CXCR4 regulates the early extravasation of metastatic tumor cells in vivo

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 -