Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Bone metastasis, which usually accompanies severe skeletal-related events, is the most common site for tumor distant dissemination and detected in more than one-third of patients with advanced lung cancer. Biopsy and imaging play critical roles in the diagnosis of bone metastasis; however, these approaches are characterized by evident limitations. Recently, studies regarding potential biomarkers in the serum, urine, and tumor tissue, were performed to predict the bone metastases and prognosis in patients with lung cancer. In this review, we summarize the findings of recent clinical research studies on biomarkers detected in samples obtained from patients with lung cancer bone metastasis. These markers include the following: (1) bone resorption-associated markers, such as N-terminal telopeptide (NTx)/C-terminal telopeptide (CTx), C-terminal telopeptide of type I collagen (CTx-I), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), pyridinoline (PYD), and parathyroid hormone related peptide (PTHrP); (2) bone formation-associated markers, including total serum alkaline phosphatase (ALP)/bone specific alkaline phosphatase(BAP), osteopontin (OP), osteocalcin (OS), amino-terminal extension propeptide of type I procollagen/carboxy-terminal extension propeptide of type I procollagen (PICP/PINP); (3) signaling markers, including epidermal growth factor receptor/Kirsten rat sarcoma/anaplastic lymphoma kinase (EGFR/KRAS/ALK), receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin (RANKL/RANK/OPG), C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 (CXCL12/CXCR4), complement component 5a receptor (C5AR); and (4) other potential markers, such as calcium sensing receptor (CASR), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2), cytokeratin 19 fragment/carcinoembryonic antigen (CYFRA/CEA), tissue factor, cell-free DNA, long non-coding RNA, and microRNA. The prognostic value of these markers is also investigated. Furthermore, we listed some clinical trials targeting hotspot biomarkers in advanced lung cancer referring for their therapeutic effects.
Highlights
Lung cancer, comprising non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), is the leading cause of cancerrelated death worldwide, with approximately 1.6 million deaths reported annually [1]
It is widely acknowledged that adenocarcinoma, pathological stage III disease, and advanced age are significantly related to a high risk of bone metastasis [12,13,14]
We summarize the findings of recent clinical research studies on markers detected in samples obtained from patients with lung cancer, and analyze their capacity for the prediction of treatment response and prognosis of bone metastasis
Summary
Lung cancer, comprising non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), is the leading cause of cancerrelated death worldwide, with approximately 1.6 million deaths reported annually [1]. ADAM17, ADAM metallopeptidase domain 17; ALK, anaplastic lymphoma kinase; bmSUVmax, maximum standardized uptake value in bone metastasis; C5A, complement component 5a; C5AR, complement component 5a receptor; CXCL12, C-X-C motif chemokine ligand 12; CXCR4, C-X-C motif chemokine receptor 4; EGFR, epidermal growth factor receptor; F-FDG PET/CT, fluorodeoxyglucose positron emission tomography/computed tomography; KRAS, Kirsten rat sarcoma; mEGFR, EGFR mutation; NSCLC, non-small-cell lung cancer; OPG, osteoprotegerin; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; TRACP-5b, tartrate-resistant acid phosphatase isoform-5b; RANK, receptor activator of nuclear factor kB; RANKL, receptor activator of nuclear factor kB ligand; VCAM1, vascular cell adhesion molecule 1. NOTCH3, a transmembrane receptor and a member of the Notch signaling pathway, plays an essential role in the development of lung cancer [158] It is overexpressed in approximately 40% of NSCLCs and has been associated with poorer disease-free survival and OS, higher TNM stage, poorer response to chemotherapy, and an increased rate of lymph node metastasis. Studies utilizing high-throughput transcriptome analysis (RNA sequencing) indicated that lncRNA, including metastasis associated
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