Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo.
To delineate the role of SDF-1 and CXCR4 in metastatic prostate cancer (CaP), positive correlations were established between SDF-1 levels and tumor metastasis. Neutralization of CXCR4 limited the number and the growth of intraosseous metastasis in vivo. Together, these in vivo metastasis data provide critical support that SDF-1/CXCR4 plays a role in skeletal metastasis.


BACKGROUND
Previously we determined that the stromal-derived factor-1 (SDF-1)/CXCR4 chemokine axis is activated in prostate cancer (CaP) metastasis to bone. To delineate the role of SDF-1/CXCR4 in CaP, we evaluated SDF-1 levels in a variety of tissues and whether neutralization of SDF-1 prevented metastasis and/or intraosseous growth of CaPs.


METHODS
SDF-1 levels were established in various mouse tissues by ELISA, immunohistochemistry, and in situ hybridization. To assess the role of SDF-1/CXCR4 in metastasis, bone metastases were established by administering CaP cells into the left cardiac ventricle of nude animals in the presence or absence of neutralizing CXCR4 antibody. The effect of SDF-1 on intraosseous growth of CaP cells was determined using intratibial injections and anti-CXCR4 antibodies and peptides.


RESULTS
There was a positive correlation between the levels of SDF-1 and tissues in which metastatic CaP lesions were observed. SDF-1 levels were highest in the pelvis, tibia, femur, liver, and adrenal/kidneys compared with the lungs, tongue, and eye, suggesting a selective effect. SDF-1 staining was generally low or undetectable in the center of the marrow and in the diaphysis. SDF-1 mRNA was localized to the metaphysis of the long bones nearest to the growth plate where intense expression was observed near the endosteal surfaces covered by osteoblastic and lining cells. Antibody to CXCR4 significantly reduced the total metastatic load compared with IgG control-treated animals. Direct intratibial injection of tumor cells followed by neutralizing CXCR4 antibody or a specific peptide that blocks CXCR4 also decreased the size of the tumors compared with controls.


CONCLUSIONS
These data provide critical support for a role of SDF-1/CXCR4 in skeletal metastasis. Importantly, these data show that SDF-1/CXCR4 participate in localizing tumors to the bone marrow for prostate cancer.
Sun
Yan-Xi
YX
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA.
Schneider
Abraham
A
Jung
Younghun
Y
Wang
Jianhua
J
Dai
Jinlu
J
Wang
Jingcheng
J
Cook
Kevin
K
Osman
Nadir I
NI
Koh-Paige
Amy J
AJ
Shim
Hyusuk
H
Pienta
Kenneth J
KJ
Keller
Evan T
ET
McCauley
Laurie K
LK
Taichman
Russell S
RS
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000502:physiology*; D014018:Tissue Distribution
D000596:Amino Acids; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010455:Peptides; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C015484:pyridinoline; D002118:Calcium