prostate cancer is the second most common cancer among men and the second leading cause of cancer- related death in men in the united states .
most prostate cancers ( 93% ) are found when the disease is confined to the prostate and nearby organs , is indolent , and has a good prognosis .
however , the 5-year survival rate sharply declines from 90% for localized prostate cancer to 28% for metastatic prostate cancer .
in fact , homing of metastatic prostate cancer cells to bone tissue is associated with the presence and activity of osteoblast lineage cells .
the process of metastasis is known to be the result of several necessary sequential steps - including the survival of tumor cells at distant locations and adaption to the foreign microenvironment , thereby facilitating cell proliferation and the formation of a metastatic lesion .
the aggressive and highly metastatic capacity makes the treatment of advanced prostate cancer a major challenge .
the therapeutic options currently available ( local radiation , cytotoxics , vaccine therapy , and hormonal therapies ) are palliative and can not control disease progression . despite the clinical significance of bone metastatic prostate cancer ,
chemokines are a family of small ( 8 to 12 kda ) peptides that function as chemo - attractant cytokines that mediate and regulate cell activation , differentiation and trafficking .
chemokines are known to interact with a superfamily of 20 c - c or c - x - c trans - membrane domain heterotrimeric g protein - coupled receptors ( gpcr ) .
the stromal - derived factor 1 alpha ( sdf1 ) , also referred to as cxcl12 , binds and initiates signaling through its receptors c - x - c chemokine receptor type 4 ( cxcr4 ) and c - x - c chemokine receptor type 7 ( cxcr7 ) .
the sdf1/cxcr4 signaling has been recognized as a critical pathway for the homing and tissue retention of hematopoietic progenitor / stem cells in the bone marrow microenvironment .
several studies have shown that cxcr4 plays a crucial and pleiotropic role in malignant tumor progression , including prostate cancer , particularly in the metastatic spread of the disease .
high levels of the chemokine receptor cxcr4 induce a more aggressive phenotype in prostate cancer cells .
interestingly , the bone environment - in which sdf1 is particularly highly expressed - is also the most common metastatic site of prostate cancer . moreover , metastatic prostate cancer cells localized in the bone metastatic lesions express higher sdf1/cxcr4 levels relative to the cells present in primary tumors and lymph node metastatic lesions .
these findings suggest that the activation of the sdf1/cxcr4 pathway may play a pivotal role in prostate cancer bone metastases .
this review focuses primarily on the sdf1/cxcr4 axis regulation , on the pre - clinical observations made in bone metastatic prostate cancer metastases , and their implication for development of more effective treatment strategies in the future .
sdf1 signaling can be activated via cxcr4 in prostate cancer cells driven by the loss of phosphatase and tensin homolog ( pten ) and subsequent activation of pi3k / akt pathway .
moreover , silencing of cxcr4 can lead to a significant down - regulation in the secretion of vascular endothelial growth factor ( vegf ) and matrix metalloproteinase 9 ( mmp-9 ) , to a delay in primary tumor growth and to inhibition of the incidence of prostate cancer bone metastases .
sdf1 is also produced by the bone marrow stromal cells of mesenchymal origin , including osteoblasts , and by vascular endothelial cells .
sdf1a transiently regulates the number and affinity of v 3 receptors by prostate cancer cells , and increases the expression of the 3 subunit to enhance their metastatic behavior by increasing adhesiveness and invasiveness in bone marrow .
additionally , sdf1 induces the expression of cd164 and blockade of cd164 in prostate cancer cell lines decreases the ability of these cells to adhere to human bone marrow endothelial cells .
this suggests that activation and increased expression of cd164 and v 3 may be important in the metastatic spread of prostate cancer cells to the skeleton .
in addition , inhibition of cxcr4 activity alters the homing of quiescent prostate cancer cells to bone .
these cells have more potential to form bone metastases than rapidly proliferating prostate cancer cells .
higher levels of cxcr4 are associated with mitotic dormancy that facilitates tumor cell colonization of the bone marrow in prostate cancer .
these dormant or slow - cycling disseminated prostate cancer cells in bone marrow are more resistant to conventional therapies .
it was shown that these cells predominantly express transforming growth factor - beta 2 ( tgf-2 ) to maintain sdf1/cxcr4 overexpression .
several studies showed that metastatic prostate cancers recruit mesenchymal stem cells , which are converted into cancer - associated fibroblasts and facilitate metastasis . in prostate tumors ,
cxcl16 , a ligand for cxcr6 , stimulates the differentiation of mesenchymal stem cells into cancer - associated fibroblasts , which secrete higher levels of sdf1. sdf1 binds to cxcr4 on prostate cancer cells and induces an epithelial - to - mesenchymal transition ( emt ) .
inhibition of the sdf1/cxcr4 axis leads to suppression of the bone marrow mesenchymal stem cell - induced prostate cancer stem cell population increase , and to downregulation of the expression of mmp-9 , zeb-1 , cd133 and cxcr4 .
accumulating evidence suggests that activated hypoxia - inducible factors , hif-1 and hif-2 , may induce the expression of emt program - associated molecules , including snail , twist , cxcr4 and angiogenic factors such as vegf .
interestingly , in an osteosarcoma study , hypoxia - induced cxcr4 expression persisted even after cultured cells were returned to normoxic conditions , suggesting more persistent phenotypic changes . in summary ,
activation of the sdf1/cxcr4 pathway may play a critical role via multiple mechanisms : by promoting prostate tumor growth , homing of prostate cancer cells to bone , and facilitating interactions among cancer cells and bone environment ( fig .
sdf-1/cxcr4 axis activation in prostate cancer cells could be driven by oncogenic events ( e.g. , the loss of pten and subsequent activation of pi3k / akt pathway ) , or by microenvironmental factors ( e.g. , hypoxia , fibrosis , inflammation ) . when cxcr4 is inhibited , it could lead to inhibition of vegf and mmp-9 expression , a delay in tumor growth and reduction in metastasis .
sdf1 can induce cd164 expression in prostate cancer cells and there by increase their ability to adhere to human bone marrow endothelial cells . in bone metastases ,
cxcl16 ( a ligand for cxcr6 ) can stimulate the differentiation of mesenchymal stem / stromal cells ( mscs ) into cancer - associated fibroblasts ( cafs ) , which secrete high levels of sdf1. sdf1 could also be locally produced by osteoblasts .
sdf1 and cxcr4 overexpression could also be stimulated by tgf-2 , which is expressed by dormant disseminated prostate cancer cells in bone marrow .
finally , hypoxia - induced factor ( hif)-1a and hif-2a may induce the expression of epithelial - to mesenchymal - transition ( emt)-associated molecules snail and twist . in turn , inhibition of sdf-1 could lead to downregulation of the expression of mmp-9 , zeb-1 , cd133 and cxcr4 in bone metastatic prostate tumors .
as summarized above , a large amount of data strongly suggest a key role of the sdf1/cxcr4 pathway in bone metastases from prostate cancer patients . however , the evidence for the involvement of this pathway in other frequent bone metastatic cancers , such as breast cancer , is very limited .
same as in prostate cancer , high levels of cxcr4 expression in breast cancer are associated with early distant and bone metastases . in various bone metastatic breast models ,
sdf1 expression was regulated by cytokines such as interleukin ( il)-17a , il-6 , macrophage colony - stimulating factor ( m - csf ) , liver - enriched inhibitory protein ( lip ) , neuregulin 1 ( nrg1 ) , smad4 , hif-1 , bach1 and mmp-1 . since tumor - stroma interactions involving
the sdf1/cxcr4 are likely to be equally important in these settings , further understanding in this area may have important implications for understanding bone metastasis in general . moreover , this improved understanding could potentially allow the development of novel strategies to reduce morbidity and mortality in bone metastatic cancer patients .
the increasing evidence that sdf1/cxcr4 signaling may contribute to prostate cancer progression and relapse warrants studies of sdf1/cxcr4 inhibition to target both primary or metastatic lesions .
the most stu- died sdf1/cxcr4 inhibitor is the cxcr4 antagonist amd3100 , an fda - approved drug known as plerixafor or mozobil and used for hematopoietic stem cell mobilization by bolus injection .
amd3100 has been shown to inhibit primary tumor growth and decrease the incidence of metastases in multiple animal models .
however , the safety of chronic treatment with a chemokine receptor antagonist remains to be confirmed in patients , given the obvious concerns related to hematologic toxicities .
an alternative approach would be to inhibit the expression of sdf1/cxcr4 in primary and metastatic prostate cancers , without directly inhibiting cxcr4 signaling . in this respect
, it is critical to identify the mechanism by which cxcr4 expression is activated in prostate cancer bone metastases , in particular by hypoxia induced by tumor growth or by therapeutic interventions .
moreover , multiple molecular pathways are likely required to work in concert with the sdf1/cxcr4 pathway for the homing of metastatic prostate cancer cells to the bone .
many of the interactions among prostate cancer cells and the bone environment remain to be characterized .
finally , sustained responses in this disease , same as in other cancers , will most likely require the development of efficacious immunotherapies .
the currently available vaccine has only limited efficacy , and checkpoint inhibitors have failed so far to show promising efficacy in advanced prostate cancer patients . combining cxcr4 inhibition with checkpoint blockade , with or without radiation therapy , may be a potential strategy to achieve synergy .
once this improved understanding is achieved , preclinical and clinical studies should translate this knowledge into real benefits for bone metastatic prostate cancer patients .
 abstractmetastatic prostate cancer is one of the leading causes of cancer - related death in men . 
 the primary site of metastasis from prostate cancers is the bone . during the last decade , 
 multiple studies have pointed to the role of the stromal cell - derived factor 1 alpha ( sdf1)/cxcr4 axis in the metastatic spread of the disease , but the mechanisms that underlie this effect are still incompletely understood . in this review , 
 we summarize the current understanding of the role of the sdf1/cxcr4 pathway in bone metastatic prostate cancer . 
 we also discuss the therapeutic potential of disrupting the interaction between prostate tumor cells and bone environment with focus on the sdf1 pathway . 
Introduction
Role of chemokines in metastatic prostate cancer: the SDF1  pathway
The SDF1/CXCR4 axis: Role in bone metastatic prostate cancer
The SDF1/CXCR4 axis in bone metastasis: Beyond prostate cancer
SDFl and bone metastatic prostate cancer therapy: Future perspective