Delayed onset of paralysis and slowed tumor growth following in situ placement of recombinant human bone morphogenetic protein 2 within spine tumors in a rat model of metastatic breast cancer

Presented at the 2011 Spine Section Meeting 

Restricted access


Recombinant human bone morphogenetic proteins (rhBMPs) are FDA-approved for specific spinal fusion procedures, but their use is contraindicated in spine tumor resection beds because of an unclear interaction between tumor tissue and such growth factors. Interestingly, a number of studies have suggested that BMPs may slow the growth of adenocarcinomas in vitro, and these lesions represent the majority of bony spine tumors. In this study, the authors hypothesized that rhBMP-2 placed in an intraosseous spine tumor in the rat could suppress tumor and delay the onset of paresis in such animals.


Twenty-six female nude athymic rats were randomized into an experimental group (Group 1) or a positive control group (Group 2). Group 1 (tumor + 15 μg rhBMP-2 sponge, 13 rats) underwent transperitoneal exposure and implantation of breast adenocarcinoma (CRL-1666) into the L-6 spine segment, followed by the implantation of a bovine collagen sponge impregnated with 15 μg of rhBMP-2. Group 2 (tumor + 0.9% NaCl sponge, 13 rats) underwent transperitoneal exposure and tumor implantation in the lumbar spine but no local treatment with rhBMP-2. An additional 8 animals were randomized into 2 negative control groups (Groups 3 and 4). Group 3 (15 μg rhBMP-2 sponge, 4 rats) and Group 4 (0.9% NaCl sponge, 4 rats) underwent transperitoneal exposure of the lumbar spine along with the implantation of rhBMP-2– and saline-impregnated bovine collagen sponges, respectively. Neither of the negative control groups was implanted with tumor. The Basso-Beattie-Bresnahan (BBB) scale was used to monitor daily motor function regression and the time to paresis (BBB score ≤ 7).


In comparison with the positive control animals (Group 2), the experimental animals (Group 1) had statistically significant longer mean (25.8 ± 12.2 vs 13 ± 1.4 days, p ≤ 0.001) and median (20 vs 13 days) times to paresis. In addition, the median survival time was significantly longer in the experimental animals (20 vs 13.5 days, p ≤ 0.0001). Histopathological analysis demonstrated bone growth and tumor inhibition in the experimental animals, whereas bone destruction and cord compression were observed in the positive control animals. Neither of the negative control groups (Groups 3 and 4) demonstrated any evidence of neurological deterioration, morbidity, or cord compromise on either gross or histological analysis.


This study shows that the local administration of rhBMP-2 (15 μg, 10 μl of 1.5-mg/ml solution) in a rat spine tumor model of breast cancer not only fails to stimulate local tumor growth, but also decreases local tumor growth and delays the onset of paresis in rats. This preclinical experiment is the first to show that the local placement of rhBMP-2 in a spine tumor bed may slow tumor progression and delay associated neurological decline.

Abbreviations used in this paper:BBB = Basso-Beattie-Bresnahan; BMP = bone morphogenetic protein; rhBMP = recombinant BMP; VB = vertebral body.

Article Information

Address correspondence to: Daniel M. Sciubba, M.D., Meyer 7-109, 600 North Wolfe Street, Baltimore, Maryland 21287. email:

Please include this information when citing this paper: published online January 20, 2012; DOI: 10.3171/2011.12.SPINE11496.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Graph depicting the mean BBB score over time (days) comparing rates of neurological decline.

  • View in gallery

    Graph depicting the median BBB score over time (days) comparing rates of neurological decline.

  • View in gallery

    Kaplan-Meier survival curve comparing survival rates between Group 1 (tumor + local rhBMP-2) and Group 2 (positive control cohort).

  • View in gallery

    Photomicrographs pieced together showing the effect of rh-BMP on tumor-bearing rat vertebra. A: Normal anatomy of a rat lumbar vertebra without tumor. B: Tumor-bearing vertebra. Bone destruction can be observed due to the osteolytic activity of cancer cells. C: Tumor-bearing vertebra treated with 15 μg of rhBMP-2 infused in a bovine collagen sponge. The VB shows de novo formation of laminar bone (asterisk) and no evident presence of malignant cells. D: Implant of an rhBMP-2 sponge in a non–tumor-bearing vertebra. SP = spinous process; TP = transverse process; SC = spinal cord; and T = rat mammary adenocarcinoma tumor. H & E, original magnification × 5.



Alarmo ELKuukasjärvi TKarhu RKallioniemi A: A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of BMP4 and BMP7. Breast Cancer Res Treat 103:2392462007


Alarmo ELPärssinen JKetolainen JMSavinainen KKarhu RKallioniemi A: BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett 275:35432009


Anderson E: The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 4:1972012002


Bach FLarsen BHRohde KBørgesen SEGjerris FBøge-Rasmussen T: Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression. Acta Neurochir (Wien) 107:37431990


Bagley CABookland MJPindrik JAOzmen TGokaslan ZLWitham TF: Local delivery of oncogel delays paresis in rat metastatic spinal tumor model. J Neurosurg Spine 7:1941982007


Bagley CABookland MJPindrik JAOzmen TGokaslan ZLWolinsky JP: Fractionated, single-port radiotherapy delays paresis in a metastatic spinal tumor model in rats. J Neurosurg Spine 7:3233272007


Bartels RHFeuth Tvan der Maazen RVerbeek ALKappelle ACAndré Grotenhuis J: Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis. Cancer 110:204220492007


Bartels RHvan der Linden YMvan der Graaf WT: Spinal extradural metastasis: review of current treatment options. CA Cancer J Clin 58:2452592008


Basso DMBeattie MSBresnahan JC: A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1211995


Bellizzi KMMustian KMPalesh OGDiefenbach M: Cancer survivorship and aging: moving the science forward. Cancer 113:12 Suppl353035392008


Bilsky MHLis ERaizer JLee HBoland P: The diagnosis and treatment of metastatic spinal tumor. Oncologist 4:4594691999


Buijs JTHenriquez NVvan Overveld PGvan der Horst GQue ISchwaninger R: Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res 67:874287512007


Burkus JKSandhu HSGornet MFLongley MC: Use of rh-BMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. J Bone Joint Surg Am 87:120512122005


Burkus JKTransfeldt EEKitchel SHWatkins RGBalderston RA: Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976) 27:239624082002


Cahill KSChi JHGroff MWMcGuire KAfendulis CCClaus EB: Outcomes for single-level lumbar fusion: The role of bone morphogenetic protein. Spine (Phila Pa 1976) 36:235423622011


Chang HBrown CWMatzuk MM: Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 23:7878232002


Cho SKStoker GEBridwell KH: Spinal reconstruction with pedicle screw-based instrumentation and rhBMP-2 in patients with neurofibromatosis and severe dural ectasia and spinal deformity: report of two cases and a review of the literature. J Bone Joint Surg Am 93:e862011


Clement JHMarr NMeissner ASchwalbe MSebald WKliche KO: Bone morphogenetic protein 2 (BMP-2) induces sequential changes of Id gene expression in the breast cancer cell line MCF-7. J Cancer Res Clin Oncol 126:2712792000


Clement JHRaida MSänger JBicknell RLiu JNaumann A: Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol 27:4014072005


Cole JSPatchell RA: Metastatic epidural spinal cord compression. Lancet Neurol 7:4594662008


Flynn DFShipley WU: Management of spinal cord compression secondary to metastatic prostatic carcinoma. Urol Clin North Am 18:1451521991


Fujibayashi SNeo MMiyaki KNakayama TNakamura T: The value of palliative surgery for metastatic spinal disease: satisfaction of patients and their families. Spine J 10:42492010


Ganz PA: Survivorship: adult cancer survivors. Prim Care 36:7217412009


Ganz PALee JJSiau J: Quality of life assessment. An independent prognostic variable for survival in lung cancer. Cancer 67:313131351991


Ghosh-Choudhury NAbboud SLNishimura RCeleste AMahimainathan LChoudhury GG: Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. J Biol Chem 277:33361333682002


Gok BMcGirt MSciubba DMAyhan SBydon AWitham TF: Surgical resection plus adjuvant radiotherapy is superior to surgery or radiotherapy alone in the prevention of neurological decline in a rat metastatic spinal tumor model. Neurosurgery 63:3463512008


Gok BMcGirt MJSciubba DMGarces-Ambrossi GNelson CNoggle J: Adjuvant treatment with locally delivered OncoGel delays the onset of paresis after surgical resection of experimental spinal column metastasis. Neurosurgery 65:1932002009


Harel RAngelov L: Spine metastases: current treatments and future directions. Eur J Cancer 46:269627072010


Hayat MJHowlader NReichman MEEdwards BK: Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12:20372007


Helweg-Larsen SSørensen PS: Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 30A:3963981994


Hespanhol VQueiroga HMagalhães ASantos ARCoelho MMarques A: Survival predictors in advanced non-small cell lung cancer. Lung Cancer 13:2532671995


Iacovou JWMarks JCAbrams PHGingell JCBall AJ: Cord compression and carcinoma of the prostate: is laminectomy justified?. Br J Urol 57:7337361985


Ibrahim ACrockard AAntonietti PBoriani SBünger CGasbarrini A: Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observational study of 223 patients Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine 8:2712782008


Jacobs WBPerrin RG: Evaluation and treatment of spinal metastases: an overview. Neurosurg Focus 11:6e102001


Janjan N: Bone metastases: approaches to management. Semin Oncol 28:4 Suppl 1128342001


Kawabata MImamura TMiyazono K: Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 9:49611998


Kohler BAWard EMcCarthy BJSchymura MJRies LAEheman C: Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 103:7147362011


Lad SPNathan JKBoakye M: Trends in the use of bone morphogenetic protein as a substitute to autologous iliac crest bone grafting for spinal fusion procedures in the United States. Spine (Phila Pa 1976) 36:E274E2812011


Loblaw DALaperriere NJMackillop WJ: A population-based study of malignant spinal cord compression in Ontario. Clin Oncol (R Coll Radiol) 15:2112172003


Luhmann SJBridwell KHCheng IImamura TLenke LGSchootman M: Use of bone morphogenetic protein-2 for adult spinal deformity. Spine (Phila Pa 1976) 30:17 SupplS110 S1172005


Maeda TBuchowski JMKim YJMishiro TBridwell KH: Long adult spinal deformity fusion to the sacrum using rh-BMP-2 versus autogenous iliac crest bone graft. Spine (Phila Pa 1976) 34:220522122009


Mantha ALegnani FGBagley CAGallia GLGaronzik IPradilla G: A novel rat model for the study of intraosseous metastatic spine cancer. J Neurosurg Spine 2:3033072005


McGirt MJGok BShepherd SNoggle JGarcés Ambrossi GLBydon A: Effect of hyperglycemia on progressive paraparesis in a rat etastatic spinal tumor model. Laboratory investigation. J Neurosurg Spine 10:9152009


Montazeri A: Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual Life Outcomes 7:1022009


Montesano R: Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth. Biochem Biophys Res Commun 353:8178222007


Mulconrey DSBridwell KHFlynn JCronen GARose PS: Bone morphogenetic protein (RhBMP-2) as a substitute for iliac crest bone graft in multilevel adult spinal deformity surgery: minimum two-year evaluation of fusion. Spine (Phila Pa 1976) 33:215321592008


Nagata MUeda TKomiya ASuzuki HAkakura KIshihara M: Treatment and prognosis of patients with paraplegia or quadriplegia because of metastatic spinal cord compression in prostate cancer. Prostate Cancer Prostatic Dis 6:1691732003


Parry CKent EEMariotto ABAlfano CMRowland JH: Cancer survivors: a booming population. Cancer Epidemiol Biomarkers Prev 20:199620052011


Pouliot FLabrie C: Role of Smad1 and Smad4 proteins in the induction of p21WAF1,Cip1 during bone morphogenetic protein-induced growth arrest in human breast cancer cells. J Endocrinol 172:1871982002


Raida MClement JHAmeri KHan CLeek RDHarris AL: Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death. Int J Oncol 26:146514702005


Reinholz MMIturria SJIngle JNRoche PC: Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 74:2552692002


Sasagawa IGotoh HMiyabayashi HYamaguchi OShiraiwa Y: Hormonal treatment of symptomatic spinal cord compression in advanced prostatic cancer. Int Urol Nephrol 23:351 3561991


Sciubba DMGokaslan ZL: Diagnosis and management of metastatic spine disease. Surg Oncol 15:1411512006


Sciubba DMPetteys RJDekutoski MBFisher CGFehlings MGOndra SL: Diagnosis and management of metastatic spine disease. A review. J Neurosurg Spine 13:941082010


Steinmetz MPMekhail ABenzel EC: Management of metastatic tumors of the spine: strategies and operative indications. Neurosurg Focus 11:6e22001


Thawani JPWang ACThan KDLin CYLa Marca FPark P: Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery 66:2332462010


van der Linden YMDijkstra SPVonk EJMarijnen CALeer JW: Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy. Cancer 103:3203282005


Witham TFKhavkin YAGallia GLWolinsky JPGokaslan ZL: Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2:87941162006


Yang SZhong CFrenkel BReddi AHRoy-Burman P: Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res 65:5769 57772005




All Time Past Year Past 30 Days
Abstract Views 49 49 13
Full Text Views 96 96 23
PDF Downloads 88 88 11
EPUB Downloads 0 0 0


Google Scholar