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.
Highlights
Surgery remains a primary treatment for 70% of solid tumors [1] but analgesia after resection is challenging
opioid growth factor receptor (OGFR) gene expression was highest while m opioid receptor (MOR) gene expression was lowest, with comparable values between control and tumor samples on every overall gene expression
Opioid receptors were significantly associated with tumor samples, albeit differently, as some genes associated positively and others negatively
Summary
Surgery remains a primary treatment for 70% of solid tumors [1] but analgesia after resection is challenging. Opioids are still the mainstay of postoperative pain management. Their primary site of action is the m opioid receptor (MOR) which is expressed at various central nervous system (CNS) locations along the pain pathway. Opioid drugs activate MORs to suppress ascending nociception and enhance descending pain inhibition [3, 4]. Opioid receptors are expressed by neural cells in the central nervous system, and 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
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