Ahmet Sinan SARI, Emre DEMİRÇAY, Ahmet ÖZTÜRK, Ayşen TERZİ, Erdal KARAÖZ

The promising effects of BMP2 transfected mesenchymal stem cells on human osteosarcoma

Selective targeting of transfected mesenchymal stem cells (MSCs) carrying specific antioncogenes to the tumor was suggested as a treatment option. Bone morphogenetic protein-2 (BMP2) was shown to inhibit the proliferation and aggressiveness of osteosarcoma (OS) cells. Here, we aimed to assess the homing efficiency of intraperitoneally administered hMSCs transfected with BMP2 to the tumoral site and their effects on OS using an orthotopic xenograft murine model. Orthotopic xenograft murine model of OS in six-week-old female NOD/SCID mice using 143B cells was established. hMSCs transfected with BMP2 (BMP2+hMSC) were used. In vivo experiments performed on four groups of mice that received no treatment, or intraperitoneally administered BMP2, hMSCs, and BMP2+hMSCs. Histopathological and immunohistochemical studies were used to evaluate the pathological identification and to assess the dimensions and necrotic foci of the tumor, the features of lung metastases, and immunostaining against p27, Ki-67, and caspase-3 antibodies. The osteogenic differentiation markers BMP2, BMP4, COL1A1, OPN, OCN and PF4 evaluated using RT-PCR. The tumor dimensions in the hMSCs group were significantly higher than those of the remaining groups (p

Keywords:

Intraperitoneal BMP2, tumor, lung metastasis, osteogenic differentiation, targeting,

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Adas G, Koc B, Adas M, Duruksu G, Subasi C et al. (2016). Effects of mesenchymal stem cells and VEGF on liver regeneration following major resection. Langenbeck’s Archives of Surgery 401 (5): 725-740. doi: 10.1007/s00423-016-1380-9
Aydin M, Basarir K, Armangil M, Yildiz HY, Saglik Y et al. (2015). Thermal necrosis induced by electrocauterization as a local adjuvant therapy in local aggressive bone tumors, what is the safe limit for surgical margins? an experimental study. Archives of Orthopaedic and Trauma Surgery 135: 1071-1076. doi: 10.1007/s00402-015-2262-2
Becker A, Riet I (2016). Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy? World Journal of Stem Cells 8 (3): 73-87. doi: 10.4252/wjsc.v8.i3.73
Chen X, Cates JMM, Du YC, Jain A, Jung SY et al. (2020). Mislocalized cytoplasmic p27 activates PAK-1 mediated metastasis and is a prognostic factor in osteosarcoma. Molecular Oncology 14: 846-864. doi: 10.1002/1878-0261.12624
Chindamo G, Sapino S, Peira E, Chirio D, Gonzalez MC et al. (2020). Bone diseases: current approach and future perspectives in drug delivery systems for bone targeted therapeutics. Nanomaterials 10: 875. doi: 10.3390/nano10050875
Edgar CM, Chakravarthy V, Barnes G, Kakar S, Gerstenfeld LC et al. (2007). Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells. Bone 40 (5): 1389-1398. doi: 10.1016/j.bone.2007.01.001
Fan TM, Roberts RD, Lizardo MM (2020). Understanding and modeling metastasis biology to improve therapeutic strategies for combating osteosarcoma progression. Frontiers in Oncology 10: 13. doi: 10.3389/fonc.2020.0013
Gallagher R, Keighley J, Tancabelic J, Garimella R, Pinson D et al. (2012). Clinicopathologic correlation of vitamin D receptor expression with retinoid X receptor and MIB-1 expression in primary and metastatic osteosarcoma. Annals of Diagnostic Pathology 16 (5): 323-329. doi: 10.1016/j.anndiagpath.2012.01.001
Garimella R, Tadikonda P, Tawfik O, Gunewardena S, Rowe P et al. (2017). Vitamin D impacts the expression of Runx2 target genes and modulates inflammation, oxidative stress and membrane vesicle biogenesis gene networks in 143B osteosarcoma cells. International Journal of Molecular Science 18: 642. doi: 10.3390/ijms18030642
Gauthaman K, Yee FC, Cheyyatraivendran S, Biswas A, Choolani M et al. (2012). Human umblical cord Wharton’s Jelly stem cell (hWJSC) extracts inhibit cancer cell growth in vitro. Journal of Cellular Biochemistry 113: 2027-2030. doi: 10.1002/jcb.24073
Huang W, Yang S, Shao J, Li YP (2007). Signaling and transcriptional regulation in osteoblast commitment and differentiation. Frontiers in Bioscience 12: 3068-3092. doi: 10.2741/2296
Huang Z, Nelson ER, Smith RL, Goodman SB (2007). The sequential expression profiles of growth factors from osteoprogenitors to osteoblasts in vitro. Tissue Engineering 13 (9): 2311-2320. doi: 10.1089/ten.2006.0423
Ishikawa H, Kitoh H, Sugiura F, Ishiguro N (2007). The effect of recombinant human bone morphogenetic protein-2 on the osteogenic potential of rat mesenchymal stem cells after several passages. Acta Orthopaedica 78 (2): 285-292. doi: 10.1080/17453670710013816
Jian J, Pang Y, Yan HH, Min Y, Achyut BR et al. (2017). Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis. Oncotarget 8 (17): 27725-27739. doi: 10.18632/oncotarget.9486
Karaöz E, Demircan PC, Sağlam O, Aksoy A, Kaymaz F et al. (2011). Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells. Histochemistry and Cell Biology 136: 455-473. doi: 10.1007/s00418-011-0858-3
Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF et al. (2006). Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. The Journal of Experimental Medicine 203 (5): 1235-1247. doi: 10.1084/jem.20051921
Lagerweij T, Perez-Lanzon M, Baglio SR (2018). A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells. Journal of Visualized Experiments. doi:10.3791/56932
Lee JE, Yin Y, Lim SY, Kim ES, Jung J et al. (2019). Enhanced transfection of human mesenchymal stem cells using a hyaluronic acid/calcium phosphate hybrid gene delivery system. Polymers 11: 798. doi: 10.3390/polym11050798
Luo X, Chen J, Song WX, Tang N, Luo J et al. (2008). Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Laboratory Investigation 88: 1264-1277. doi: 10.1038/labinvest.2008.98
Luu HH, Kang Q, Park JK, Si W, Luo Q et al. (2005). An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. Clinical & Experimental Metastasis 22: 319-329. doi: 10.1007/s10585-005-0365-9
Miron RJ, Zhang Y (2012). Osteoinduction: a review of old concepts with new standards. Journal of Dental Research 91 (8): 736-744. doi: 10.1177/0022034511435260
Mishima S, Nagai A, Abdullah S, Matsuda C, Taketani T et al. (2010). Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. European Journal of Haematology 84: 538-546. doi: 10.1111/j.1600-0609.2010.01419.x
NguyenThai QA, Sharma N, Luong do H, Sodhi SS, Kim JH et al. (2015). Targeted inhibition of osteosarcoma tumor growth by bone marrow-derived mesenchymal stem cells expressing cytosine deaminase/5-fluorocytosine in tumor-bearing mice. The Journal of Gene Medicine 17: 87-89. doi: 10.1002/jgm.2826
Qiao B, Shui W, Cai L, Guo S, Jiang D (2015). Human mesenchymal stem cells as delivery of osteoprotegerin gene: homing and therapeutic effect for osteosarcoma. Drug Design, Development and Therapy 9: 969-976. doi: 10.2147/DDDT.S77116
Reg R, Sea W, Po F (2013). Modulation of angiogenesis and immune response in canine osteosarcoma by BMP-2 and mesenchymal stem cells. Journal of Stem Cell Research & Therapy 3: 3. doi: 10.4172/2157-7633.1000143
Rutkovskiy A, Stenslokken KO, Vaage IJ (2016). Osteoblast differentiation at a glance. Medical Science Monitor Basic Research 22: 95-106. doi: 10.12659/msmbr.901142
Si J, Wang C, Zhang D, Wang B, Zhou Y (2020). Osteopontin in bone metabolism and bone diseases. Medical Science Monitor 26: e919159. doi: 10.12659/MSM.919159
Thawani JP, Wang AC, Than KD, Lin CY, La Marca F et al. (2010). Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery 66 (2): 233-246. doi: 10.1227/01.NEU.0000363722.42097.C2
Tian H, Zhou T, Chen H, Li C, Jiang Z et al. (2019). Bone morphogenetic protein-2 promotes osteosarcoma growth by promoting epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin signaling pathway. Journal of Orthopaedic Research 37 (7): 1638-1648. doi: 10.1002/jor.24244
Tome Y, Tsuchiya H, Hayashi K, Yamauchi K, Sugimoto N et al. (2009). In vivo gene transfer between interacting human osteosarcoma cell lines is associated with acquisition of enhanced metastatic potential. Journal of Cellular Biochemistry 108: 362-367. doi: 10.1002/jcb.22259
Villanueva F, Araya H, Briceño P, Varela N, Stevenson A et al. (2019). The cancer-related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis. Journal of Cellular Physiology 234 (8): 13659-13679. doi: 10.1002/jcp.28046
Wright V, Peng H, Usas A, Young B, Gearhart B et al. (2002). BMP-4 expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. Molecular Therapy 6 (2): 169-178. doi: 10.1006/mthe.2002.0654
Xiong Q, Wang X, Wang L, Huang Y, Tian X et al. (2018). BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model. OncoTargets and Therapy 11: 7543-7553. doi: 10.2147/OTT.S176724
Zhang Y, Chen X, Qiao M, Zhang BQ, Wang N et al. (2014). Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncology Reports 32: 1013-1020. doi: 10.3892/or.2014.3308
Zheng Y, Wang G, Chen R, Hua Y, Cai Z (2018). Mesenchymal stem cells in the osteosarcoma microenvironment: their biological properties, influence on tumor growth, and therapeutic implications. Stem Cell Research & Therapy 9 (1): 22. doi: 10.1186/s13287-018-0780-x