The Novel Role of the Mu Opioid Receptor in Lung Cancer Progression

Abstract

Background The possibility that mu 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 based on mu opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models. Methods We utilized 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 methylnalnaltrexone (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 FMT 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 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 as compared to wildtype controls. Finally, continuous infusion of the peripheral opioid antagonist methylnaltrexone attenuates primary LLC tumor growth and reduces lung metastasis. Conclusions Taken together, our data suggests a possible direct effect of opiates on lung cancer progression, and provides a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.

Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis?

“…52 The theory regarding MOR involvement in metastasis is further supported by the diminished progression of lung carcinoma in MOR knockout mice treated with the opioid receptor antagonist naltrexone. 53 Morphine does not influence the initiation of tumour development; rather, it affects the progression of established breast tumour, as recently shown in a transgenic mouse study that found significantly decreased survival in a mouse model of breast adenocarcinoma. 54 In the same study, it was found that morphine promoted lymphangiogenesis, mast cell activation and degranulation, and increased levels of inflammatory cytokines, tryptase, and substance P. In addition, the morphine-treated mice had increased tumour burden and decreased duration of survival.…”

Perioperative Interventions During Cancer Surgery: Can Anesthetic and Analgesic Techniques Influence Outcome?

“…This study also found that when the MOR expression and opioid requirement were included in the multivariate model, the significance of other known prognostic variables diminished considerably. It was also found that injecting Lewis lung cancer cells into nude MOR knockout mice did not result in the growth of a tumor while it almost invariably did in the case of normal mice [47]. The in vitro work of Ecimovic et al [48] demonstrated that morphine increases the migration of both estrogen positive and negative breast cancer cells in a dose-dependent way by 17-27 %.…”

Optimization of anesthetic management of surgical treatment of colorectal cancer. Part III: clinical and morphological aspects

“…Значительное уменьшение коли-чества опиоидных аналгетиков и качество обез-боливания у пациентов онкологического профи-ля за счет использования регионарных методик особенно актуально, так как снижается выра-женность отрицательных эффектов наркотиче-ских препаратов, в том числе угнетение иммуни-тета и устойчивости к метастазированию. Дока-зано прямое влияние агонистов µ-опиатных ре-цепторов на развитие и прогрессию рака [4,5]. Показано, что механическое повреждение вызы-вает подавление активности естественных кил-леров и распространение опухолевого процесса в эксперименте [6].…”