title: The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation.
abstract: BACKGROUND
  The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models.
  
  
  METHODS
  We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis.
  
  
  RESULTS
  We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ∼5- to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage-independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ∼65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis.
  
  
  CONCLUSIONS
  Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.
authors.affiliation: University of Chicago, Chicago, Illinois, USA.
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.forename: Jessica
authors.initials: J
authors.lastname: Siegler
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.forename: Nurbek
authors.initials: N
authors.lastname: Mambetsariev
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Lynnette M
authors.initials: LM
authors.lastname: Gerhold
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: LaRiviere
authors.forename: Chin-Tu
authors.initials: CT
authors.lastname: Chen
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moss
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000473:pathology; D017450:Receptors, Opioid, mu / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017450:Receptors, Opioid, mu