Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

Abstract

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.

BMP antagonists in tissue development and disease

“…Exemplarily, BMPs are involved in proliferation, migration, and invasion of epithelial cancer cells [62] , but also sensitize tumor-initiating cells to mechanical cues from the extracellular tumor microenevirnment [63] . The role and influence of BMP antagonists has recently been reviewed in detail by Ouahoud and colleagues [64] . In human carcinomas elevated levels of certain antagonists such as gremilin-1 [65] , [66] , and chordin-like-1 [67] have been found which may block the general anti-proliferative functions of BMP ligands, while elevated levels of BMP signalling, possibly through dysregulation of BMP antagonist expression, can promote certain tumours [68] .…”

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…Bone morphogenetic protein 9 (BMP9) is a cytokine that belongs to the highly conserved transforming growth factor (TGF-β) superfamily of proteins. This superfamily includes a massive pool of growth factors such as the TGF-β subfamily (with five isoforms: TGF-β1 to 5), the bone morphogenetic protein (BMP) subfamily, the activins and inhibins subfamilies, the nodal group, the growth differentiation factors (GDF) subfamily and the anti-Müllerian hormone, among others [64,65].…”

“…BMP9 is part of the BMPs, the largest subgroup of signaling molecules in the TGF-β superfamily. They were first discovered due to their ability to induce bone and cartilage formation [72], but they also participate in embryonic development, adult tissue homeostasis, control of stem cells, fracture repair, and cellular differentiation [64,[73][74][75]. BMP9 is encoded by the GDF2 gene (chromosome 10q11) in humans.…”

“…Besides the Smad-dependent signaling pathway, there is also a non-canonical signaling via mitogen-activated protein kinase (MAPKs), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), AMP-activated kinase (AMPK), small GTPase Ras-ERK pathways, c-Jun N-terminal kinase (JNK), and others [64,65,74]. The activation of these pathways has been demonstrated by numerous cell types.…”

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

“…Blood vasculature-The BMP antagonists (Figure 2; number 3) are classified into three classes based on their structure: the Chordin/Noggin family, Twisted/Gastrulation (TWSG1) and the DAN/Cerberus family (which includes Gremlin1 (GREM1)) [99].…”