CXCR4 regulates the early extravasation of metastatic tumor cells in vivo
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CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. / Gassmann, Peter; Haier, Jörg; Schlüter, Kerstin; Domikowsky, Britta; Wendel, Claudia; Wiesner, Ulrike; Kubitza, Robert; Engers, Rainer; Schneider, Stephan W; Homey, Bernhard; Müller, Anja.
In: NEOPLASIA, Vol. 11, No. 7, 07.2009, p. 651-61.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CXCR4 regulates the early extravasation of metastatic tumor cells in vivo
AU - Gassmann, Peter
AU - Haier, Jörg
AU - Schlüter, Kerstin
AU - Domikowsky, Britta
AU - Wendel, Claudia
AU - Wiesner, Ulrike
AU - Kubitza, Robert
AU - Engers, Rainer
AU - Schneider, Stephan W
AU - Homey, Bernhard
AU - Müller, Anja
PY - 2009/7
Y1 - 2009/7
N2 - Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3% vs anti-CXCR4: 6.0% +/- 5.0%, P < .001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.
AB - Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3% vs anti-CXCR4: 6.0% +/- 5.0%, P < .001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.
KW - Cell Adhesion
KW - Cell Line, Tumor
KW - Chemokine CXCL12
KW - Colorectal Neoplasms
KW - Flow Cytometry
KW - Humans
KW - Immunohistochemistry
KW - Liver Neoplasms
KW - Microscopy, Fluorescence
KW - Neoplasm Invasiveness
KW - Neoplasm Metastasis
KW - Receptors, CXCR4
KW - Reverse Transcriptase Polymerase Chain Reaction
M3 - SCORING: Journal article
C2 - 19568410
VL - 11
SP - 651
EP - 661
JO - NEOPLASIA
JF - NEOPLASIA
SN - 1476-5586
IS - 7
ER -