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. Author manuscript; available in PMC: 2020 Aug 12.
Published in final edited form as: Spine (Phila Pa 1976). 2015 Dec;40(23):1862–1871. doi: 10.1097/BRS.0000000000001126

Association Between BMP-2 and Carcinogenicity

Branko Skovrlj *, Steven M Koehler †, Paul A Anderson ‡, Sheeraz A Qureshi †, Andrew C Hecht †, James C Iatridis †, Samuel K Cho †
PMCID: PMC7423158  NIHMSID: NIHMS1608637  PMID: 26274524

Abstract

Study Design

Literature review.

Objective

To evaluate the association between recombinant human bone morphogenetic protein-2 (rhBMP-2) and malignancy.

Summary of Background Data

The use of rhBMP-2 in spine surgery has been the topic of much debate as studies assessing the association between rhBMP-2 and malignancy have come to conflicting conclusions.

Methods

A systematic review of the literature was performed using the PubMed-National Library of Medicine/National Institute of Health databases. Only non-clinical studies directly addressing BMP-2 and cancer were included. Articles were categorized by study type (animal, in vitro cell line/human/animal), primary malignancy, cancer attributes, and whether BMP-2 was pro-malignancy or not.

Results

A total of 4,131 articles were reviewed. Of those, 515 articles made reference to both BMP-2 and cancer, 99 of which were found to directly examine the role of BMP-2 in cancer. Seventy-five studies were in vitro and 24 were animal studies. Forty-three studies concluded that BMP-2 enhanced cancer function, whereas 18 studies found that BMP-2 suppressed malignancy. Thirty-six studies did not examine whether BMP-2 enhanced or suppressed cancer function. Fifteen studies demonstrated BMP-2 dose dependence (9 enhancement, 6 suppression) and one study demonstrated no dose dependence. Nine studies demonstrated BMP-2 time dependence (6 enhancement, 3 suppression). However, no study demonstrated that BMP-2 caused cancer de novo.

Conclusion

Currently, conflicting data exist with regard to the effect of exogenous BMP-2 on cancer. The majority of studies addressed the role of BMP-2 in prostate (17%), breast (17%), and lung (15%) cancers. Most were in vitro studies (75%) and examined cancer invasiveness and metastatic potential (37%). Of 99 studies, there was no demonstration of BMP-2 causing cancer de novo. However, 43% of studies suggested that BMP-2 enhances tumor function, motivating more definitive research on the topic that also includes clinically meaningful dose- and time-dependence.

Keywords: bone morphogenetic protein, carcinogenicity, fusion, InFuse®, malignancy, rhBMP-2, Spine surgery

Bone morphogenetic proteins (BMPs) are pluripotent factors belonging to the transforming growth factor-beta (TGF-β) superfamily involved in the regulation of embryonic development and postnatal homeostasis of various tissues and organs through their potent regulation of cellular differentiation, proliferation, survival and apoptosis. 1 Since their discovery by Marshall Urist in 1965, over 20 different BMPs have been described in humans.1–6 However, only BMP-2, −4, −6, −7, and −9 have been shown to have significant osteogenic properties through facilitation of intramembranous and endochondral bone formation as well as cartilage formation.3,7,8

BMP-2 appears to be the most oseteogenic BMP discovered and multiple studies have suggested that it could cause bone induction in various animal models.9,10 In 2002, following 13 industry sponsored recombinant human BMP-2 (rhBMP-2) publications regarding safety and efficacy, rhBMP-2 (InFuse; Medtronic Sofamor Danek, Memphis, TN) was Food and Drug Administration (FDA) approved as a bone graft substitute for human use.11 Although it was only approved for single-level anterior lumbar fusion surgery using a tapered titanium cage, 85% of rhBMP-2 has been reported to have been used off-label.12 The original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols reported a 0% rhBMP-2 – associated adverse events.10 Recently, however, the use of rhBMP-2 in spine surgery has been the topic of much debate as rhBMP-2 has been reported to be associated with a higher incidence of developing new malignancy compared to iliac crest bone graft (Appendix Table 1).

Based on the identified increase cancer risk in patients who received rhBMP-2 and its widespread use in spine surgery, determining the answer to whether BMP-2 is associated with malignancy is of utmost importance. The goal of this study is to evaluate the association between BMP-2 and malignancy by systematically reviewing and analyzing all published literature for all studies examining the role of BMP-2 in malignancy.

MATERIALS AND METHODS

A systematic review and analysis of the published literature in the English language was performed using the PubMed-National Library of Medicine/National Institute of Health databases. Only studies that directly addressed BMP-2 and cancer were included. The terms “bone morphogenetic protein”, “BMP”, “neoplasm”, “tumor”, “malignancy”, “cancer”, “tumorigenesis”, and “metastasis” were used as search terms. Articles were categorized by the study type (animal, in vitro cell line, in vitro human, in vitro animal), primary malignancy, cancer attributes, and whether BMP-2 was pro-malignancy or not. Only articles in English journals or published with English translations were included. Level of evidence (I-V) was assessed for each included article according to published criteria.13

RESULTS

A total of 4,131 articles were reviewed. Of those, 515 made reference to both BMP-2 and cancer. The 515 studies were further analyzed and a total of 99 studies were found to directly examine the role of BMP-2 in cancer.14–112 Seventeen articles examined the role of BMP-2 in prostate cancer, 17 in breast cancer, 15 in lung cancer, 9 in osteosarcoma, 6 in gastric cancer, 5 in oral cancer, 4 in ovarian cancer, 3 in bladder cancer, 3 in chondrosarcoma, 3 in colon cancer, 3 in melanoma, 3 in pancreatic cancer, 3 in salivary cancer, 1 in adrenal carcinoma, 1 in giant cell tumor, 1 in glioma, 1 in leukemia, 1 in liver cancer, 1 in renal cell carcinoma, 1 in squamous cell carcinoma and 1 in thyroid carcinoma [Table 1]. Twenty-four studies were animal studies and 75 studies were in vitro studies. In vitro studies were further separated based on whether the study used a cultured cell line versus human or animal tissue. Of the 75 in vitro studies, 43 used cell lines, 31 used human tissue and 1 study used animal tissue [Figure 1]. Thirty-seven studies evaluated cancer invasiveness (8 animal, 21 in vitro cell, 8 in vitro human), 27 cancer proliferation (8 animal, 21 in vitro cell, 5 in vitro human, 1 in vitro animal), 16 BMP-2 expression in cancer (4 in vitro cell, 12 in vitro human), 11 effect on cancer (3 animal, 5 in vitro cell, 3 in vitro human), 6 angiogenesis (5 animal, 1 in vitro human), and 2 outcome (2 in vitro human) [Figure 2]. Lastly, the pro-malignancy versus tumor suppression by BMP-2 was assessed. Forty-three studies concluded that BMP-2 enhanced cancer function (43.4%, 13 animal, 25 in vitro cell, 5 in vitro human), 18 studies found that BMP-2 inhibited cancer function (18.2%, 5 animal, 9 in vitro cell, 3 in vitro human, 1 in vitro animal), 2 studies revealed that BMP-2 had no effect on cancer function (2.0%, 1 animal, 1 in vitro human) and 36 studies did not evaluate the role of BMP-2 on cancer function (36.3%, 5 animal, 9 in vitro cell, 22 in vitro human) [Figure 3]. Fifteen studies demonstrated BMP-2 dose dependence (9 enhancement, 6 suppression) and 1 study demonstrated no dose dependence. Nine studies revealed BMP-2 time dependence (6 enhancement, 3 suppression) [Figure 4]. No studies showed that BMP-2 caused cancer de novo, i.e. transformation of normal cells into malignant cells.

TABLE 1.

BMP-2 and Type of Cancer Studied

Type of Cancer Number of Studies
Prostate 18
Breast 17
Lung 15
Osteosarcoma 9
Gastric 6
Oral 5
Ovarian 4
Bladder 3
Chondrosarcoma 3
Colon 3
Melanoma 3
Pancreas 3
Salivary 3
Adrenal 1
Giant Cell Tumor 1
Glioma 1
Leukemia 1
Liver 1
Renal Cell 1
Squamous Cell 1
Thyroid 1
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Figure 1.

Figure 1.

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Table depicting the type and number of BMP-2 studies published in the literature.

Figure 2.

Figure 2.

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Table depicting the number and type of cancer studies evaluating the role of BMP-2 in various cancer properties.

Figure 3.

Figure 3.

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Table depicting the role of BMP-2 on cancer function by evaluating its effects on various cancer properties.

Figure 4.

Figure 4.

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Table depicting the dose- and time-dependent effects of BMP-2 on cancer cells.

DISCUSSION

The widespread off-label use of BMP-2 in fusion surgery and the subsequent concerns of increased risk of malignancy related to its use have led to a whirlwind of controversy in spine surgery. The latest independent review of all published and unpublished data on safety and effectiveness of rhBMP-2 by the Yale University Open Data Access Project (YODA) concluded that at 24 months, cancer risk was increased (RR, 3.45 [95% CI, 1.98–6.00] with rhBMP-2.113,114 However, a recent retrospective review of 467,916 Medicare patients undergoing spinal arthrodesis with and without the use of rhBMP-2 found that BMP-2was not associated with a detectable increase in the risk of cancer within a mean of 2.9-year time window.115 The conflicting findings from studies investigating the use of BMP-2 in spinal fusion surgery and its relationship to cancer continue to be a topic of intense research and debate.

BMPs are a family of proteins secreted to the extracellular environment as an intracellular communication mechanism through their role as ligands of specific receptors found on target cells.116 They form part of a much larger pathway, the TGF-β signaling pathway, responsible for the maintenance of tissue homeostasis and prevention of tumor progression to malignancy by regulation of cellular proliferation, differentiation, survival and adhesion, as well as the cellular microenviroment.117 In order for tumor cells to become malignant, they must elude the tumor-suppressive effects of the regulatory cytokine TGF-β. Malignant cells can do so by bypassing the suppressive effects of TGF-β either through inactivation of core components of the pathway (TGF-β receptors), or by downstream alterations that disable the tumor-suppressive arm of the pathway.117 If cancer cells succeed to circumvent the downstream arm of the pathway, they have at their disposal the remaining regulatory effects of the TGF-β regulatory functions acquiring invasion capabilities, producing autocrine mitogens, or releasing prometastatic cytokines.117

BMP-2 mediates signaling by binding serine/threonine kinase type IA and IB together with a type II receptor with subsequent phosphorylation of Smad 1/5/8 and activation of downstream targets.118 The current theory of stem cell differentiation argues that cell fate decisions are determined by the actions of intracellular signaling networks in response to combinations of extracellular ligands and that crosstalk between different signaling pathways via different transcription factors ultimately results in the expression of patterns of target genes that specify cell fate.119 The effect of BMPs on target cells would thus depend on the context in which the BMP signals are received by those cells. Cells in different organs at different stages of development may express specific combinations of BMP effectors that influence responses to BMP.

The switch of BMP from a differentiation to a self-renewal signal is highly dependent on the activity of other signaling pathways activated at different times in different tissues.119 The fine balance between self-renewal and differentiation must be maintained in order to maintain normal growth and homeostasis.120 Disruption of this balance can lead to a loss of cellular control in terms of cell growth and proliferation.121 Stem cells have the characteristics of immortality and the loss of contact inhibition, both of which are exhibited by cancer cells.

BMP-2 regulates many essential cellular processes in development including cell proliferation, apoptosis, differentiation, cell-fate determination, and morphogenesis. Given the demonstrated impact of BMP-2 in various stem cell populations and their broad modes of signaling, it is easy to see how BMP-2 may contribute to or foster changes leading to cancer and its spread.122

In this study, the authors aimed to evaluate the effect BMP-2 had on various cancer attributes such as cancer proliferation, invasiveness, and angiogenesis. The goal of this study was to improve our understanding of the effects of exogenous BMP-2 on malignancy, in hopes of further elucidating the intricate relationship between BMP-2 and cancer in the clinical setting.

Of the 99 studies that directly examined the role of BMP-2 in malignancy, 49 were found to examine the role of BMP-2 in prostate (17), breast (17) and lung (15) cancers, the three most common types of cancer as reported by the American Cancer Society.123 Of these three, lung cancer was the only type of cancer where BMP-2 was found to have a role in tumorigenesis through the regulation of the PI3K/mTOR pathway, known to have an important role in regulating growth of human carcinomas.35 BMP-2 is highly expressed in approximately 98% of human lung carcinomas with little to no expression in normal lung tissue or benign lung tumors.35,43 Bieniasz et al.79 revealed that expression of BMP-2 mRNAs was 25.7-fold higher in lung cancer samples compared to normal adjacent lung tissue. Feeley et al.57 found that Noggin, an inhibitor of BMP-2, inhibited mixed metastatic lung lesions in bone and the tumor growth in vivo.

Sixty-three studies assessed whether BMP-2 enhanced or inhibited malignancy. Of those, 43 (68%) studies found BMP-2 to be pro-oncogenic, while 18 (29%) found BMP-2 to be inhibitory and 2 (3%) studies did not find BMP-2 to affect cancer. The specific pro-oncogenic and inhibitory effects of BMP-2 on different tumor types can be found in Tables 2 and 3, respectively. The inhibitory effects of BMP-2 on cancer were only found in studies assessing cancer proliferation. In studies evaluating cancer invasiveness, 73% found that BMP-2 enhanced cancer invasiveness and metastatic potential. Studies evaluating the effects of BMP-2 on angiogenesis found BMP-2 to be enhancing in 67% of the studies. From this early understanding of the effects of BMP-2 on cancer it appears that under specific circumstances, BMP-2 may have the ability to inhibit cancer formation by inhibiting early cellular changes that result in cellular atypia and dysplasia. However, once cells lose further control and become more carcinogenic, BMP-2 may enhance their ability to grow by facilitating neovascularization, and their ability to metastasize and spread to distant organs by enhancing their invasive properties.122,124

TABLE 2.

Breakdown of Studies That Found BMP-2 to be Pro-oncogenic

Cancer Type Author Conclusion of BMP-2 Effect
Breast Steinert, S72 BMP-2 affected apoptosis-related genes which showed pronounced alteration
Raida, M68 BMP-2 expression is activated in invasive breast cancers
Clement, JH36 Enhances the tumorigenic properties of breast carcinoma cells and drive the cells towards a more aggressive phenotype
Katsuno, Y90 BMP-2 promotes invasion and bone metastasis of breast cancer
Neman, J92 Metastatic cells create a permissive niche by steering differentiation through paracrine BMP-2 signaling
Pouliot, F67 BMPs interacting with type II BMP receptors contribute to the proliferation and/or survival of human breast cancer cells
Lung Langenfeld, E96,29,43 Promotes growth, transformation and survival of cancer cells
Enhances angiogenic response by stimulating endothelial cells
Highly overexpressed an growth promoting in cancer cells
Hsu, Y50 Induced lung cancer migration, invasion, and epithelial-to-mesenchymal transition
Lee, KB71 Sequestration of BMP-2 reduced tumor growth
Feeley, BT57 Mixed metastatic lung lesions in bone are inhibited by noggin overexpression which is a direct inhibitor of BMP-2
Prostate Yang, S32 Induces tube formation in angiogenesis, modulates the biological behavior of prostate tumor cells in diverse and cell type-specific manner
Feeley, BT49 Critical in the formation of the osteoblastic lesions associated with prostate cancer metastases, influence the formation of the osteolytic prostate cancer metastases
Kwon, H52 Promotes migration of cancer cells in a 3-dimensional gel system
Graham, TR60 Enhances the invasiveness of C4–2B prostate cancer cell line
Lai, TH42 Contributes to the migration of prostate cancer cells
Gastric Kang, MH63 BMP-2 strongly increases motility and invasiveness, BMP-2 signaling pathways strongly enhance tumor metastasis
Park, Y73 Seems to have a role in progression to metastatic disease, especially in the late stage of tumorigenesis, including invasion and metastasis
Bladder Hung, TT87 BMP-2 expression was significantly associated with in vivo tumorigenicity of the cell lines
Yang, ZJ95 Responsible for the mechanism involved in triggering bone metastasis in bladder cancer
Oral Jin,Y51 BMP-2 might be involved in the metastasis of oral carcinoma cells
Kokorina, NA92 rhBMP-2 treatment of tumor cells makes them more locally aggressive with worse survival and has adverse effects on invasiveness in human cell lines in vitro
Pancreatic Chen, X56 BMP-2 accelerates invasion of panc-1 cells via the PI3K/AKT pathway
Gordon, KJ59 BMP signaling, through Smad1 induction and up-regulation of MMP-2, is an important mediator of pancreatic cancer invasiveness
Chondrosarcoma Hou, CH39 Enhances invasiveness of chondrosarcoma cells
Fong, YC38 Contributes to the migration of chondrosarcoma cells through PI3K/AKT pathway
Osteosarcoma Rubio, R99 Enhances development of osteoid areas
Sotobori, T46 Enhances cell migration by modulating fibronectin-integrin beta-1 signaling
Melanoma Rothhammer, T31 Induces tube formation and migration efficiency of microvascular endothelial cells, play an important role in dissemination of tumor cells from the primary tumor
Ovarian LePage, C85 Contributes to a modification of tumor cell behavior through a change in motility and adherence
Glioma Guo, M98 BMP-2 treatment causes marked stimulation of glioma cell growth, migration and invasion
Leukemia Lapperouzas, B88 Deregulation of intracellular BMP signaling in primary CP-CML samples corrupts and amplifies their response to exogenous BMP2
Chondroblastoma Yang, X90 BMP-2 induced protumorigenic effects on chonroblastoma cells
Colon Kang, MH20 BMP-2 causes resistance and invasion of cancer cells
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TABLE 3.

Breakdown of Studies That Found BMP-2 to be Inhibitory to Cancer

Cancer Type Author Conclusion of BMP-2 Effect
Breast Ye, S94 Inhibited the proliferation of MDA-MB-231 breast cancer cells in vitro
Chen, A96 Significantly inhibited the proliferation of MDA-MB-231 and MCF-7 breast cancer cells
Buijs, JT99 BMP-2 and -7 strongly inhibited the activity of the breast cancer phenotype
Gosh, N57 Inhibits estradiol-induced proliferation of human breast cancer cells
Arnold, SF55 rhBMP-2 decreases proliferation of various breast cancer cell lines
Osteosarcoma Wang, L25 Suppresses tumor growth by reducing the gene expression of tumorigenic factors
Rici, RE98 Inhibits the proliferation capacity of osteosarcoma cells by mechanisms of apoptosis and tumor suppression mediated by p53
Murphy, MG28 BMP-2 has an inhibitory effect at high doses
Huang, W19 Increased BMP-2 proliferation caused decreased cellular proliferation and increased osteoblastic differentiation
Prostate Brubaker, KD16 BMPs have growth inhibitory effects on prostate cancer cell lines
Tomari, K54 Inhibits dihydrotestosterone-induced growth of prostate cancer cell line LNCaP
Kumagai, T41 BMP-2 identified in several inhibitory pathways
Gastric Zhang, J97 Exerted inhibitory effect on the growth of all types of cells and the inhibition become more evident with the increase of BMP-2 dose
Shirai, YT22 BMP-2 functions as potent tumor suppressors in diffuse-type gastric carcinoma
Adrenal Johnsen, IK15 BMP inhibits cell proliferation/viability in a dose and time dependent fashion
Colon Beck, SE18 RAS/ERK activation prohibits growth suppressive effects of BMP signaling
Renal Cell Wang, L24 BMP-2 inhibits growth of RCC and causes induction of osseous bone formation
Multiple Cancers Soda, H23 Significant inhibition was seen in 16 of 65 specimens (24.6%)
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Fifteen studies evaluated the effect of BMP-2 dose on malignancy; 60% of which found a BMP-2 dose-dependent enhancement of cancer cells. Fourteen of the studies used BMP-2 doses ranging from 0–500 ng/mL while one study evaluating tumor growth of human renal cell carcinoma in a rat model used a dosage of 30 μg/mL, three orders of magnitude greater. The current FDA-approved dosage of rh-BMP2 in InFUSE® is 1.5 mg/mL, a value based on nonhuman primate data and adopted to human use.125 A more concentrated preparation of rhBMP-2, Amplify® (2.0 mg/mL) was discontinued from use after a review of the original FDA SSED studies showed increased cancer rates in patients who received Amplify® versus controls (3.8% vs. 0.89%).126 There is currently no available data on the optimal dose of rhBMP-2 for use in humans.

Pharmacokinetic studies using rat and nonhuman primate models have shown that rhBMP-2 is rapidly eliminated from the systemic circulation after intravenous administration with half-lives (t1/2) of 16 minutes in rats and 6.7 minutes in nonhuman primates.127 These half-life values are significantly shorter compared to those of certain established human carcinogens such as cyclosporine (t1/2 in rat, 6–10 hours), 4-aminobiphenyl (t1/2 in rat, 17 hours) and busulfan (t1/2 in rat, 3–8 hours).128–131 Implantation of rhBMP-2 in conjunction with an absorbable collagen sponge resulted in the retention of rhBMP-2 at the site of application (mean resident time (MRT), 4–8 days in the rat) and low levels of detectable rhBMP-2 in the systemic circulation.127 The slow release of rhBMP-2 from an implant site coupled with rapid clearance from the systemic circulation is thought to result in low systemic exposure.132

Only nine studies exist evaluating the time-dependent effect of BMP-2 on cancer cells. Of the currently available data on time dependent effects of BMP-2 on cancer, 67% of the studies revealed a positive association. It is currently unknown whether rhBMP-2, when implanted in the human fusion bed, remains at that location locally or whether it enters the intravascular space and spreads to distant organs. If it does, the concentration and duration of the effect of exogenous rhBMP-2 on distant end organs in humans are unknown.

Two studies assessed the correlation of BMP-2 levels in human serum with patient outcomes. Fei et al.100 showed that BMP-2 up-regulation was an indicator of poor survival in advanced non-small cell lung cancer. The authors concluded that serum BMP-2 level is positively correlated with clinical stage and metastatic burden and may serve as an independent negative predictor for prognosis. Sand et al.97 showed that head and neck squamous cell carcinomas with high baseline BMP-2 protein levels were associated with higher rates of local recurrence, however, overall survival, regional failure, and distant failure were not affected by level of BMP-2 expression.

There are several limitations to this study. It is important to note that 75 of the 99 studies evaluating BMP-2 and malignancy in the literature were cell culture experiments. Although these were validated studies, cell culture experiments may not reveal the full biological effects of BMP-2 since its activity is highly variable depending on the local environment in which it is encountered. A concern with the use of cell lines is that they are engineered for use in proliferation and growth studies and their response to growth factors may not reflect that of normal cells. Another limitation to this study is that only non-clinical (in-vitro and animal) studies were evaluated. Non-clinical studies may not be comparable to human clinical data giving rise to the limitation of inference. A third limitation to this study is the fact that wide ranges of cell and cancer types were evaluated.

In conclusion, this study revealed the existence of conflicting data with regards to the effect of exogenous BMP-2 on cancer. We establish the fact that BMP-2 is a ubiquitous growth factor integral to growth, development and homeostasis with a wide range of effects on both normal and malignant cells. Of the 99 studies we examined, there was no demonstration of BMP-2 causing cancer de novo. However, 43% of studies suggested that BMP-2 enhances tumor function, motivating more definitive research on this topic that also includes clinically meaningful dose- and time-dependence.

Key Points.

  • BMP-2 is an ubiquitous growth factor integral to growth, development and homeostasis of both normal and malignant cells.

  • The use of rhBMP-2 in spine surgery has been the topic of much debate as rhBMP-2 has been reported to be associated with a higher incidence of developing new malignancy compared to iliac crest bone graft.

  • Of the 99 non-clinical studies examined, sixty-three assessed whether BMP-2 enhanced or inhibited malignancy. Of those, 43 (68%) studies found BMP-2 to be pro-oncogenic, while 18 (29%) found BMP-2 to be inhibitory and 2 (3%) studies did not find BMP-2 to affect cancer.

  • There was no demonstration of BMP-2 causing cancer de novo, however, 43% of studies suggested that BMP-2 enhances tumor function, motivating more definitive research on this topic that also includes clinically meaningful dose- and time-dependence.

  • This study revealed the existence of conflicting data with regards to the effect of exogenous BMP-2 on cancer.

Acknowledgments

No funds were received in support of this work.

Relevant financial activities outside the submitted work: board membership, consultancy, employment, grants, payment for lectures, royalties, stocks.

Footnotes

The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication.

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