Dysregulation of developmental pathways in bone metastasis

Abstract

It is well-known that pathways normally functioning during embryonic development are dysregulated in cancer. Experimental and clinical studies have established strong connections between aberrant developmental pathways and transformation, as well as other early stage events of cancer progression. There is now emerging evidence that also indicates the contribution of developmental pathways to the pathogenesis of distant metastasis, including bone metastasis. In particular, the Wnt, BMP, and Hedgehog signaling pathways have all been implicated in the development of bone metastasis. These developmental pathways participate in the regulation of cell-autonomous functions in tumor cells as well as tumor–stromal interactions in the bone microenvironment, eventually promoting the formation of osteolytic or osteoblastic bone metastasis.

Introduction

Bone metastasis is a devastating and frequent complication of several malignancies, especially advanced stages of breast and prostate adenocarcinoma, both of which are the most prevalent cancers in women and men, respectively [1]. Metastatic tumors of the bone are directly responsible for debilitating bone fractures, severe pain, nerve compression, and hypercalcemia [2]. The development and outgrowth of these secondary lesions depends on the intricate cellular and molecular interactions between tumor cells and stromal cells of the bone microenvironment. The two main functional bone cells that participate in this crosstalk are osteoblasts, the cells responsible for producing new bone matrix, and osteoclasts, the cells responsible for breaking down the bone matrix. In the absence of metastatic tumor cells, the coordinated activity of these two cell types supports a homeostatic bone microenvironment. In fact, there is a strong interdependence between osteoblasts and osteoclasts, often mediated by the paracrine bone cytokine receptor activator of nuclear factor-κB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). RANKL is an essential osteoclast differentiation cytokine that binds to its receptor RANK on the surface of osteoclasts, stimulating their maturation via NF-κB signaling; OPG competitively binds to RANKL and prevents it from activating osteoclasts. The balanced production of these two factors by osteoblasts regulates osteoclast activity and as a result maintains an appropriate level of bone formation and resorption. The ability of tumor cells to disrupt the balance of bone homeostasis maintained by osteoblasts and osteoclasts has been shown to drive bone destruction and metastatic tumor progression [2], [3], [4].

Bone metastatic tumor cells compromise bone homeostasis by directly producing factors and/or by indirectly affecting the production of factors in the local bone microenvironment. When prostate cancer cells metastasize to the bone, they secrete factors that promote osteoblast differentiation and therefore stimulate bone-forming secondary lesions [5]. In fact, 90% of prostate cancer bone metastases are osteosclerotic, manifesting as lesions with an increased bone mineral density [6]. In contrast, metastatic breast cancer cells often tip the bone homeostatic balance in favor of osteoclast maturation and activity, leading to predominantly osteolytic bone lesions. They accomplish this by secreting signaling proteins, such as parathyroid hormone-related peptide (PTHrP), Interleukin-6, Interleukin-11, and EGF-like growth factors, to promote osteoclast differentiation and activity, often indirectly through altering osteoblast production of RANKL and its antagonist OPG [2], [3], [4], [7], [8]. The resultant bone destruction releases a number of growth factors sequestered in the bone matrix, such as transforming growth factor-β (TGFβ), insulin-growth factor (IGF) and fibroblast growth factor (FGF), which can then feedback onto the tumor cells, further stimulating their malignancy. The positive feedback mechanism propagated by tumor–stromal interactions in the bone microenvironment is referred to as the “vicious cycle” of bone metastasis. Although several molecular contributors of bone metastasis have been identified, effective therapies still await a more comprehensive understanding of the complex molecular and cellular network of tumor–stromal interactions in bone metastasis.

Developmental signaling pathways are charged with the essential duty of directing the coordinated activity of several cellular and tissue processes during embryonic development. The temporal and spatial specificity of these signaling pathways ensures the proper development of distinct tissues and organs. We are now aware that aberrant activation of these pathways can also contribute to the pathogenesis of cancer. The Notch, Wnt, BMP, TGFβ, and Hedgehog pathways have all been shown to promote the tumorigenesis of several malignancies. There is also evidence supporting a role for these pathways in the regulation of normal and cancer stem cells and pathogenic transition of epithelial tumor cells into more invasive mesenchymal ones. Beyond their contribution to early stage events in cancer progression, developmental signaling pathways are now being implicated in the pathogenesis of distant metastasis, including bone metastasis. This review will cover the recent evidence supporting a role for the Wnt, BMP, and Hedgehog pathways in bone metastasis.