title: CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells.
abstract: BACKGROUND
  Metastasis is associated with poor prognosis for melanoma. The formation of metastases is a multi-step process, in which cancer cells can subsequently acquire the potential to intravasate into the blood or lymph vessels, disseminate through the circulation, extravasate through the endothelium and invade the connective tissue. There is increasing evidence that chemokines have a pivotal role in the dissemination and establishment of melanoma metastasis.
  
  
  METHODS
  We isolated melanoma cells from melanoma metastasis and performed different migration assays and transendothelial resistance measurements of endothelial monolayers co-cultured with melanoma cells, in order to monitor barrier function and diapedesis and confirmed these results by confocal microscopy.
  
  
  RESULTS
  We observed that tumour endothelial cells (ECs) secrete high levels of CXCL9 in all, and CXCL10 in most melanoma metastases. Migration studies revealed that low concentrations of these chemokines induce chemotaxis, whereas high concentrations induce spontaneous migration of melanoma cells (chemokinesis/chemorepulsion) and the disruption of the endothelial barrier, resulting in an accelerated transendothelial migration (TEM). Addition of anti-CXCL9 or anti-CXCR3 antibodies to the co-cultures delayed the TEM of melanoma cells.
  
  
  CONCLUSIONS
  Our data represent novel mechanisms by which tumour cells in melanoma metastases might use the chemokine-expressing endothelium to leave the tumour and eventually to form additional metastases at distinct sites.
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Amatschek
authors.forename: R
authors.initials: R
authors.lastname: Lucas
authors.forename: A
authors.initials: A
authors.lastname: Eger
authors.forename: M
authors.initials: M
authors.lastname: Pflueger
authors.forename: H
authors.initials: H
authors.lastname: Hundsberger
authors.forename: C
authors.initials: C
authors.lastname: Knoll
authors.forename: S
authors.initials: S
authors.lastname: Grosse-Kracht
authors.forename: W
authors.initials: W
authors.lastname: Schuett
authors.forename: F
authors.initials: F
authors.lastname: Koszik
authors.forename: D
authors.initials: D
authors.lastname: Maurer
authors.forename: C
authors.initials: C
authors.lastname: Wiesner
mesh_terms: D054370:Chemokine CXCL9 / Q000378:metabolism*; D002633:Chemotaxis; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000096:biosynthesis*; D012878:Skin Neoplasms / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*
chemical_list: D054370:Chemokine CXCL9; D054367:Receptors, CXCR3