Bone morphogenetic protein 4—a fascinating regulator of cancer cell behavior

doi:10.1016/j.cancergen.2012.05.009

Cancer Genetics

Volume 205, Issue 6, June 2012, Pages 267-277

https://doi.org/10.1016/j.cancergen.2012.05.009 Get rights and content

Bone morphogenetic proteins (BMPs) are extracellular signaling molecules that belong to the transforming growth factor β (TGFβ) superfamily and are well-known for their indispensable roles in vertebrate development. In recent years, important new information has been generated on the contribution of BMP family members, such as BMP4, in cancer pathogenesis. First of all, BMP4 gene variants have been shown to predispose to colorectal cancer. In sporadic cancer, BMP4 expression levels are commonly altered in many tumor types and have been linked to patient prognosis in hepatocellular and ovarian cancer. In terms of BMP4 function in cancer cells, the majority of studies demonstrate that BMP4 suppresses cell growth both in vitro and in vivo, and at the same time is able to induce migration, invasion, and epithelial–mesenchymal transition. These latter phenotypes are typically associated with cancer metastasis and progression, and thus BMP4 seems to elicit effects that are both detrimental and beneficial for the cancer cells. The functional effects of BMP4 are not restricted to the control of cell proliferation and mobility, since it also contributes to the regulation of differentiation, apoptosis, and angiogenesis. The latter is especially intriguing since the formation of new blood vessels is a prerequisite for sustained tumor growth and cancer progression. Mainly due to its growth suppressive abilities, BMP4 has been suggested as a possible therapeutic target in cancer cells. However, the other functional characteristics of BMP4, especially the promotion of cell mobility, make such strategies less appealing. Improved knowledge of the downstream mediators of BMP4 effects in cancer cells may allow dissection of the different BMP4-induced phenotypes and thereby generation of specific targeted therapies.

Section snippets

BMPs and their signaling pathways

The BMP family consists of over 20 members, some of which are called growth and differentiation factors (GDF) (15). The family members can be further classified into subgroups based on their amino acid sequence 1, 16. Like other members of the TGFβ superfamily, BMPs share a common structure (15). The precursor BMPs are 400–500 amino acids long and contain an N-terminal signal domain, a prodomain, and a C-terminal mature growth factor domain (16). All BMPs also share a cysteine knot motif

BMP4 as a developmental regulator

As mentioned previously, BMPs were originally identified based on their ability to induce bone and cartilage formation in extraskeletal tissues, and their importance in the regulation of embryonic development was only realized at a later time 6, 7. Bmp4 is essential for development since Bmp4 null mice embryos die between 6.5 and 9.5 days post-coitum (42). More detailed analyses of these embryos implicated that BMP4 contributes to several fundamental processes in early mouse development,

BMP4 in cancer predisposition

Germline mutations in the genes encoding key mediators of the BMP signaling pathway, SMAD4 and BMPR1A, are well-known to cause juvenile polyposis, an autosomal dominant syndrome with an increased risk of colorectal cancer (CRC) 53, 54. BMPR1A mutations are also associated with some cases of Cowden syndrome, which is characterized by an increased risk of thyroid, renal, and endometrial cancers (55). Recent evidence also implicates BMP4 in CRC predisposition. Three common variants (rs4444235,

BMP4 protein expression in human tumors

BMP4 expression levels have been evaluated both in cancer cell lines and tumor tissues of animal and human origin using a variety of methods. Focusing entirely on data from immunohistochemical analyses of human tumor tissues indicates that BMP4 protein is expressed in multiple tumor types, including melanoma, ovarian, gastric, basal cell, and renal cell carcinomas, as well as squamous cell carcinomas of the head and neck 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72. Increased BMP4 expression

The functional role of BMP4 in cancer cells in vitro

The contribution of BMP4 on various cancer-associated phenotypes, including cell growth, differentiation, migration, and invasion, have been most frequently evaluated in in vitro studies (Table 1). Most of these studies have utilized a simple approach where cells are treated with recombinant human BMP4 protein. The dose of BMP4 used (range 5–833 ng/mL) and the duration of exposure (from 48 hours to 2 weeks) has varied tremendously from one study to another and is likely to influence the data

BMP4 as a regulator of cancer cell growth

In the majority of tumor types, BMP4 elicits an inhibitory effect on cancer cell growth, but opposite or even conflicting results have also been reported (Table 1). For example, reduced cell growth after BMP4 treatment or overexpression was observed in cell lines derived from basal cell carcinomas, myeloma, breast, gastric, lung, and pancreatic cancers 61, 74, 76, 77, 78, 79, 80. In contrast, BMP4 manipulation had no effect on the growth of melanoma, colon cancer, hepatocellular cancer, ovarian

The role of BMP4 in differentiation and apoptosis

In addition to the effects on cell growth, BMP4 has also been linked to the differentiation of cancer cells (Table 1). In primary basal cell carcinoma cells, BMP4 treatment induced differentiation and the expression of keratinocyte differentiation markers (61). Similar induction of differentiation was also observed in glioblastoma, medulloblastoma, and colorectal cancer stem cells 68, 91, 93.

The impact of BMP4 on apoptosis in cancer cells has been evaluated in few tumor types (Table 1).

BMP4 in cell migration and invasion

Several studies (Table 1) have implicated BMP4 as an important regulator of cell migration and invasion as well as in the induction of the epithelial–mesenchymal transition (EMT), an event that is crucial for the ability of cancer cells to acquire mobility and eventually the ability to metastasize (98). The migration analyses have occasionally used wound healing measurements but typically relied on commercially available Boyden Chamber assays, where the capacity of the cells to pass through a

Studies of BMP4 in in vivo tumor formation

In the evaluation of the contribution of BMP4 to tumor formation in vivo, both direct alterations of BMP4 levels and indirect methods (i.e., manipulating various components of the BMP signaling pathway) have been used (Table 2). The first evidence on the role of BMP4 in in vivo tumorigenesis came from a study where expression of noggin or a dominant negative form of SMAD4 in mouse GH3 pituitary tumor cells led to reduced tumorigenicity in nude mice, thus implying that BMP4 promotes tumor

Other cancer-associated roles of BMP4

BMP4 has also been implicated in other processes that are critical for cancer development and progression, such as the angiogenesis (107). Although BMP4 was first implicated in apoptosis of the endothelial cells in the pupillary membrane in rats (108), the majority of the studies propose an opposite role. BMP4 promoted the proliferation and migration of mouse embryonic stem cell-derived endothelial cells and induced migration and tube formation of human microvascular endothelial cells 105, 109.

Molecular mechanisms of BMP4-induced growth regulation

As mentioned previously, inhibition of cell growth is the most commonly described consequence of induction of BMP4 signaling in cancer cells. A few studies have addressed the molecular mechanisms behind this growth suppression and have shown that BMP4 treatment typically induces senescence or G1-arrest of the cell cycle 77, 78, 79, 85, 94. These events have been linked to down-regulation of CCND1 expression 68, 94 and induction of p16 and/or p21 expression 78, 85, 111. All of these proteins are

BMP4 target genes in cancer cells

BMP target genes have been identified in many cell types, with the Id genes being the most well-known 24, 117, but only a few studies have addressed this issue in terms of BMP4 and cancer cells 81, 102, 118. A global expression survey in NTERA2 undifferentiated human cancer cells after 24-hour treatment with BMP4 resulted in over 1,300 differentially expressed genes, with about 70% of these having increased expression (81). As might be expected, similar analysis in cells treated with BMP4 for 8

Summary and conclusions

Bone morphogenetic proteins, including BMP4, are versatile signaling molecules that play an essential role during development and have now also been firmly connected to cancer pathogenesis. First of all, explicit evidence implicates BMP4 in genetic predisposition to colorectal cancer. On a functional level, BMP4 is involved in many cancer-related cellular activities, including the regulation of cell growth, migration, invasion, differentiation, apoptosis, and angiogenesis. At this point, the

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ReviewBone morphogenetic protein 4—a fascinating regulator of cancer cell behavior

Section snippets

BMPs and their signaling pathways

BMP4 as a developmental regulator

BMP4 in cancer predisposition

BMP4 protein expression in human tumors

The functional role of BMP4 in cancer cells in vitro

BMP4 as a regulator of cancer cell growth

The role of BMP4 in differentiation and apoptosis

BMP4 in cell migration and invasion

Studies of BMP4 in in vivo tumor formation

Other cancer-associated roles of BMP4

Molecular mechanisms of BMP4-induced growth regulation

BMP4 target genes in cancer cells

Summary and conclusions

Cytokine Growth Factor Rev

Cytokine Growth Factor Rev

Curr Opin Genet Dev

Cytokine Growth Factor Rev

FEBS Lett

Cell Signal

Kidney Int

J Biol Chem

Biochem Biophys Res Commun

Cell

Cell Signal

Cytokine Growth Factor Rev

Mol Cell Endocrinol

Curr Opin Cell Biol

Dev Biol

J Biol Chem

J Biol Chem

Kidney Int

Gene Expr Patterns

J Urol

Arch Med Res

Exp Cell Res

Blood

Am J Pathol

Exp Cell Res

Differentiation

Cancer Lett

Genetic analysis of the mammalian transforming growth factor-beta superfamily

Endocrine Rev

Novel regulators of bone formation: molecular clones and activities

Science

Overview of bone morphogenetic proteins

Spine

Bone morphogenetic proteins: multifunctional regulators of vertebrate development

Genes Dev

Consequences of knocking out BMP signaling in the mouse

Genesis

Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis?

Endocr Relat Cancer

Bone morphogenetic proteins and cancer: review of the literature

Neurosurgery

TGF-beta signaling in tumor suppression and cancer progression

Nat Genet

Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer

Nat Rev Cancer

TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility

Nat Rev Mol Cell Biol

Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily

Proc Natl Acad Sci U S A

Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases

J Cell Biol

Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo

Growth Factors

Bone morphogenetic protein receptors and signal transduction

J Biochem

Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction

Biol Chem

Specificity and versatility in tgf-beta signaling through Smads

Annu Rev Cell Dev Biol

Smad transcription factors

Genes Dev

Bone morphogenetic proteins and their antagonists

Rev Endocr Metab Disord

Regulation of cell proliferation by Smad proteins

J Cell Physiol

Review
Bone morphogenetic protein 4—a fascinating regulator of cancer cell behavior