The Yin and Yang of bone morphogenetic proteins in cancer

Abstract

Bone morphogenetic proteins (BMPs) were first studied as growth factors or morphogens of the transforming growth factor-beta superfamily. These growth molecules, originally associated with bone and cartilage development, are now known to play an important role in morphogenesis and homeostasis in many other tissues. More recently, significant contributions from BMPs, their receptors, and interacting molecules have been linked to carcinogenesis and tumor progression. On the other hand, BMPs can sometimes function as a tumor suppressor. Our report highlights these new roles in the pathogenesis of cancer that may suggest novel targets for therapeutic intervention.

Introduction

Bone morphogenetic proteins (BMPs) are a family of evolutionarily conserved growth factors and morphogens, most of which belong to the transforming growth factor-β (TGF-β) superfamily. BMPs were discovered by Marshall Urist in 1965, who found that decalcified bone matrix fragments have bone induction activity when transplanted into rats and rabbits [1]. Wozney et al. isolated and identified molecules from bone extracts capable of inducing bone and cartilage formation and named them BMPs [2]. Further studies reveal that BMPs not only regulate bone and cartilage, but also a wide range of morphogenetic activity that is both tissue and context-dependent [3], [4], [5].

BMPs exist as dimeric pro-protein complexes in the cytoplasm that are cleaved by proteases before their intended action. After the BMP molecules are secreted, they are further processed by another layer of regulators, Noggin and Chordin, and then bind to their specific receptors on the plasma membrane of their target cells [6], [7]. BMPs exert their activities by way of serine-threonine kinase receptors, of which there are three, type-I and three type-II [8]. Different BMPs show a preference in the combination of receptors, but in general utilize one receptor of each type [9], [10]. As most BMPs are TGF-β family members, they tend to use the same signaling pathways, principally MAPK and SMAD, although Notch and WNT are also used [11], [12], [13]. Binding of the BMPs to their specific receptors triggers cross-phosphorylation of the type-I receptor by the type-II receptor [14]. The type-I receptor then releases R-SMADs that oligomerize with SMAD-4 to form a complex that translocates from the cytoplasm to the nucleus, where it exerts transcriptional activity for the activation or repression of BMP-specific genes [15]. Some BMPs are under the control of tissue-specific cis-regulatory elements [16].

Recent literature suggests that BMPs may be involved in human cancers in addition to their roles as tissue morphogens. This review focuses on the role of BMPs in oncogenic cellular processes including proliferation, metastasis, angiogenesis, differentiation, and epigenetic regulation. In preparing this review, we found that BMPs exert both pro- and anti-carcinogenic activities.