The role of biomarkers in the management of bone-homing malignancies

Abstract

Bone represents a common site of metastasis from several solid tumours, including breast, prostate and lung malignancies. The onset of bone metastases (BM) is associated not only with serious skeletal complications, but also shortened overall survival, owing to the lack of curative treatment options for late-stage cancer. Despite the diagnostic advances, BM detection often occurs in the symptomatic stage, underlining the need for novel strategies aimed at the early identification of high-risk patients. To this purpose, both bone turnover and tumour-derived markers are being investigated for their potential diagnostic, prognostic and predictive roles. In this review, we summarize the pathogenesis of BM in breast, prostate and lung tumours, while exploring the current research focused on the identification and clinical validation of BM biomarkers.

Keywords: 1CTP, cross-linked carboxy-terminal telopeptide of type 1 collagen; BALP, bone specific alkaline phosphatase; BC, breast cancer; BM, bone metastases; BMDC, bone marrow derived cells; BMPs, bone morphogenetic proteins; BSP, bone sialoprotein; BTA, bone-targeting agents; BTM, bone turnover markers; Biomarkers; Bone metastasis; Bone turnover markers; Breast cancer; CAPG, macrophage-capping protein; CCL2, chemokine C-C ligand 2; CTC, circulating tumour cells; CXCL, C–X–C motif chemokine ligand; CXCR, C–X–C motif chemokine receptor; CaSR, calcium sensing receptor; DPD, deoxypyridinoline; DTC, disseminated tumour cells; EMT, epithelial to mesenchymal transition; ER, estrogen receptor; FGF, fibroblast growth factor; GIPC1, PDZ domain–containing protein member 1; HR, hormone receptor; Her2, human epidermal growth factor receptor 2; IGF, insulin-like growth factor; IL, interleukin; IL-1R, IL-1 receptor; LC, lung cancer; Lung cancer; M-CSF, macrophage colony stimulating factor; MAF, v-maf avian musculo-aponeurotic fibrosarcoma oncogene homolog; NSCLC, non-small cell LC; NTX and CTX, N- and C- telopeptides of type 1 collagen; OPG, osteoprotegerin; P1NP and P1CP, N and C terminal pro-peptides of type 1 collagen; PC, prostate cancer; PDGF, platelet-derived growth factor; PDGFRα, PDGF receptor α; PSA, prostate specific antigen; PTH, parathyroid hormone; PTH-rP, PTH related protein; PYD, pyridinoline; PlGF, placental growth factor; Prostate cancer; RANK, receptor activator of nuclear factor kB; RANK-L, RANK-ligand; SDF-1, stromal cell-derived factor 1; SREs, skeletal related events; TGF-β, transforming growth factor-β; TNF, tumour necrosis factor; TRACP-5b, tartrate-resistant acid phosphatase type 5b; TRAF3, TNF receptor associated factor 3; VEGF, vascular endothelial growth factor; ZNF217, zinc-finger protein 217; miRNA, micro RNA; sBALP, serum BALP; shRNA, short hairpin RNA; uNTX, urinary NTX; β-CTX, CTX β isomer.

Fig. 1

Physiological bone turnover. Bone turnover physiologically results from the opposite activities of osteoclasts and osteoblasts. The former derive from the monocyte/macrophage lineage and exert a bone resorptive function, through the secretion of H⁺ ions and enzymes, such as TRACP-5b. Osteoclastogenesis is enhanced by pro-osteoclastogenic cytokines (e.g. M-CSF, IL-6, IL-1). During bone erosion, type 1 collagen undergoes proteolytic cleavage which results in the release of degradation peptides (NTX, CTX, PYD, DPD), that are measurable in blood and urine. Conversely, osteoblasts have a mesenchymal origin and are deputed to osteogenesis. In particular, they synthesize pro-collagen whose cleavage at N- and C-terminals produces type 1 collagen, P1NP and P1CP peptides. Osteoblasts secrete also BALP which is necessary for the mineralization of bone matrix. Some osteoblasts become osteocytes, namely dendritic cells acting as mechano-transducers. Bone turnover is regulated by the RANK-L/RANK/OPG axis. Indeed, osteoblasts and stromal cells release RANK-L that, by binding its receptor RANK expressed by pre-osteoclasts, promotes their differentiation in osteoclasts. OPG partially inhibits this process, in order to prevent excessive bone resorption. Similarly, sex hormones exert a predominant anabolic effect. Adapted from D’Oronzo et al. 2015 . Abbreviations: bone alkaline phosphatase (BALP), C-terminal fragment (CTX), deoxypyridinoline (DPD), interleukin-1 (IL-1), interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), N-terminal fragment (NTX), osteoprotegerin (OPG). pro-collagen type 1 C-terminal propeptide (P1CP), pro-collagen type 1 N-terminal propeptide (P1NP), pyridinoline (PYD), receptor activator of nuclear factor kB (RANK), receptor activator of nuclear factor kB-ligand (RANK-L), tartrate-resistant acid phosphatase type 5b (TRACP-5b).

Fig. 2

Establishment of osteolytic bone metastases. The onset of bone metastases is driven by the primary tumour through the recruitment of bone marrow derived cells. The latter promote the creation of a “pre-metastatic niche” by remodeling the extracellular matrix, exerting immune suppressive function and enhancing vascular permeability. Thanks to the up-regulation of specific chemokine receptors, some cancer cells migrate towards the bone niche, where they are able to survive for long periods in a quiescent state, until local and systemic conditions become suitable for the metastasis outgrowth. Thus, cancer cells alter the physiological bone turnover by releasing CKs that promote osteoclastogenesis and bone erosion. This phenomenon frees bone matrix-stored GFs which in turn promote cancer cell proliferation and perpetuate this vicious cycle. Adapted from D’Oronzo et al., 2017 . Abbreviations: growth factors (GFs), cytokines (CKs).