Molecular alterations that drive breast cancer metastasis to bone

Abstract

Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis.

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

“…79,91,119 On a larger scale, physical features of the bone marrow microenvironment, including acidic pH, high extracellular calcium concentrations, and adjacent sinusoidal blood vessels, also enhance bone colonization by tumour cells (as they do for HSCs) and contribute to the vicious cycle, as described previously. 91,120 Hypoxia has been implicated both in the induction of tumour quiescence 74 and in egress of tumour cells from the marrow; 121 these effects, often driven by HIF signalling, are also seen in HSCs. 121–123 As described above, hypoxia is a characteristic of the bone marrow, but whether the HSC niche (or tumour-homing niche) is always or necessarily hypoxic is still contentious, as HSCs and tumour cells are often found in close proximity to blood vessels.…”

“…88,89 TGF-β (through Smad pathway signalling), hypoxia (through HIF-1α), and extracellular calcium (through Akt and MAPK pathways) alter gene expression within tumour cells in the bone microenvironment, enabling the survival and growth of these cells in the marrow cavity. 88,90,91 Many osteolytic tumour cells produce PTHrP, TGF-β, dickkopf-1, sclerostin, and RANKL; moreover, osteoblastic tumours often secrete bone morphogenic proteins and other growth factors (such as fibroblast growth factors and Wnt family members), but many of the mechanisms of osteoblastic lesion development remain undetermined. 92 Metabolic changes in tumour cells induced by their local microenvironment are also now recognized as important contributors to tumour growth and potential therapeutic targets.…”

“…113 Rather than central marrow, the endosteum seems to be the preferential site for HSCs and tumour cells. 114 Ligand–receptor interactions of adhesion molecules, such as SDF1–CXCR4, 115 integrin α-4–VCAM-1, CD44–osteopontin, and integrin α v β 3 –bone sialoprotein, 116 are important in the homing of HSCs and tumour cells to bone. 117 Calcium receptors also have a role in the niche-homing of HSCs and in the homing and proliferation of cancer cells.…”

Establishment and characterization of highly osteolytic luminal breast cancer cell lines by intracaudal arterial injection

“…Bone generation and homeostasis are mainly operated by osteoclasts and osteoblasts (Bonnans, Chou, & Werb, ); RANKL expressed by cancer cells also promotes osteoclast differentiation and osteolytic bone metastasis in MDA‐MB‐231 metastasis models (Blake, Tometsko, Miller, Jones, & Dougall, ; Liu, Zhang, et al, ; Ottewell, O’Donnell, & Holen, ; Owen, Ye, Sanders, Mason, & Jiang, ). Our microarray analysis, however, showed that RANKL was not up‐regulated in MCF7‐BM cell lines.…”

Cancer Cell Colonisation in the Bone Microenvironment

“…Gene expression analysis showed increased RANKL and DKK-1 and decreased OPG; this was accompanied by increased MMP-9 and cathepsin K activity, suggesting increased bone resorption through elevated osteoclast activity [85]. This was proposed to be due to the stimulation of the mesenchymal stem cell niche and thereby promote DTC proliferation [86]. Similar to the breast cancer model, castration in mouse models of prostate cancer resulted in osteoclastic bone resorption, which increased bone metastasis [87].…”