title: CXCR4 Expression and Treatment with SDF-1α or Plerixafor Modulate Proliferation and Chemosensitivity of Colon Cancer Cells.
abstract: BACKGROUND
  Signaling through stromal cell-derived factor-1α (SDF-1α), strongly secreted by bone marrow stromal cells and the CXC chemokine receptor 4 (CXCR4) exposed on tumor cells has pivotal roles in proliferation, metastasis, and tumor cell "dormancy." Dormancy is associated with cytostatic drug resistance and is probably a property of tumor stem cells and minimal residual disease. Thus, hampering the SDF-1α/CXCR4 cross talk by a CXCR4 antagonist like Plerixafor (AMD3100) should overcome tumor cell dormancy bymobilization of tumor cells from "sanctuary" niches. Our aim was to elucidate the direct effects exerted by SDF-1α and Plerixafor on proliferation, chemosensitivity, and apoptosis of CXCR4-expressing tumor cells.
  
  
  METHODS
  The ability of SDF-1α and Plerixafor to regulate intracellular signaling, proliferation, and invasion was investigated using two colon cancer cell lines (HT-29 and SW480) with either high endogenous or lentiviral expression of CXCR4 compared to their respective low CXCR4-expressing counterparts as a model system. Efficacy of Plerixafor on sensitivity of these cell lines against 5-fluorouracil, irinotecan, or oxaliplatin was determined in a cell viability assay as well as stroma-dependent cytotoxicity and apoptosis assays.
  
  
  RESULTS
  SDF-1α increased proliferation, invasion, and ERK signaling of endogenously and lentivirally CXCR4-expressing cells. Exposure to Plerixafor reduced proliferation, invasion, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Combination of chemotherapy with Plerixafor showed an additive effect on chemosensitivity and apoptosis in CXCR4-overexpressing cells. An SDF-1-secreting feeder layer provideda"protective niche" for CXCR4-overexpressing cells resulting in decreased chemosensitivity.
  
  
  CONCLUSIONS
  CXCR4-antagonistic therapy mobilizes and additionally sensitizes tumor cells toward cytoreductive chemotherapy.
authors.affiliation: Molecular Oncology of Solid Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Heckmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Maier
authors.forename: Stephanie
authors.initials: S
authors.lastname: Laufs
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: W Jens
authors.initials: WJ
authors.lastname: Zeller
authors.forename: Stefan
authors.initials: S
authors.lastname: Fruehauf
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
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