Abstract:Objective To investigate the impact of inhibiting the function of sclerostin by antibodies in tumor cells on MDA-MB-231 induced bone metastasis.Methods MDA-MB-231 cells were co-cultured with sclerostin antibody(Sci-Ab). Twenty-four female nude mice aged 6 -8 weeks were divided randomly into two groups (n=12).MDA-MB-231 cells (6×105) were injected into the bone marrow space. The mice were treated with normal saline (NS) and sclerostin antibody (Sci-Ab), respectively. Thirty-five days after the treatment, all the nude mice were subjected to pathological examination to determine bone metastasis.The bone remodelling activities were compared between PBS treatment group and antibody treatment group using micro-CT analysis. Student’s t-test was used for the comparison of quantitative data, and Fisher's exact test was used for the comparison of qualitative data.Results According to MTT assay and Wound Healing, higher Sci-Ab promoted the proliferation and invasion of MDA-MB-231 cells. There were six bone metastasis lesions detected in control group(treated with normal saline) , and nine in experimental group(treated with Sci-Ab) , but there was no statistically significant difference between the two groups(P=0.30) .The bone tumor volume of control group and experimental group was (0.87±0.244) cm3 and (0.73±0.118) cm3, respectively (P=0.35) . The survival of experimental group was significantly longer than that of control group(P<0.05). Micro-CT analysis of the tumor-bearing mice indicated that Sci-Ab was effective in bone protection against breast cancer-induced bone destruction as the bone mineral density (BMD; g/cm2)was significantly increased(P<0.05).Conclusions Bone metastasis from breast cancer is closely correlated with the sclerostin expression level in tumor cells.Inhibiting the expression of sclerostin can promote proliferation and invasion of MDA-MB-231 cells in vitro and improve the survival of mice in vivo.
祝孟海,李世飞,张树东,姚 琦. 乳腺癌骨转移骨硬化蛋白抗体的治疗作用[J]. 武警医学, 2017, 28(6): 609-613.
ZHU Menghai, LI Shifei, ZHANG Shudong,and YAO Qi. The role of sclerostin antibody in treatment of bone metastasis from breast cancer. Med. J. Chin. Peop. Armed Poli. Forc., 2017, 28(6): 609-613.
Kozlow W, Guise T A. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy[J]. J Mammary Gland Blol, 2005,10(2):169-180.
[2]
Early Breast Cancer Trialists’ Collaborative Group. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials[J]. Lancet, 2015,386(10001):1353-1361.
Mundy G R. Metastasis to bone: causes, consequences and therapeutic opportunities[J].Nat Rev Cancer, 2002,2(8):584-593.
[5]
Mantyh P. Bone cancer pain: causes, consequences, and therapeutic opportunities[J].Pain,2013,154(Suppl 1):S54-562.
[6]
Oster G, Lamerato L, Glass A G, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems[J]. Support Care Cancer, 2013,21(12):3279-3286.
Qin W, Zhao W, Li X, et al. Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury[J]. Osteoporosis Iin, 2016, 27(12): 3627-3636.
[9]
van Dinther M, Zhang J, Weidauer S E, et al. Anti-Sclerostin antibody inhibits internalization of Sclerostin and Sclerostin-mediated antagonism of Wnt/LRP6 signaling[J]. Plos One, 2013, 8(4): e62295.
[10]
Li Y, Lu W, King T D, et al. Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation[J]. Plos One, 2010,5(6):e11014.
[11]
Khramtsov A I, Khramtsova G F, Tretiakova M, et al. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome[J].Am J Pathol,2010,176(6):2911-2920.
[12]
Johnson R W, Merkel A R, Page J M, et al. Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer[J]. Clin Exp Metastas, 2014,31(8):945-959.
[13]
Wang X T, He Y C, Zhou S Y, et al. Bone marrow plasma macrophage inflammatory protein protein-1 alpha(MIP-1 alpha) and sclerostin in multiple myeloma: relationship with bone disease and clinical characteristics[J]. Leukemia Res, 2014,38(5):525-531.
[14]
Colucci S, Brunetti G, Oranger A, et al. Myeloma cells suppress osteoblasts through sclerostin secretion[J]. Blood Cancer J, 2011,1(6):e27.
[15]
Tang P, Yao Q, Zhang W, et al. A study of femoral neck fracture repair using a recombinant human bone morphogenetic protein-2 directional release system[J]. Tissue Eng Part A, 2009,15(12):3971-3978.
Brunetti G, Oranger A, Mori G, et al. Sclerostin is overexpressed by plasma cells from multiple myeloma patients[J]. Ann Ny Acad Sci, 2011,1237(1):19-23.
[19]
Li X, Xu Y, Chen Y, et al. SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/beta-catenin signal network[J]. Cancer Lett, 2013, 336(2): 379-389.
[20]
Yamada N, Noguchi S, Mori T, et al. Tumor-suppressive microRNA-145 targets catenin delta-1 to regulate Wnt/beta-catenin signaling in human colon cancer cells[J]. Cancer Lett, 2013,335(2):332-342.
[21]
Schouten C, Meijer G J, van den Beucken J J, et al. The quantitative assessment of peri-implant bone responses using histomorphometry and micro-computed tomography[J]. Biomaterials, 2009,30(27):4539-4549.
[22]
Ji W, Yang F, Ma J, et al. Incorporation of stromal cell-derived factor-1alpha in PCL/gelatin electrospun membranes for guided bone regeneration[J]. Blomaterials, 2013,34(3):735-745.
[22]
Hambli R. Micro-CT finite element model and experimental validation of trabecular bone damage and fracture[J]. Bone, 2013,56(2):363-374.
[24]
Eda H, Santo L, Wein MN, et al. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease[J]. J Bone Miner Ras, 2016,31(6):1225-1234.