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 

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Object

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.

Methods

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).

Results

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.

Conclusions

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: dsciubb1@jhmi.edu.

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.

Headings

Figures

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    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.

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    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.

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