Epidermal growth factor signalling and bone metastasis

Abstract

Epidermal growth factor (EGF) signalling is well known for its multifaceted functions in development and tissue homoeostasis. The EGF family of ligands and receptors (ERBB family) have also been extensively investigated for their roles in promoting tumourigenesis and metastasis in a variety of cancer types. Recent findings indicate that EGF signalling is an important mediator of bone metastasis in breast, prostate and kidney cancers. The EGF signalling stimulates the growth of bone metastasis directly by increasing tumour cell proliferation and indirectly by engaging bone stromal cell in metastasis-promoting activities. Therefore, molecular targeting of ERBB receptors may benefit patients with bone metastasis and should be evaluated in clinical trials.

Figure 1

Multifunctional role of epidermal growth factor (EGF) signalling in bone development and metastasis. (A) In healthy bone, a proper level of osteoclast differentiation is ensured by a balance of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) expression by osteoblasts and stromal cells. (B) During bone development, EGF-like ligands secreted by bone cells promotes the proliferation of osteoblast progenitors. (C) The EGF-like ligands secreted by bone cells inhibit differentiation of osteoblast progenitors. (D) Osteolytic tumour cells (e.g. breast cancer) express cytokines that regulate the expression of RANKL or OPG in osteoblasts, and ultimately activate osteoclasts and bone resorption. (E) Bone resorption releases growth factors and Ca²⁺ to promote tumour growth and more bone osteolysis. Continuous processes of D and E constitute the ‘vicious cycle’. (F) Osteoblastic tumour cells (e.g. prostate cancer) secret cytokines that activate osteoblast proliferation. (G) Overexpression of metalloproteinases, such as matrix metalloproteinase 1 (MMP1) and a disintegrin-like and metalloprotease with thrombospondin 1 (ADAMTS1), in metastatic tumour cells mediate ectodomain shedding of EGF-like ligands. (H) The soluble EGF-like ligands can promote tumour cell proliferation through an autocrine loop. (I) The soluble EGF-like ligands inhibit OPG expression from osteoblasts and tip the RANKL/OPG balance towards osteoclastogenesis. Whether EGF-like ligands from tumour cells can influence osteoblast progenitor proliferation (B) and differentiation (C) is unknown. CTGF, connective tissue growth factor.