2022, Number 1
Use of bone morphogenetic proteins in reconstruction of maxillofacial defects caused by oral squamous cell carcinoma: is their use safe?
Full text
10.35366/103405
Language: English
References: 58
Page: 19-24
PDF size: 219.91 Kb.
ABSTRACT
In the maxillofacial region, large defects that require bone reconstruction most commonly arise from resection of oral squamous cell carcinoma advanced-stage. Human bone morphogenetic proteins (BMPs), have recently gained favor as a potential growth factor for de novo bone formation in maxillofacial reconstruction because of its osteoinductive activity, but its use for patients with craniomaxillofacial defects after oral squamous cell carcinoma resections remains contraindicated due to the paucity of data regarding the biologic effects of BMPs on cancer. The purpose of this study is to examines the role of BMPs in oral malignancy. Depending on the BMPs ligand and cancer type, BMPs can either promote or inhibit tumorigenesis. According to the data collected by us, we do not recommend the use of BMPs to reconstruct maxillofacial bone defects caused by resection of oral squamous cell carcinoma.INTRODUCTION
Maxillofacial cancer, including lesions arising from the oral cavity, oropharynx and face, is one of the leading causes of cancer-related deaths worldwide.1 More than 90% of head and neck cancers are oral squamous cell carcinoma (OSCC), which is associated with smoking, drinking alcohol and betel nut chewing.2 In the maxillofacial region, large defects that require bone reconstruction most commonly arise from resection of advanced-stage OSCC. This critical-size osseous defects cannot heal without surgical intervention and pose a significant challenge to craniofacial reconstruction.3,4 The gold standard for large defects is now vascularized free tissue flaps. This approach successfully restores form and function when performed by appropriately trained surgeons. However, free tissue transfer has limitations, including donor site morbidity, difficulty restoring the complex three-dimensional structure of the defect, and significantly extending the surgical time.5
These limitations have led to newer regenerative approaches using tissue engineering concepts being considered for the reconstruction of these defects. One such tissue engineering approach uses growth factors and scaffolds to support osteogenesis. In particular, recombinant human bone morphogenetic proteins (rhBMP), have recently gained favor as a potential growth factor for de novo bone formation in maxillofacial reconstruction because of its osteoinductive activity.6
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor TGF-β superfamily that mediates a multitude of developmental processes in various tissues. This family of more than 20 proteins has been shown to have roles in cellular lineage commitment, differentiation, proliferation, patterning/morphogenesis, cellular maintenance/survival, and apoptosis.7,8 Preclinical animal models and clinical experience from orthopedics show that BMPs are critically important osteoinductive molecules for regenerative approaches.9 Two recombinant human BMPs (rhBMP-2 and rhBMP-7) are now commercially available and have already led to improvements in the treatment of patients undergoing surgery for spinal fusion and long bone nonunions.10,11 Human recombinant BMP-2 is also approved by the U.S. Food and Drug Administration (FDA) for some orodental applications, but its use for patients with craniomaxillofacial defects after OSCC resections remains contraindicated due to the paucity of data regarding the biologic effects of BMPs on cancer.12
The potential role of BMPs in malignant transformation and progression of cancer is poorly understood.13 BMPs overexpression has been demonstrated to result in changes in cell morphology and increased cell motility and invasiveness in the pancreatic, gastric, prostate and breast cancer cells.12-17 Bach et al.18 analyzed the double role of BMPs in cancer, and they claimed that BMPs are a double-edged sword in cancer biology, as they can serve as tumor suppressors or tumor promoters depending on the type of cell or tissue in the microenvironment, epigenetic background of the patient, or stage of tumor growth. There are no unifying conclusions that can be made from the currently available data as to whether BMPs promotes, inhibits, or has no role in carcinogenesis of OSCC. Therefore, it is imperative to establish methods that could accurately evaluate whether BMPs exogenously grafted for maxillofacial hard tissue regeneration is associated with OSCC (Figure 1).18
Commercially available rhBMP-2 is the only FDA approved product for intraoral applications in the craniofacial skeleton; however, off-label use of rhBMP-2 and rhBMP-7 has been attempted in some cases to solve other particularly significant reconstructive challenges in the craniomaxillofacial area.19 Notable cases involve the reconstruction of the cranial vault, the reconstruction of alveolar cleft deformities, and the reconstruction of bone defects secondary to traumatic injury or neoplasms.4,6 It is therefore important to deepen the study about the safety in the use of BMPs and the biological effects on malignant neoplasms before using this molecule for the reconstruction of maxillofacial bone defects in the vicinity of a resected tumor or in patients undergoing treatment for malignancy. From a practical standpoint, our knowledge in this area needs to be increased before considering the translation of basic science advances in bone tissue engineering using BMPs for reconstruction of craniomaxillofacial defects in patients treated for OSCC (Figure 2). The purpose of this study is to examines the role of BMPs in oral malignancy.
ROLE OF BMPS IN ORAL SQUAMOUS CELL CARCINOMA
Many studies analyze the role of BMPs in cancer.12-58 An ideal osseous grafting treatment should involve the use of a bone-inductive material that would be reliable, biocompatible, long lasting and capable of regenerate with minimal morbidity. Particulate marrow and cancellous autogenous bone meet these requirements, but they must be harvested from a donor site, which often results in insufficient bone graft material, added cost and patient harvest-graft-site discomfort. BMPs are a group of osteoinductive, sequentially arranged amino acids and polypeptides that are capable of stimulating adult mesenchymal stem cells to become osteoblastic and form bone.48 Recombinant BMP-2 has been FDA approved for its use as an alternative to autografts in spinal fusions, adjuvant use in open tibia fractures, maxillary sinus augmentation and for alveolar ridge defects associated with extraction sockets in the form of bone graft coating, membranes, or solutions.40,49
Currently, recombinant human BMPs (rhBMP-2 and rhBMP-7) are the most extensively studied proteins and are commercially available for specific indications. The suggested human therapeutic doses (0.88 mg/mL of sterile water for rhBMP-7 and 1.50 mg/mL of sterile water for rhBMP-2) were derived from nonhuman primate studies and verified in clinical orthopedic studies. The doses of rhBMP required to induce bone formation in humans must be higher than endogenous concentrations of BMPs. Because BMPs act locally, the proteins must be transferred to the implantation site via a carrier matrix, which prevents prompt rhBMP clearance.50
The package insert for rhBMP describes contraindications for its use, including active infection at the operative site, pregnant women or those planning to become pregnant within one year, patients with a known hypersensitivity to rhBMP or bovine type I collagen, and any patient with an active malignant neoplasm or a history of malignant neoplasm in the vicinity of the proposed surgery. This important oncologic contraindication stems from concerns about the unknown effects of this growth factor on cancer cells. The potential carcinogenic effects of BMPs have been explored, but no definitive link has been established.50
At present, there is a greater understanding of the critical functions of BMPs in cancer. BMP-4 was reported to stimulate breast cancer cell invasion and promote bone remodeling. Clinically, Paez-Pereda et al.51 described the role of BMP-4 in tumorigenesis with the stimulation of tumor formation. In contrast, emerging studies have suggested that BMPs exhibit tumor-suppressive functions in cancer development. Ye et al.52 suggested that BMP-10 suppressed the growth and aggressiveness of malignant cells by inducing apoptosis via a SMAD-independent pathway, which was correlated to the modulation of extracellular signal-regulated kinase and X-linked inhibitor of apoptosis protein. Cao et al.53 also reported that BMP-4 suppresses breast cancer metastasis by inhibiting myeloid-derived suppressor cell activity in mice. They also suggested that BMP-4 decreases granulocyte-colony stimulating factor secretion via the suppression of nuclear factor-kB activity (Figure 3).
Taken together, the wealth of conflicting studies indicated that the same ligand may work differently depending on the cancer type, and it seems that multiple members in the BMPs family should not be tested as simply equals. BMPs can suppress tumor growth and metastasis, acting as tumor suppressors. Paradoxically, BMPs also accelerate tumorigenesis as tumor promoters through various mechanisms, such as activation of oncogenes and stimulation of metastasis in tumor microenvironment. BMPs are a double-edged sword in cancer biology, as they can serve as tumor suppressors or tumor promoters depending on the type of cell or tissue in the microenvironment, epigenetic background of the patient or stage of tumor growth.18
A report published by the FDA described BMP-2-induced adverse effects such as bone resorption, local inflammation, ectopic bone formation, and cancer; specifically, 86 reports of oral and maxillofacial surgery from 2002 to 2011 were found to display negative outcomes.54 Recent studies,12,39 showed increased pathogenicity of oral cancer cell lines after transient exposure to rhBMP. This is a significant consideration since the majority of segmental bone defects in the head and neck region are caused by resection of OSCC.39
However, off-label use of rhBMP-2 and rhBMP-7 has been attempted in some cases to solve particularly significant reconstructive challenges in the craniomaxillofacial skeleton.4 Desai et al.6 described the use of rhBMP-2 in six patients with significant mandibular defects secondary to traumatic injury or neoplasms. In addition, Zhou et al.43 performed gene microarray analysis with quantitative polymerase chain reaction in 25 oral tongue squamous cell carcinomas and found that increased BMP-2 gene expression was associated with regional lymph node metastasis and extracapsular spread. Based on this, the authors believe that rhBMPs should not be used for reconstruction of mandibular defects originating from OSCC.
Kokorina et al.39 developed a laboratory investigation using six human OSCC cell lines, with three cell lines having baseline gene expression of BMP-2 and three cell lines without baseline gene expression of BMP-2, in order to determine if rhBMP-2 has biological effects on the invasiveness of human OSCC cell lines. They concluded that rhBMP-2 has an adverse biological effect on invasiveness of human OSCC cell lines in vitro. These findings raise concern for the safe application of rhBMP-2 for reconstruction of bone defects in oral cancer patients. Kim et al.40 discussed the probability of adverse effects caused by 1 mg/ml of rhBMP-2 and they warned that rhBMP-2 induced invasion and progression of pre-existing cancer cells that might not be detected in a diagnostic process. This study also emphasized the importance of the in vitro coculture system (cancer cells with fibroblasts) for the evaluation of cancer progression induced by regenerative biomaterials. They considered that malignant tissues near the defective areas should be treated or removed in advance to eliminate the possibility of adverse effects caused by rhBMP-2 in OSCC.
Kokorina et al.,12 developed an investigation to establish the relevance of the BMPs signaling pathway in human OSCC cell lines and determine if there is a biologic impact of stimulating this pathway with rhBMP-2. They found that exogenous treatment of human OSCC cell lines with rhBMP-2 prior to engraftment in an orthotopic animal model caused the subsequent tumors to be more locally aggressive with worse survival rates. The authors affirmed in their research that caution should be taken when considering the therapeutic use of BMPs for reconstruction of bone defects in oral cancer patients.
Alternatively, a recent report showed that rhBMP-2 did not have any adverse effects on proliferation or angiogenesis in human OSCC cell lines when tested in vitro or in vivo using an ectopic site animal model.3 Subsequently, Lappin et al.,45 investigated the effects of rhBMP-7 on the behavior of oral keratinocytes and human OSCC cells in vitro. They found that rhBMP-7 exhibited significant dose-related inhibitory effects on the doubling time and viability of cancer cells, but not on the proliferation or viability of oral keratinocytes. These authors affirmed that in cell culture, rhBMP-7 exerts antineoplastic effects. However, Jin et al.,38 studied 29 oral carcinomas by immunohistochemistry and found that BMP-2/4, BMP-5 and BMP type IA receptors were expressed in 73%, 73%, and 83% of tumors, respectively. They concluded that the BMPs pathway is involved in carcinogenesis of oral epithelium.
As reflected in the literature, the role of BMPs in the OSCC is poorly understood and the research in this regard is contradictory. BMPs affect not just human OSCC cells but also the surrounding tumor microenvironment, including tumor microvasculature and immune cells.55 Gao et al.,3 despite stating that rhBMP-2 did not have any adverse effects on proliferation or angiogenesis in human OSCC cell lines, affirmed that further studies are needed before using rhBMP-2 for bone tissue engineering in oral cancer-related skeletal defects. All these findings further contribute to contraindicating the use of BMPs to reconstruct maxillofacial bone defects in the vicinity of a resected tumor or in patients undergoing treatment for malignancy.
To elucidate the physiological roles of BMPs in OSCC, it is extremely important to analyze a large number of materials simultaneously by using the latest high-throughput technologies. These high-throughput analyses may prove valuable for elucidating the context-dependent roles of BMPs in a comprehensive manner and must be performed in order to better understand the potential roles these molecules may have in OSCC tumorigenesis and metastasis.
CONCLUSION
Although a relationship between BMPs and cancer has been noted for over 20 years, the precise roles of BMPs signaling in cancer development and progression are just beginning to be elucidated. Depending on the BMPs ligand and cancer type, BMPs can either promote or inhibit tumorigenesis. According to the data collected by us, we do not recommend its use to reconstruct maxillofacial bone defects caused by resection of OSCC. This review serves to further clarify the role of exogenous BMPs in OSCC and shed light on the recent development and use of small molecule BMPs in maxillofacial reconstructions.
REFERENCES
AFFILIATIONS
1 Oral and Maxillofacial Surgeon. Oral and Maxillofacial Surgery Unit. Hospital Coromoto. Zulia, Venezuela.
2 Resident. Oral Surgery Post-Graduated Program. School of Dentistry. Universidad del Zulia. Venezuela.
Conflict of interest: All the authors declare that they have no conflict of interest.
Funding: No funding was received for conducting this research.
CORRESPONDENCE
Enmanuel David Parra. E-mail: enmanuelparra04@gmail.comReceived: 16/09/2021. Accepted: 15/10/2021