title: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion.
abstract: BACKGROUND
  Cannabinoids bind to cannabinoid receptors CB(1) and CB(2) and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2) may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.
  
  
  RESULTS
  We observed high expression of both CB(2) and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB(2)-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.
  
  
  CONCLUSIONS
  This study provides novel insights into the crosstalk between CB(2) and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB(2) receptors could be used for developing innovative therapeutic strategies against breast cancer.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.forename: Zahida
authors.initials: Z
authors.lastname: Qamri
authors.forename: Yadwinder S
authors.initials: YS
authors.lastname: Deol
authors.forename: Diane
authors.initials: D
authors.lastname: Smith
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zou
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D054377:Chemokine CXCL12; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4; C402944:JHW 015