Solid Tumor Opioid Receptor Expression and Oncologic Outcomes: Analysis of the Cancer Genome Atlas and Genotype Tissue Expression Project

Abstract

BackgroundOpioid receptors are expressed not only by neural cells in the central nervous system, but also by many solid tumor cancer cells. Whether perioperative opioids given for analgesia after tumor resection surgery might inadvertently activate tumor cells, promoting recurrence or metastasis, remains controversial. We analysed large public gene repositories of solid tumors to investigate differences in opioid receptor expression between normal and tumor tissues and their association with long–term oncologic outcomes.MethodsWe investigated the normalized gene expression of µ, κ, δ opioid receptors (MOR, KOR, DOR), Opioid Growth Factor (OGFR), and Toll-Like 4 (TLR4) receptors in normal and tumor samples from twelve solid tumor types. We carried out mixed multivariable logistic and Cox regression analysis on whether there was an association between these receptors’ gene expression and the tissue where found, i.e., tumor or normal tissue. We also evaluated the association between tumor opioid receptor gene expression and patient disease–free interval (DFI) and overall survival (OS).ResultsWe retrieved 8,780 tissue samples, 5,852 from tumor and 2,928 from normal tissue, of which 2,252 were from the Genotype Tissue Expression Project (GTEx) and 672 from the Cancer Genome Atlas (TCGA) repository. The Odds Ratio (OR) [95%CI] for gene expression of the specific opioid receptors in the examined tumors varied: MOR: 0.74 [0.63–0.87], KOR: 1.27 [1.17–1.37], DOR: 1.66 [1.48–1.87], TLR4: 0.29 [0.26–0.32], OGFR: 2.39 [2.05–2.78]. After controlling all confounding variables, including age and cancer stage, there was no association between tumor opioid receptor expression and long–term oncologic outcomes.ConclusionOpioid receptor gene expression varies between different solid tumor types. There was no association between tumor opioid receptor expression and recurrence. Understanding the significance of opioid receptor expression on tumor cells remains elusive.

Pan-Cancer Analysis and Validation of Opioid-Related Receptors Reveals the Immunotherapeutic Value of Toll-Like Receptor 4

“…These low expressions are consistent with previous observations on triple-negative breast cancer 10 and pan-cancer tissues. 27 In addition, the gene activity scores ( Figures S1D - F ) for OPRD1, OPRK1, and OPRL1 in tumor tissues calculated using the ssGSEA method were lower than those for GAPDH ( Figure 2E ), OGFR ( Figure 2F ), and TLR4 ( Figure 2G ); on the other hand, the expression of OPRM1 was too low to evaluate the activity. Given that certain levels of expression and activity of a gene in tumor tissues is necessary for biological function, these results imply that OPRM1, OPRD1, OPRK1, and OPRL1 may not play an important regulatory function in tumor tissues.…”

“…Opioids are still the main drugs for the induction and intraoperative maintenance of anesthesia and postoperative analgesia. 27 However, they can elicit a range of undesired consequences, including the inhibition of both cellular and humoral immune functions in humans, increase in angiogenesis, and promotion of tumor growth in rodents. 9 Opioids are known to act indirectly on the nervous system, leading to the release of biogenic amines.…”

“…On one hand, this would allow a more objective assessment of the molecular backgrounds of human patients with tumors for direct evidence of opioid effects in the tumor microenvironment; on the other hand, we focused only on the direct targets of opioid effects, which are the known opioid receptors, on tumor cells and the tumor microenvironment. The use of large validated databases such as TCGA and GTEx is effective 27 for mapping the genetic footprint of opioid receptors in tumor cells.…”

Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma

“…The expression of the OGFr receptor in different cell types varies and depends on many factors. However, the expression of OGFr in pancreatic cancer cells is higher than in normal cells [ 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The above reports may explain the selective effect of our conjugate.…”

Anaesthesia and cancer recurrence: the influence of perioperative anaesthetic technique on cancer recurrence after surgery

“…In a retrospective analysis, opioid receptor expression in colorectal cancer was increased in stage 2 and stage 3 but not associated with recurrence [12]. Meanwhile, an analysis of over 8000 patient samples in the Cancer Genome Atlas found no association between opioid receptor expression and cancer outcomes [13]. Another study found that mu-opioid receptor expression was not associated with overall survival or disease-free survival in patients with ovarian cancer [14].…”