Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 Oct;9(10):862-70.
doi: 10.1593/neo.07559.

Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis

Otto Kollmar  1 , Kathrin Rupertus, Claudia Scheuer, Bastian Junker, Bettina Tilton, Martin K Schilling, Michael D Menger
Affiliations

Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis

Otto Kollmar et al. Neoplasia. 2007 Oct.

Abstract

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.

Conclusion: 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.

Keywords: Cancer; SDF-1; angiogenesis; chemokine; metastasis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
FACScan analysis of CT26.WT (A and C; white squares) and CT26.WT-GFP (B and D; black squares) cells demonstrating ∼ 30% positively stained cells for the chemokine receptor CXCR4 (C and D). Isotype-matched control antibody served as a negative control (A and B). Note that there is no difference in CXCR4 expression between GFP-transfected and nontransfected cells. The two cell lines showed comparable growth characteristics during the 7-day observation period (E). Data are expressed as mean ± SEM.
Figure 2
Figure 2
Cell migration assay consisting of a chemotaxis chamber and polyvinylpyrrolidone-coated polycarbonate filters with an 8-µm pore size. Note that only a few cells migrate under control conditions (control in A and B), whereas stimulation with a low dose (1 nM) of SDF-1 exerts the most pronounced increase in the fraction of migrated cells adhering to the lower surface of the filters (A). In contrast, analysis of cell migration to the lower wells (B) shows a dose-dependent increase after SDF-1 exposure. Data are expressed as mean ± SEM.
Figure 3
Figure 3
Time course of tumor growth in dorsal skinfold chambers after implantation of CT26.WT-GFP cells in BALB/c mice. Day 9 stereomicroscopy photomicrographs of representative tumors from mice that underwent, on day 0, local sham treatment (A) and exposure to 100 nM SDF-1 (B). Quantitative analysis of the tumor area over time (C) shows progressive tumor growth in both sham-treated controls (white circles) and animals that underwent SDF-1 treatment (black squares). Note, however, that tumor growth after SDF-1 application is significantly increased compared to PBS controls. Data are expressed as mean ± SEM. *P < .05 vs PBS control. (A and B) Original magnification, x4.
Figure 4
Figure 4
Time course of neovascularization and functional capillary density of CT26.WT-GFP tumors in dorsal skinfold chambers as determined by intravital fluorescence microscopy. Fluorescence microscopic images display the capillary network in the tumor margins of a control animal (A) and an SDF-1-treated animal (B) on day 4. Analysis of the onset of neovascularization, expressed as a score from 0 to 8, (C) in control tumors (white circles) and SDF-1-treated tumors (black squares) showed accelerated angiogenesis after SDF-1 treatment compared to PBS controls (C). Analysis of capillary density within the tumor margin confirms an acceleration of vascularization due to SDF-1 treatment, as indicated by an increased capillary density on day 4 after chemokine exposure (D). Data are expressed as mean ± SEM. *P < .05 vs PBS control. (A and B) Original magnification, x40.
Figure 5
Figure 5
Time course of capillary diameters of newly formed tumor vessels as determined by intravital fluorescence microscopy. Fluorescence microscopic images display the capillary network in the tumor center of a PBS control animal (A) and an SDF-1-treated animal (B) on day 9 after treatment induction. Quantitative analysis showed a significantly greater capillary diameter after SDF-1 exposure (black squares) when compared to PBS controls (white circles) (C). Data are expressed as mean ± SEM. *P < .05 vs PBS control. (A and B) Original magnification, x80.
Figure 6
Figure 6
PCNA (A and B) and cleaved caspase-3 (C and D) immunohistochemistry in CT26.WT-GFP tumors on day 9 after PBS (control; A and C) and SDF-1 treatment (SDF-1; B and D). Quantitative analysis of the number of PCNA-positive cells (expressed as a percentage of all cells) revealed significantly more positively stained cells in SDF-1-treated tumors when compared with tumors of controls (E). Analysis of cleaved caspase-3 expression (expressed as a percentage of all cells) showed a significantly reduced number of apoptotic cells after SDF-1 treatment when compared to PBS controls (F). Data are expressed as mean ± SEM. *P < .05 vs PBS control. (A–D) Original magnification, x175.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, Hess K, Curley SA. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239:818–825. - PMC - PubMed
    1. Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, Lillemoe KD, Yeo CJ, Cameron JL. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:759–766. - PMC - PubMed
    1. Yamamoto J, Shimada K, Kosuge T, Yamasaki S, Sakamoto M, Fukuda H. Factors influencing survival of patients undergoing hepatectomy for colorectal metastases. Br J Surg. 1999;86:332–337. - PubMed
    1. Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin. 1999;49:231–255. - PubMed
    1. Elias D, Liberale G, Vernerey D, Pocard M, Ducreux M, Boige V, Malka D, Pignon JP, Lasser P. Hepatic and extrahepatic colorectal metastases: when resectable, their localization does not matter, but their total number has a prognostic effect. Ann Surg Oncol. 2005;12:900–909. - PubMed

Publication types

MeSH terms