Mu Opioid Receptor 1 (MOR-1) Expression in Colorectal Cancer and Oncological Long-Term Outcomes: A Five-Year Retrospective Longitudinal Cohort Study

Díaz‐Cambronero, Óscar; Mazzinari, Guido; Giner, Francisco; Belltall, Amparo; Ruiz-Boluda, Lola; Marqués-Marí, Anabel; Sánchez‐Guillén, Luis; Eroles, Pîlar; Cata, Juan P.; Argente-Navarro, Maria Pilar

doi:10.3390/cancers12010134

Cited by 23 publications

(31 citation statements)

References 43 publications

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“…Our experimental results reveal that MOR expression is associated with CRC progression and EMT. However, our findings are contradictory to a recent study in investigating the expression of MOR in CRC patients (Diaz‐Cambronero et al, 2020).…”

Section: Discussioncontrasting

confidence: 99%

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

Lü

Zhang

Weng

et al. 2020

Journal Cellular Physiology

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Morphine, a mu‐opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time‐concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transactivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT‐MTOR and RAS‐MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine‐EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab‐resistant CRC patients.

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Section: Discussioncontrasting

confidence: 99%

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

Lü

Zhang

Weng

et al. 2020

Journal Cellular Physiology

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“…in 103 patients with advanced PDAC (11). Also, Oscar Dıáz-Cambronero et al found that there was no association between high expression and lower 5-year OS and DFS in colorectal cancers (10). In a cohort of 239 patients with esophageal squamous cell carcinoma, the expression of MOR did not affect survival (14).…”

Section: Discussionmentioning

confidence: 98%

“…Two investigators (physician pathologists) blinded to the data were asked to assessed and scored MOR expression based on previously published criteria (8). The total MOR score was calculated based on staining intensity and proportion of immun0possitive in cancer cells (10).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Studies indicate that a high expression of MOR in malignant specimens were associated with worse survival outcome in patients with lung cancer, hepatocellular carcinoma, and laryngeal squamous cell carcinoma (6)(7)(8). However, other studies have found that high levels of expression of MOR were not associated with poor prognosis in colorectal and oesophageal squamous cell carcinomas (9,10). The prognosis significance of MOR expression in PDAC has been recently investigated in patients with advanced disease (11).…”

Section: Introductionmentioning

confidence: 99%

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Association of Mu-Opioid Receptor(MOR) Expression and Opioids Requirement With Survival in Patients With Stage I-III Pancreatic Ductal Adenocarcinoma

Zhang

Görür

et al. 2021

Front. Oncol.

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BackgroundThe use of opioids in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is associated with shorter survival and not dependent on the expression of the mu-opioid receptor (MOR). The role of opioid use and MOR expression in stage I-III PDAC has not been investigated.MethodsWe conducted retrospective study in patients with stage I-III PDAC. MOR expression and OPRM1 gene expression in tumour tissue and non-tumour tissue was measured. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Secondary endpoints included perineural invasion, intraoperative sufentanil consumption, and length of stay. We performed a subgroup group analysis to evaluate the interaction between levels of MOR expression, amount of opioids use (high versus low) and its association with survival.ResultsA total of 236 patients were enrolled in this study.There were no significantly difference in OS rates in patients with high versus low levels of MOR (1-year OS: 65.2% versus 70.6%, P=0.064; 3-year: 31.4% versus 35.8%, P=0.071; 5-year: 19.4% versus. 16.2%, P=0.153, respectively) in the tumours. The DFS rates between the groups were no significantly difference. Of note, a high expression of MOR combined with high opioid consumption was associated with poor prognosis in stage I-III PDAC patients. Tumor expressing high levels of MOR show higher rates of perineural invasion.ConclusionMOR is not an independent predictor of poor survival in stage I-III PDAC but associated with perineural invasion. Patients requiring high amounts of opioids intraoperatively show worse outcome if they are expressing high levels of MOR.

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“…These μ-opioid receptors are present in lung cancer, breast cancer, neural tumors, leukemia, gastrointestinal cancers, and bladder cancers. [7][8][9][10][11][12][13][14][15] This theory is supported by research examining the effect of opioid antagonists on cancer. Janku et al reported an increased median overall survival in patients with advanced cancer who received the opioid antagonist methylnaltrexone to treat opioid-induced constipation.…”

Section: Discussionmentioning

confidence: 91%

The association of prescription opioid use with incident cancer: A Surveillance, Epidemiology, and End Results‐Medicare population‐based case‐control study

Havidich

Weiss

Onega

et al. 2020

Cancer

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BACKGROUND: Cancer is the second leading cause of death globally, and researchers seek to identify modifiable risk factors Over the past several decades, there has been ongoing debate whether opioids are associated with cancer development, metastasis, or recurrence. Basic science, clinical, and observational studies have produced conflicting results. The authors examined the association between prescription opioids and incident cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. A complex relation was observed between prescription opioids and incident cancer, and cancer site may be an important determinant. METHODS: By using linked SEER cancer registry and Medicare claims from 2008 through 2013, a case-control study was conducted examining the relation between cancer onset and prior opioid exposure. Logistic regression was used to account for differences between cases and controls for 10 cancer sites. RESULTS: Of the population studied (n = 348,319), 34% were prescribed opioids, 79.5% were white, 36.9% were dually eligible (for both Medicare and Medicaid), 13% lived in a rural area, 52.7% had ≥1 comorbidity, and 16% had a smoking-related diagnosis. Patients exposed to opioids had a lower odds ratio (OR) associated with breast cancer (adjusted OR, 0.96; 95% CI, 0.92-0.99) and colon cancer (adjusted OR, 0.90; 95% CI, 0.86-0.93) compared with controls. Higher ORs for kidney cancer, leukemia, liver cancer, lung cancer, and lymphoma, ranging from lung cancer (OR, 1.04; 95% CI, 1.01-1.07) to liver cancer (OR, 1.19; 95% CI, 1.08-1.31), were present in the exposed population. CONCLUSIONS: The current results suggest that an association exists between prescription opioids and incident cancer and that cancer site may play an important role. These findings can direct future research on specific patient populations that may benefit or be harmed by prescription opioid exposure.

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Mu Opioid Receptor 1 (MOR-1) Expression in Colorectal Cancer and Oncological Long-Term Outcomes: A Five-Year Retrospective Longitudinal Cohort Study

Cited by 23 publications

References 43 publications

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

Association of Mu-Opioid Receptor(MOR) Expression and Opioids Requirement With Survival in Patients With Stage I-III Pancreatic Ductal Adenocarcinoma

The association of prescription opioid use with incident cancer: A Surveillance, Epidemiology, and End Results‐Medicare population‐based case‐control study

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