Determinants of bone specific metastasis in prostate cancer
Introduction
As for any type of metastasis, bone-metastatic tumor cells retain specific properties that make them specifically fit only for the establishment of skeletal metastasis (Croucher et al., 2016). Although most patient with metastatic prostate cancer (PCa) will develop bone metastases, visceral metastasis occur in up to 15% of patients with PCa and, depending on the series, roughly 5% of PCa patients will develop only visceral metastasis (Gandaglia et al., 2015).
The metastatic process occurs through different steps (Massague and Obenauf, 2016). Each of these steps is potentially detectable and useful in a clinical setting. Prediction of bone metastasis might help change the clinical approach as for prevention and treatment is concerned. Patients at high risk for bone metastasis would likely benefit more from adjuvant androgen deprivation therapy or from bone targeted therapy to prevent or delay bone metastasis, and could be monitored proportionally to their clinical risk, allowing an optimization of disease follow up (Briganti et al., 2014).
The pathophysiology of bone metastasis formation is still far to be fully understood but is increasingly being elucidated by different experimental models and clinical evidences. Here we aim to review all those factors that demonstrated to predict bone metastasis occurrence in PCa patients.
Section snippets
CTCs and DTCs
The metastatic process, in order to occur, needs some cancerous cells from the primary tumor to acquire the capability of enter and survive in the systemic circulation. A minority of these circulating tumor cells (CTCs) can extravasate to other site and enter a quiescent status: these dormant cells are referred to as disseminated tumor cells (DTCs). Eventually these dormant cells can start proliferate and – even years after their establishment – form new metastasis (Massague and Obenauf, 2016).
Bone turnover markers
Bone turnover markers (BTMs) are biochemical products whose level in peripheral blood reflects the metabolism of the bone. Since any bone metastatic cancer determines changes in bone metabolism it has been postulated that BTMs might somehow be exploited in order to figure out bone metastasis presence and progression in different cancer subtypes. BTMs include markers of bone formation (P1NP, P1CP, bALP and OC) and markers of bone resorption (OP, NTX-I, CTX-I and BSP) (Ferreira et al., 2015) (
RANK/RANKL/OPG
It is well-established that the pathway of receptor activator of NF-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) is crucial for the formation of bone metastasis and this is particularly true for PCa (Chu and Chung, 2014). In a preclinical setting the activity of RANKL in PCa has shown to drive epithelial to mesenchymal transition (EMT) in vitro and to enhance aggressiveness of PCa cell lines in vivo (Odero-Marah et al., 2008); similarly in PCa cell lines exogenous RANKL was shown to
miRNAs
The relatively recent discovery of microRNAs (miRNAs) release by tumor cells led to great efforts in trying to define their possible clinical role in different settings (Endzelins et al., 2016).
Josson et al. found that cancer associated fibroblast could promote PCa cells EMT through a extracellular vescicle-mediated transfer of miR-409 and, in fact, cancer associated fibroblast from PCa patients have higher expression of miR-409 compared to healthy tissue fibroblast (Josson et al., 2015).
Exosomes
Tumor derived exosomes affect metastasis development in several ways (Zhang and Grizzle, 2014). Exosome can modify the metastatic niche prior to the arrival of tumor: when bone marrow coming from mice treated with exosome deriving from different melanoma cell lines was transplanted in a new mouse, the latter mouse was more prone to bone metastasis formation compared to a negative control mouse (Peinado et al., 2012). Single cells can modify the phenotype of withstanding cancerous and
Others
The analysis of genomic signature has been investigated in different settings. The Decipher score is a risk score obtained from the expression of 22 different genes linked to PCa aggressiveness; this score, calculated from surgical samples of patients with localized PCa underwent radical prostatectomy, is effective in predicting biochemical relapse, metastasis occurrence (Ross et al., 2016) and cancer specific mortality (Cooperberg et al., 2015). A higher Decipher score is correlated to a
Conclusions
The issue of bone metastasis prediction has been addressed by several authors. Although the identification of different types of markers, the clinical practice still relies on “classical” markers of PCa progression in order to predict bone metastasis recurrence (such as PSA, Gleason score and pTNM). We suggest that future studies conducted on bone targeted therapies should evaluate outcomes depending on baseline patients characteristics different from classical markers of disease relapse;
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