Bone morphogenetic protein and bone metastasis, implication and therapeutic potential
Lin Ye1, Malcolm D. Mason1, Wen G. Jiang1
1Metastasis and Angiogenesis Research Group, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. Bone morphogenetic proteins
- 3.1. Structural characteristics of BMPs
- 3.2. BMP receptors
- 3.3. Intracellular signal transduction
- 3.3.1. Smad dependent pathway
- 3.3.2. Smad independent pathway
- 3.4. Regulatory system of BMP signaling
- 3.4.1. Extracellular regulatory factors
- 3.4.1.1. BMP antagonists
- 3.4.1.2. Pseudoreceptor
- 3.4.1.3. Co-receptors
- 3.4.2. Intracellular regulatory factors for Smad signaling
- 3.4.2.1. Inhibitory Smads (I-Smads)
- 3.4.2.2. Smad interacting proteins
- 3.4.2.3. Molecules that regulate degradation of the Smads
- 4. BMP and predisposition of metastasis to bone
- 4.1. Aberrant expression and signaling of BMPs in primary tumors and, their association with bone metastasis
- 4.1.1. Prostate cancer
- 4.1.2. Breast cancer
- 4.2. BMPs affect growth and survival of cancer cells
- 4.2.1. BMP and proliferation of cancer cells
- 4.2.2. BMP and apoptosis
- 4.3. Epithelial-mesenchymal transition (EMT) and aggressive phenotypes acquired by metastatic cancer cells before dissemination from primary tumors
- 4.3.1. BMP and EMT
- 4.3.2. Influence of BMPs on cellular motility and invasion
- 4.4. Regulatory factors of BMP
- 4.4. Sexual hormones
- 4.4.2. DNA methylation
- 4.4.3. Others
- 5. BMP and colonisation of cancer cells in bone
- 5.1. Tumor cell derived osteoblastic factors
- 5.2. Osteolytic factors secreted from metastatic cancer cells
- 5.3. Abundant deposition of growth factors and molecules in bone contributes to the vicious circle
- 5.4. Pivotal role of BMPs in bone metastasis
- 5.4.1. Adaptable expression of BMPs in bone metastases
- 5.4.2. BMP and angiogenesis
- 5.4.3. Therapeutic potential of targeting BMPs
- 6. Conclusions and Perspective
- 7. Acknowledgements
- 8. References
1. ABSTRACT
Bone metastasis is one of the most common and severe complications in advanced malignancies, particularly in the three leading cancers; breast cancer, prostate cancer and lung cancer. It is currently incurable and causes severe morbidities, including bone pain, hypercalcemia, pathological fracture, spinal cord compression and consequent paralysis. However, the mechanisms underlying the development of bone metastasis remain largely unknown. Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and are pluripotent factors involved in the regulation of embryonic development and postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. Since they are potent regulators for bone formation, there is an increasing interest to investigate BMPs and their roles in bone metastasis. BMPs have been implicated in various neoplasms, at both primary and secondary tumors, particularly skeletal metastasis. Recently studies have also suggested that BMP signaling and their antagonists play pivotal roles in bone metastasis. In this review, we discuss the current knowledge of aberrations of BMPs which have been indicated in tumor progression, and particularly in the development of bone metastasis.
