Cannabinoid receptor 2 expression in early-stage non-small cell lung cancers identifies patients with good prognosis and longer survival

Abstract

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death with a 5-year survival of only 21%. Reliable prognostic and/or predictive biomarkers are needed to improve NSCLC patient stratification, particularly in curative disease stages. Since the endogenous cannabinoid system is involved in both carcinogenesis and anticancer immune defense, we hypothesized that tumor tissue expression of cannabinoid 1 and 2 receptors (CB1 and CB2) may affect survival.Methods: Tumor tissue samples collected from 100 NSCLC patients undergoing radical surgery were analyzed for CB1 and CB2 gene and protein expression using the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The gene and protein expression data were correlated with disease stage, histology, tumor grading, application of chemotherapy, and survival.Additional paired tumor and normal tissue samples of 10 NSCLC patients were analyzed independently for comparative analysis of CB1 and CB2 gene expression.Results: Patients with tumors expressing the CB2 gene had significantly longer overall survival (OS) (P<0.001), cancer specific survival (CSS) (P=0.002), and disease-free survival (DFS) (P<0.001). They also presented with fewer lymph node metastases at the time of surgery (P=0.011). A multivariate analysis identified CB2 tumor tissue gene expression as a positive prognostic factor for CSS [hazard ratio (HR) =0.274; P=0.013] and DFS (HR =0.322; P=0.009), and increased CSS. High CB2 gene and protein expression were detected in 79.6% and 31.5% of the tested tumor tissue samples, respectively. Neither CB1 gene nor CB1 or CB2 protein expression affected survival. When comparing paired tumor and tumor-free lung tissue samples, we observed reduced CB1 (P=0.008) and CB1 (P=0.056) gene expression in tumor tissues. Conclusions:In NSCLC patients undergoing radical surgery, expression of the CB1 and CB2 receptor genes is significantly decreased in neoplastic versus tumor-free lung tissue. CB2 tumor tissue gene expression is strongly associated with longer survival (OS, CSS, DFS) and fewer lymph node metastases at the time of surgery. More studies are needed to evaluate its role as a biomarker in NSCLC and to investigate the potential use of CB2 modulators to treat or prevent lung cancers.

The clinical and pathological significance of increased expression of the cannabinoid receptors CB-1R and CB-2R in patients with papillary thyroid carcinomas compared to benign thyroid lesions

“…The reason could be that apart from the limiting psychotic effects of cannabinoid agonists through activation of CB-1R in the test candidate's central nervous system, the results of many studies are discrepant on whether cannabinoid receptor activation inhibits or enhances tumor development and progression. Vidlarova et al 47 found that tumors expressing CB-2R mRNA were associated with significantly longer overall, cancer-specific, and disease-free survival, whereas CB-2R protein expression was associated with a less advanced disease stage and grade. Similar results were observed in hepatocellular carcinomas; increased expression of CB-1R and CB-2R significantly related to disease-free survival and was associated with histologically well-differentiated tumors as well as less portal vein involvement.…”

Morphine Analgesia, Cannabinoid Receptor 2, and Opioid Growth Factor Receptor Cancer Tissue Expression Improve Survival after Pancreatic Cancer Surgery

“…Because CB2 expression has been linked to longer survival in both lung [ 15 ] and hepatocellular cancer [ 16 ], similar mechanisms may be active in PDAC. In particular, CB2 is a likely target for endo- and exocannabinoids with anticancer activity resulting from effects on motility and migration, reductions in invasiveness and angiogenesis, and the induction of apoptosis [ 17 , 46 ].…”

“…Quantitative RT-PCR reactions were performed in LightCycler 384 Multiwell plates (Roche, Basel, Switzerland). In each reaction, 50 ng of cDNA was mixed with LightCycler 480 DNA Probes Master (Roche, Basel, Switzerland) and the appropriate TaqMan Gene Expression Assay (Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA; CB1: Hs01038532_m1; CB2: Hs00275635_m1; OPRK: Hs00175127_m1; OPRD: Hs00538331_m1; OPRM: Hs01053957_m1; OPRL: 00173471_m1; OGFR: Hs01071266_m1; ACTB: Hs99999903_m1) [ 15 ]. The volumes of the reagent mixture and the sample were 9 µL and 1 µL, respectively, and each sample was applied to the plate in four replicates.…”

“…At the cellular level, our group and others have shown that the persistence of circulating tumor cells (CTCs) after radical cancer surgery is a negative prognostic factor [ 10 , 11 , 12 ]. We also showed that piritramide opioid analgesia reduces the presence of CTCs in colon cancer patients after surgery, potentially affecting survival [ 13 , 14 ], and that the expression of the cannabinoid-2 receptor (CB2) in cancer tissues improves survival in small-cell lung cancer [ 15 ]. Similar effects were also observed in hepatocellular cancer [ 16 ].…”

Clinical and prognostic significance of detecting CEA, EGFR, LunX, c-met and EpCAM mRNA-positive cells in the peripheral blood, tumor-draining blood and bone marrow of non-small cell lung cancer patients

“…The study was registered at ClinicalTrials.gov (NS10285). A total of 166 patients were prospectively enrolled in the study, which was conducted between August 2009 and April 2013 ( 26 ). However, 47 patients were excluded (R>0, histologically not NSCLC, stage IIIB–IV, neoadjuvant chemotherapy, death caused by perioperative complications), finally 119 patients were analyzed ( Table 1 ).…”