Duality of bone morphogenetic proteins in cancer: A comprehensive analysis

Over 20 different growth factors belonging to the bone morphogenetic proteins (BMPs) family have been identified, that were initially discovered as growth factors that promote osteogenesis, and play a vital role in bone remodeling and various developmental processes. Numerous studies have explored the aberrance level of BMPs in various cancer types, questioning their role in tumorigenesis. These growth factors have been studied extensively over the decades to define their function during cancer progression and metastasis. Nonetheless, the BMP expression profiles in clinical samples correlate with cancer prognosis. Based on clinical data, various in vitro, and in vivo findings, it has been reported that BMPs have dual roles, that is, they can act as a tumor suppressor, tumor promoter, and both. On contrary, some studies have reported that BMPs have an oncogenic role while others reported their tumor-suppressive role. So, this creates a knowledge gap in the behavior of different types of BMPs. Thus, this review updates and bridges the knowledge gap while considering the dual behavior of various BMPs including BMP-2, 4, 6, 7, 9, and 10. Moreover, the comprehensive analysis provides insight into the role of different BMPs in cancer potential and how the behavior of BMPs alters in the tissue-dependent context in various cancers by modulating canonical SMAD signaling, various noncanonical pathways such as PI3K/AKT, NF-κB, MAPK, STAT, cMYC, cJUN, and so forth. This review also enlightens the role of BMP heterodimers, several ligand-binding proteins (agonists and antagonists), mutational status of BMP receptors, and the tumor microenvironment in relating to the bi-functional aspects of the BMPs in various cancerous tissues by regulating the levels of BMP's canonical and noncanonical signals.