The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation.

TitleThe novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation.
Publication TypeJournal Article
Year of Publication2011
AuthorsMathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, Gerhold LM, LaRiviere PJ, Chen C-T, Garcia JGN, Salgia R, Moss J, Singleton PA
JournalAnesth Analg
Volume112
Issue3
Pagination558-67
Date Published2011 Mar
ISSN Number1526-7598
KeywordsAnimals, Carcinoma, Lewis Lung, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Line, Tumor, Disease Progression, Female, Humans, Lung Neoplasms, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, Receptors, Opioid, mu, Xenograft Model Antitumor Assays
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>

DOI10.1213/ANE.0b013e31820568af
Alternate JournalAnesth. Analg.
PubMed ID21156980
PubMed Central IDPMC4327979
Grant ListP01 HL058064 / HL / NHLBI NIH HHS / United States
R01 CA134680 / CA / NCI NIH HHS / United States