Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis.
In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cell-derived factor (SDF) 1 stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo.


METHODS
Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis and tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, and growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, and immunohistochemistry. Tumors exposed to PBS only served as controls.


RESULTS
In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization and induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen and a downregulation of cleaved caspase-3.


CONCLUSIONS
Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro and tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation and inhibition of apoptotic cell death.
Kollmar
Otto
O
Department of General, Visceral, Vascular, and Pediatric Surgery, University of Saarland, D-66421 Homburg/Saar, Germany. otto.kollmar@uniklinikum-saarland.de
Rupertus
Kathrin
K
Scheuer
Claudia
C
Junker
Bastian
B
Tilton
Bettina
B
Schilling
Martin K
MK
Menger
Michael D
MD
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism
D054377:Chemokine CXCL12; D018809:Proliferating Cell Nuclear Antigen; D019718:Receptors, CXCR4