Abstract
Bone metastasis is the terminal stage disease of prostate, breast, renal, and lung cancers, and currently no therapeutic approach effectively cures or prevents its progression to bone metastasis. One of the hurdles to the development of new drugs for bone metastasis is the complexity and heterogeneity of the cellular components in the metastatic bone microenvironment. For example, bone cells, including osteoblasts, osteoclasts, and osteocytes, and the bone marrow cells of diverse hematopoietic lineages interact with each other via numerous cytokines and receptors. c-Met tyrosine kinase receptor and its sole ligand hepatocyte growth factor (HGF) are enriched in the bone microenvironment, and their expression correlates with the progression of bone metastasis. However, no drugs or antibodies targeting the c-Met/HGF signaling axis are currently available in bone metastatic patients. This significant discrepancy should be overcome by further investigation of the roles and regulation of c-Met and HGF in the metastatic bone microenvironment. This review paper summarizes the key findings of c-Met and HGF in the development of novel therapeutic approaches for bone metastasis.
Highlights
Bone metastasis is uniquely positioned in cancer research because of its diverse cellular populations comprising the metastatic microenvironment
Inhibitors of chemokines and chemokine receptors, such as anti-C-C chemokine ligand 2 antibodies, have been tested for prostate cancer bone metastasis [13,14]. None of these drugs or antibodies resulted in significant benefits during clinical trials in patients with bone metastasis, suggesting that the signaling pathways in the metastatic bone microenvironment are extremely heterogeneous and complex and that no single target can effectively stop progression of the disease
This review will summarize the new findings on the roles of hepatocyte growth factor (HGF) and c-Met receptor tyrosine kinase in the progression of bone metastasis
Summary
Bone metastasis is uniquely positioned in cancer research because of its diverse cellular populations comprising the metastatic microenvironment. Anti-resorptives such as bisphosphonates and denosumab are used to delay or prevent the skeletal-related events (SREs), yet have not been proven to show significant overall survival benefits [4] This conflict between important unmet clinical needs and the absence of effective therapeutic approaches is mostly due to the complexity in the signaling pathways among the diverse stromal cell types in the metastatic bone microenvironment [5]. Inhibitors of Wnt antagonists, such as anti-Sclerostin and anti-Dickkopf-related protein 1 (DKK1), have been investigated in the context of bone metastasis Tyrosine kinases, such as Src family kinases, platelet-derived growth factor receptor (PDGFR), and c-Kit, have previously been highlighted as promising therapeutic targets in cancer-induced osteolysis and metastatic tumor growth in bone [9,10,11,12]. This review will summarize the new findings on the roles of hepatocyte growth factor (HGF) and c-Met receptor tyrosine kinase in the progression of bone metastasis
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