Altered CXCL12 expression reveals a dual role of CXCR4 in osteosarcoma primary tumor growth and metastasis.
OBJECTIVE
Better understanding of the molecular mechanisms of metastasis-the major cause of death in osteosarcoma (OS)-is a key for the development of more effective metastasis-suppressive therapy. Here, we investigated the biological relevance of the CXCL12/CXCR4 axis in OS.


METHODS
We interfered with CXCL12/CXCR4 signaling in CXCR4-expressing human 143-B OS cells through stable expression of CXCL12, of its competitive antagonist P2G, or of CXCL12-KDEL, designed to retain CXCR4 within the cell. Intratibial OS xenograft mouse model metastasizing to the lung was used to assess tumorigenic and metastatic potential of the manipulated cell lines.


RESULTS
Constitutive expression of native CXCL12 promoted lung metastasis without affecting tumor growth. Stable expression of P2G or CXCL12-KDEL significantly accelerated tumor growth but diminished lung metastasis. Tumors grown from P2G- or CXCL12-KDEL-expressing cells contained higher levels of CXCR4-encoding mRNA going along with a higher percentage of CXCR4-expressing tumor cells. Lung metastases of all groups were predominantly enriched with CXCR4-expressing tumor cells.


CONCLUSIONS
Higher abundance of CXCR4 possibly contributed to increased local retention of tumor cells by bone marrow-derived CXCL12, reflected in the increased primary tumor growth and decreased number of lung metastases in P2G and CXCL12-KDEL groups. Higher percentage of CXCR4-expressing lung metastatic cells compared to the corresponding primary tumors point to important functions of the CXCL12/CXCR4 axis in late steps of metastasis. In conclusion, based on the here reported results, local treatment of lung metastases with novel CXCR4-targeting therapeutics might be considered and favored over anti-CXCR4 systemic therapy.
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Olga
O
Neklyudova
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Matthias J E
MJ
Arlt
Alpinia Institute, Walenstadt, Switzerland.
Patrick
P
Brennecke
Institute for Research in Biomedicine, Università Della Svizzera Italiana, Bellinzona, Switzerland.
Marcus
M
Thelen
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Ana
A
Gvozdenovic
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Aleksandar
A
Kuzmanov
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Bernhard
B
Robl
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Sander M
SM
Botter
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.
Walter
W
Born
Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. research@balgrist.ch.
Bruno
B
Fuchs
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4
CXCL12; CXCR4; Metastasis; Mouse model; Osteosarcoma