article  CAS  PubMed  Google Scholar 

  63. Van der Weyden L, Patton EE, Wood GA, Foote AK, Brenn T, Arends MJ, Adams DJ (2015) Cross-species models of human melanoma. J Pathol 238:152–165. https://doi.org/10.1002/path.4632

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wang J, Ma D, Li Y, Yang Y, Hu X, Zhang W, Fang Q (2014) Targeted delivery of CYP2E1 recombinant adenovirus to malignant melanoma by bone marrow-derived mesenchymal stem cells as vehicles. Anticancer Drugs 25:303–314. https://doi.org/10.1097/CAD.0000000000000046

    Article  CAS  PubMed  Google Scholar 

  65. Xu C, Lin L, Cao G, Chen Q, Shou P, Huang Y, Han Y, Wang Y, Shi Y (2014) Interferon-α-secreting mesenchymal stem cells exert potent antitumor effect in vivo. Oncogene 33:5047–5052. https://doi.org/10.1038/onc.2013.458

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Marcos F Cordeiro would like to thank Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), and Luana P Marmitt would like to thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), for financial support. The authors would like to thank Dr. Fernando Cesar Wehrmeister for statistical support.

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Cordeiro, M.F., Marmitt, L.P. & Horn, A.P. Subcutaneous injection of multipotent mesenchymal stromal cells admixed with melanoma cells in mice favors tumor incidence and growth: a systematic review and meta-analysis. Arch Dermatol Res 310, 231–240 (2018). https://doi.org/10.1007/s00403-018-1819-7

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