title: CXCR4 regulates the early extravasation of metastatic tumor cells in vivo.
abstract: 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.
authors: Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany. Peter.Gassmann@ukmuenster.de
authors: Peter
authors: P
authors: Gassmann
authors: Jörg
authors: J
authors: Haier
authors: Kerstin
authors: K
authors: Schlüter
authors: Britta
authors: B
authors: Domikowsky
authors: Claudia
authors: C
authors: Wendel
authors: Ulrike
authors: U
authors: Wiesner
authors: Robert
authors: R
authors: Kubitza
authors: Rainer
authors: R
authors: Engers
authors: Stephan W
authors: SW
authors: Schneider
authors: Bernhard
authors: B
authors: Homey
authors: Anja
authors: A
authors: Müller
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4