bims-netuvo 2024-02-11 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2024–02–11
seventeen papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

The Gut Microbiome Controls Liver Tumors via the Vagus Nerve.
Skin cancer metastasis via the nervous system?
Targeting TRPV1 for Cancer Pain Relief: Can It Work?
Preoperative prediction of perineural invasion and lymphovascular invasion with CT radiomics in gastric cancer.
Preoperative Prediction of Perineural Invasion and Prognosis in Gastric Cancer Based on Machine Learning through a Radiomics-Clinicopathological Nomogram.
Epithelioid malignant peripheral nerve sheath tumor of the bladder and concomitant urothelial carcinoma: A case report.
Perineural differentiation in neurotized nevi.
Development of a Predictive Nomogram for Circumferential Resection Margin in Rectal Cancer Surgery.
Keratinocyte-Derived Cytokine in the Hippocampus Disrupts Extinction of Conditioned Fear Memory in Tumor-Bearing Mice.
Chronic stress promotes gastric cancer progression via the adrenoceptor beta 2/PlexinA1 pathway.
Effects of anesthesia on long-term survival in cancer surgery: A systematic review and meta-analysis.
Association between sleep duration, depression and breast cancer in the United States: a national health and nutrition examination survey analysis 2009-2018.
O-arm guided minimally invasive resection of intrathoracic epidural schwannoma: how I do it.
METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.
Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR.
Altered gut microbiome drives heightened pain sensitivity in a murine model of metastatic triple-negative breast cancer.
β2-Adrenoceptor Activation Favor Acquisition of Tumorigenic Properties in Non-Tumorigenic MCF-10A Breast Epithelial Cells.

bioRxiv. 2024 Jan 25. pii: 2024.01.23.576951. [Epub ahead of print]

The Gut Microbiome Controls Liver Tumors via the Vagus Nerve.

Kylynda C Bauer, Rajiv Trehan, Benjamin Ruf, Yuta Myojin, Mohamed-Reda Benmebarek, Chi Ma, Matthias Seifert, Amran Nur, Jonathan Qi, Patrick Huang, Marlaine Soliman, Benjamin L Green, Simon Wabitsch, Danielle A Springer, Francisco J Rodriguez-Matos, Shadin Ghabra, Stephanie N Gregory, Jennifer Matta, Brian Dawson, Jihye Golino, Changqing Xie, Amiran Dzutsev, Giorgio Trinchieri, Firouzeh Korangy, Tim F Greten.

Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of Chrm3 on CD8 + T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer-associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, increasing Desulfovibrionales and Clostridial taxa. Strikingly, in tumor-free mice, vagotomy permitted HCC-associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis.

DOI: https://doi.org/10.1101/2024.01.23.576951
Australas J Dermatol. 2024 Feb 09.

Skin cancer metastasis via the nervous system?

Rainer Ebid.

DOI: https://doi.org/10.1111/ajd.14220
Cancers (Basel). 2024 Feb 02. pii: 648. [Epub ahead of print]16(3):

Targeting TRPV1 for Cancer Pain Relief: Can It Work?

Arpad Szallasi.

  Chronic intractable pain affects a large proportion of cancer patients, especially those with metastatic bone disease. Blocking sensory afferents for cancer pain relief represents an attractive alternative to opioids and other drugs acting in the CNS in that sensory nerve blockers are not addictive and do not affect the mental state of the patient. A distinct subpopulation of sensory afferents expresses the capsaicin receptor TRPV1. Intrathecal resiniferatoxin, an ultrapotent capsaicin analog, ablates TRPV1-expressing nerve endings exposed to the cerebrospinal fluid, resulting in permanent analgesia in women with cervical cancer metastasis to the pelvic bone. High-dose capsaicin patches are effective pain killers in patients with chemotherapy-induced peripheral neuropathic pain. However, large gaps remain in our knowledge since the mechanisms by which cancer activates TRPV1 are essentially unknown. Most important, it is not clear whether or not sensory denervation mediated by TRPV1 agonists affects cancer progression. In a murine model of breast cancer, capsaicin desensitization was reported to accelerate progression. By contrast, desensitization mediated by resiniferatoxin was found to block melanoma growth. These observations imply that TRPV1 blockade for pain relief may be indicated for some cancers and contraindicated for others. In this review, we explore the current state of this field and compare the analgesic potential of TRPV1 antagonism and sensory afferent desensitization in cancer patients.

Keywords:  TRPV1 receptor; cancer pain; capsaicin; resiniferatoxin

DOI:  https://doi.org/10.3390/cancers16030648
Eur J Radiol Open. 2024 Jun;12 100550

Preoperative prediction of perineural invasion and lymphovascular invasion with CT radiomics in gastric cancer.

Yaoyao He, Miao Yang, Rong Hou, Shuangquan Ai, Tingting Nie, Jun Chen, Huaifei Hu, Xiaofang Guo, Yulin Liu, Zilong Yuan.

   Objectives: To determine whether contrast-enhanced CT radiomics features can preoperatively predict lymphovascular invasion (LVI) and perineural invasion (PNI) in gastric cancer (GC).
Methods: A total of 148 patients were included in the LVI group, and 143 patients were included in the PNI group. Three predictive models were constructed, including clinical, radiomics, and combined models. A nomogram was developed with clinical risk factors to predict LVI and PNI status. The predictive performance of the three models was mainly evaluated using the mean area under the curve (AUC). The performance of three predictive models was assessed concerning calibration and clinical usefulness.
Results: In the LVI group, the predictive power of the combined model (AUC=0.871, 0.822) outperformed the clinical model (AUC=0.792, 0.728) and the radiomics model (AUC=0.792, 0.728) in both the training and testing cohorts. In the PNI group, the combined model (AUC=0.834, 0.828) also had better predictive power than the clinical model (AUC=0.764, 0.632) and the radiomics model (AUC=0.764, 0.632) in both the training and testing cohorts. The combined models also showed good calibration and clinical usefulness for LVI and PNI prediction.
Conclusion: CECT-based radiomics analysis might serve as a non-invasive method to predict LVI and PNI status in GC.

Keywords:  Contrast-enhanced CT; Gastric cancer; Lymphovascular invasion; Perineural invasion; Radiomics

DOI:  https://doi.org/10.1016/j.ejro.2024.100550
Cancers (Basel). 2024 Jan 31. pii: 614. [Epub ahead of print]16(3):

Preoperative Prediction of Perineural Invasion and Prognosis in Gastric Cancer Based on Machine Learning through a Radiomics-Clinicopathological Nomogram.

Heng Jia, Ruzhi Li, Yawei Liu, Tian Zhan, Yuan Li, Jianping Zhang.

   PURPOSE: The aim of this study was to construct and validate a nomogram for preoperatively predicting perineural invasion (PNI) in gastric cancer based on machine learning, and to investigate the impact of PNI on the overall survival (OS) of gastric cancer patients.
METHODS: Data were collected from 162 gastric patients and analyzed retrospectively, and radiomics features were extracted from contrast-enhanced computed tomography (CECT) scans. A group of 42 patients from the Cancer Imaging Archive (TCIA) were selected as the validation set. Univariable and multivariable analyses were used to analyze the risk factors for PNI. The t-test, Max-Relevance and Min-Redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select radiomics features. Radscores were calculated and logistic regression was applied to construct predictive models. A nomogram was developed by combining clinicopathological risk factors and the radscore. The area under the curve (AUC) values of receiver operating characteristic (ROC) curves, calibration curves and clinical decision curves were employed to evaluate the performance of the models. Kaplan-Meier analysis was used to study the impact of PNI on OS.
RESULTS: The univariable and multivariable analyses showed that the T stage, N stage and radscore were independent risk factors for PNI (p < 0.05). A nomogram based on the T stage, N stage and radscore was developed. The AUC of the combined model yielded 0.851 in the training set, 0.842 in the testing set and 0.813 in the validation set. The Kaplan-Meier analysis showed a statistically significant difference in OS between the PNI group and the non-PNI group (p < 0.05).
CONCLUSIONS: A machine learning-based radiomics-clinicopathological model could effectively predict PNI in gastric cancer preoperatively through a non-invasive approach, and gastric cancer patients with PNI had relatively poor prognoses.

Keywords:  gastric cancer; machine learning; perineural invasion; radiomics

DOI:  https://doi.org/10.3390/cancers16030614
World J Clin Cases. 2024 Jan 26. 12(3): 551-559

Epithelioid malignant peripheral nerve sheath tumor of the bladder and concomitant urothelial carcinoma: A case report.

Sami Berk Ozden, Muhammed Fatih Simsekoglu, Ipek Sertbudak, Cetin Demirdag, Iclal Gurses.

   BACKGROUND: Epithelioid malignant peripheral nerve sheath tumor (EMPNST) of the bladder is a rare entity with devastating features. These tumors are thought to originate from malignant transformation of pre-existing schwannomas of pelvic autonomic nerve plexuses, and unlike the conventional malignant peripheral nerve sheath tumor (MPNST), are not associated with neurofibromatosis. The tumor has distinctive morphological, immunohistochemical and molecular features. Additionally, it tends to be more aggressive and have a higher mortality. This is the first case that presents with a synchronous urothelial carcinoma of the bladder and the epithelioid variant of MPNST in the literature. It's also the second reported case of EMPNST originating from the bladder wall.
CASE SUMMARY: In this case report, we present the detailed clinical course of a 71-year-old patient with EMPNST of the bladder alongside a literature review.
CONCLUSION: During the management of EMPNST cases, offering aggressive treatment modalities to the patient, such as radical cystectomy, is appropriate for the best chance to contain the disease, regardless of the tumor stage and the extent of local disease at initial diagnosis.

Keywords:  Bladder; Case report; Cystoprostatectomy; Epithelioid; Peripheral nerve sheath tumor; Urothelial

DOI:  https://doi.org/10.12998/wjcc.v12.i3.551
Pathol Res Pract. 2024 Feb 01. pii: S0344-0338(24)00095-5. [Epub ahead of print]255 155184

Perineural differentiation in neurotized nevi.

Cem Leblebici, Beste Noyan Mod, Merve Cin, Burcu Özcan.

   BACKGROUND: Perineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized melanocytic nevi may resemble nerve sheath tumors histologically, and show schwannian differentiation. However, literature on whether neurotized nevi differentiate into perineural cells is controversial. We examined our cases of neurotized nevi for evidence of perineural differentiation.
MATERIALS AND METHODS: A total of 100 benign nevi with large neurotized component (microscopically involved a low power field 4.2 mm in diameter) were prospectively evaluated in excisional biopsy samples. Immunohistochemical stainings for EMA, Claudin1, Glut1 and neurofilament were performed.
RESULTS: Perineural differentiation was immunohistochemically detected in the neurotized component of the nevi in 61% of the cases with EMA and in all the cases with Glut1 and Claudin1. Axonal differentiation was not detected with neurofilament. The expression pattern, especially with Glut1, was usually in form of partial or complete staining surrounding the Meissner's corpuscle-like structure (MCLS). Also, a linear/curvilinear staining pattern was observed particularly with Claudin1. A diffuse staining pattern with EMA, Glut1 and Claudin1 was detected in a case with a microscopically distinct whorl structure, and in which spindle cells are separated from the superficial epithelioid melanocytes with an abrupt transition histologically. These findings of the case are compatible with previous reports of perineuromatous nevus.
CONCLUSION: Perineural differentiation is not uncommon and immunohistochemically observed in all nevi with a relatively large component of neurotization. To prevent misdiagnosing desmoplastic melanoma and overtreating patients, it is crucial to be aware of perineuromatous nevi.

Keywords:  Claudin1; EMA; Glut1; Neurotization; Nevus; Perineural differentiation

DOI:  https://doi.org/10.1016/j.prp.2024.155184
J Surg Res. 2024 Feb 08. pii: S0022-4804(24)00019-2. [Epub ahead of print]296 532-540

Development of a Predictive Nomogram for Circumferential Resection Margin in Rectal Cancer Surgery.

Megan Shroder, Molly M Ford, Fei Ye, Zhiguo Zhao, Aimal Khan, Shannon McChesney, M Benjamin Hopkins, Alexander T Hawkins.

   INTRODUCTION: Circumferential resection margin (CRM) is a key quality metric and predictor of oncologic outcomes and overall survival following surgery for rectal cancer. We aimed to develop a nomogram to identify patients at risk for a positive CRM in the preoperative setting.
METHODS: We performed a retrospective evaluation of the National Cancer Database from 2010 to 2014 for patients with clinical stage I-III rectal cancer who underwent total mesorectal excision. Patients were excluded for emergency operation, resection for cancer recurrence, palliative resection, transanal resection, and missing CRM status. The primary outcome was positive CRM. Secondary outcomes included overall survival.
RESULTS: There were 28,790 patients included. 2245 (7.8%) had a positive CRM. Higher tumor grade, lack of neoadjuvant chemotherapy, mucinous/signet tumor histology, open approach, abdominoperineal resection, higher T stage, lymphovascular invasion, and perineural invasion were all significantly associated with positive CRM (P < 0.05) and were included in the nomogram. The C-statistic was 0.703, suggesting a good predictive model.
CONCLUSIONS: Positive CRM is associated with specific patient demographics and tumor characteristics. These factors can be used along with preoperative MRI to predict CRM positivity in the preoperative period and plan accordingly.

Keywords:  Colorectal surgery; Rectal cancer; Surgical oncology

DOI:  https://doi.org/10.1016/j.jss.2023.12.047
Mol Neurobiol. 2024 Feb 03.

Keratinocyte-Derived Cytokine in the Hippocampus Disrupts Extinction of Conditioned Fear Memory in Tumor-Bearing Mice.

Hiroko Ikeda, Aimi Yamagishi, Naomi Yonemochi, Shogo Yamamoto, Takatsune Shimizu, Akihiro Muto, John L Waddington, Junzo Kamei.

  While patients with cancer show a higher prevalence of psychiatric disorders than the general population, the mechanism underlying this interaction remains unclear. The present study examined whether tumor-bearing (TB) mice show psychological changes using the conditioned fear paradigm and the role of cytokines in these changes. TB mice were established by transplantation with mouse osteosarcoma AXT cells. These TB mice were then found to exhibit disruption in extinction of conditioned fear memory. Eighteen cytokines in serum were increased in TB mice, among which i.c.v. injection of interleukin (IL)-1β and IL-6 strengthened fear memory in normal mice. Contents of IL-17 and keratinocyte-derived cytokine (KC) in the amygdala and KC in the hippocampus were increased in TB mice. KC mRNA in both the amygdala and hippocampus was also increased in TB mice, and i.c.v. injection of KC dose-dependently strengthened fear memory in normal mice. In addition, injection of IL-1β, but not IL-6, increased KC mRNA in the amygdala and hippocampus. In TB mice KC mRNA was increased in both astrocytes and microglia of the amygdala and hippocampus. The microglia inhibitor minocycline, but not the astrocyte inhibitor fluorocitrate, alleviated disruption in extinction of conditioned fear memory in TB mice. Microinjection of KC into the hippocampus, but not into the amygdala, increased fear memory in normal mice. These findings indicate that TB mice show an increase in serum cytokines, including IL-1β, that increases KC production in microglia of the hippocampus, which then disrupts extinction of fear memory.

Keywords:  Astrocytes; Conditioned fear memory; Interleukin-1β; Interleukin-6; Keratinocyte derived cytokine; Microglia

DOI:  https://doi.org/10.1007/s12035-024-03992-1
Cell Stress Chaperones. 2024 Feb 06. pii: S1355-8145(24)00049-X. [Epub ahead of print]

Chronic stress promotes gastric cancer progression via the adrenoceptor beta 2/PlexinA1 pathway.

Yanjie Lu, Die Cheng, Jiayu Pang, Yuqiao Peng, Shunkang Jin, Xinyu Zhang, Yanzhen Zuo, Yuhong Li.

   BACKGROUND: Chronic stress is a common emotional disorder in cancer patients. Chronic stress promotes progression of gastric cancer (GC) and leads to poor outcomes. However, the underlying mechanisms remain not clear. Herein, we explored the possible mechanisms of chronic stress in GC progression.
METHODS: TCGA datasets were analyzed for differentially expressed genes. Clinical data of GC were evaluated for their association with PlexinA1 using The Cancer Genome Atlas (TCGA) and Kaplan-Meier (KM)-plotter databases. Chronic stress of GC patients was evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Chronic unpredictable mild stress (CUMS) was used to induce chronic stress in mice. Gastric xenograft tumor was constructed using the sewing method. Chronic stress-like behaviors were assessed using light/dark box and tail suspension tests. Protein expression was detected using immunohistochemistry and Western blot analysis.
RESULTS: Analyses of TCGA and the KM-plotter databases showed that patients with high levels of PlexinA1 in GC had worse overall survival than those with low levels of PlexinA1. A total of 36 GC patients were enrolled in the study, and about 33% of the patients had chronic stress. Compared with patients without chronic stress, higher expression levels of adrenoceptor beta 2 (ADRB2) and PlexinA1 were observed in patients with chronic stress. The tumor size in mice under CUMS was significantly increased compared with the control mice. ADRB2, PlexinA1, N-cadherin, and alpha-smooth muscle actin (α-SMA), as well as Ki67 were highly expressed in the tumors of CUMS group. However, E-cadherin was lowly expressed in the tumors of CUMS group. Importantly, chemical sympathectomy with 6-hydroxydopamine (6-OHDA) or treatment with a selective β2 adrenergic receptor antagonist (ICI118,551) could reverse these effects.
CONCLUSIONS: Our findings suggest that chronic stress plays an important role in GC progression and there is a potential for blocking the epinephrine-β2AR/PlexinA1 pathway in the treatment of GC.

Keywords:  PlexinA1; adrenoceptor beta 2; chronic stress; epinephrine; gastric cancer

DOI:  https://doi.org/10.1016/j.cstres.2024.02.001
Heliyon. 2024 Feb 15. 10(3): e24791

Effects of anesthesia on long-term survival in cancer surgery: A systematic review and meta-analysis.

Yaxing Tang, Lele Tang, Yuting Yao, He Huang, Bing Chen.

   Backgrounds: The association between anesthesia and long-term oncological outcome after cancer surgery remains controversial. This study aimed to investigate the effect of propofol-based anesthesia and inhalation anesthesia on long-term survival in cancer surgery.
Methods: A comprehensive literature search was performed in PubMed, Medline, Embase, and the Cochrane Library until November 15, 2023. The outcomes included overall survival (OS) and recurrence-free survival (RFS). The hazard ratio (HR) and 95 % confidence interval (CI) were calculated with a random-effects model.
Results: We included forty-two retrospective cohort studies and two randomized controlled trials (RCTs) with 686,923 patients. Propofol-based anesthesia was associated with improved OS (HR = 0.82, 95 % CI:0.76-0.88, P < 0.00001) and RFS (HR = 0.80, 95 % CI:0.73-0.88, P < 0.00001) than inhalation anesthesia after cancer surgery. However, these positive results were only observed in single-center studies (OS: HR = 0.76, 95 % CI:0.68-0.84, P < 0.00001; RFS: HR = 0.76, 95 % CI:0.66-0.87, P < 0.0001), but not in multicenter studies (OS: HR = 0.98, 95 % CI:0.94-1.03, P = 0.51; RFS: HR = 0.95, 95 % CI:0.87-1.04, P = 0.26). The subgroup analysis revealed that propofol-based anesthesia provided OS and RFS advantages in hepatobiliary cancer (OS: HR = 0.58, 95 % CI:0.40-0.86, P = 0.005; RFS: HR = 0.62, 95 % CI:0.44-0.86, P = 0.005), gynecological cancer (OS: HR = 0.52, 95 % CI:0.33-0.81, P = 0.004; RFS: HR = 0.51, 95 % CI:0.36-0.72, P = 0.0001), and osteosarcoma (OS: HR = 0.30, 95 % CI:0.11-0.81, P = 0.02; RFS: HR = 0.32, 95 % CI:0.14-0.75, P = 0.008) surgeries.
Conclusion: Propofol-based anesthesia may be associated with improved OS and RFS than inhalation anesthesia in some cancer surgeries. Considering the inherent weaknesses of retrospective designs and the strong publication bias, our findings should be interpreted with caution. Well-designed multicenter RCTs are still urgent to further confirm these findings.

Keywords:  Cancer surgery; Inhalation anesthesia; Intravenous anesthesia; Long-term survival; Meta-analysis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24791
Ann Med. 2024 Dec;56(1): 2314235

Association between sleep duration, depression and breast cancer in the United States: a national health and nutrition examination survey analysis 2009-2018.

Yufan Cai, Yizhou Zhaoxiong, Wei Zhu, Haiyu Wang.

   OBJECTIVE: Breast cancer is the most common cancer in women, threatening both physical and mental health. The epidemiological evidence for association between sleep duration, depression and breast cancer is inconsistent. The aim of this study was to determine the association between them and build machine-learning algorithms to predict breast cancer.
METHODS: A total of 1,789 participants from the National Health and Nutrition Examination Survey (NHANES) were included in the study, and 263 breast cancer patients were identified. Sleep duration was collected using a standardized questionnaire, and the Nine-item Patient Health Questionnaire (PHQ-9) was used to assess depression. Logistic regression yielded multivariable-adjusted breast cancer odds ratios (OR) and 95% confidence intervals (CI) for sleep duration and depression. Then, six machine learning algorithms, including AdaBoost, random forest, Boost tree, artificial neural network, limit gradient enhancement and support vector machine, were used to predict the development of breast cancer and find out the best algorithm.
RESULTS: Body mass index (BMI), race and smoking were statistically different between breast cancer and non-breast cancer groups. Participants with depression were associated with breast cancer (OR = 1.99, 95%CI: 1.55-3.51). Compared with 7-9h of sleep, the ORs for <7 and >9 h of sleep were 1.25 (95% CI: 0.85-1.37) and 1.05 (95% CI: 0.95-1.15), respectively. The AdaBoost model outperformed other machine learning algorithms and predicted well for breast cancer, with an area under curve (AUC) of 0.84 (95%CI: 0.81-0.87).
CONCLUSIONS: No significant association was observed between sleep duration and breast cancer, and participants with depression were associated with an increased risk for breast cancer. This finding provides new clues into the relationship between breast cancer and depression and sleep duration, and provides potential evidence for subsequent studies of pathological mechanisms.

Keywords:  Breast cancer; depression; machine learning; prediction; sleep duration

DOI:  https://doi.org/10.1080/07853890.2024.2314235
Acta Neurochir (Wien). 2024 Feb 06. 166(1): 68

O-arm guided minimally invasive resection of intrathoracic epidural schwannoma: how I do it.

Pengcheng Xu, Baofeng Wang, Qingfang Sun, Liuguan Bian, Yuhao Sun.

   BACKGROUND: Schwannomas are the most common intrathoracic neurogenic tumors. In the past, they were often treated by traditional open surgery. Video-assisted thoracic surgery (VATS) has also been used for some large tumors. Recently, minimally invasive posterior neurosurgical technique provides a new option for some of these tumors.
METHOD: Here, we describe the specific steps involved in the O-arm guided minimally invasive removal of intrathoracic epidural schwannoma, as well as its advantages and limitations.
CONCLUSION: O-arm guided minimally invasive resection of intrathoracic epidural schwannoma is safe and effective and causes little damage.

Keywords:  Minimally invasive surgery; O-arm; Schwannoma; Tubular retractor

DOI:  https://doi.org/10.1007/s00701-024-05916-3
J Clin Invest. 2024 Feb 06. pii: e174847. [Epub ahead of print]

METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.

Weicheng Lu, Xiaohua Yang, Weiqiang Zhong, Guojun Chen, Xinqi Guo, Qingqing Ye, Yixin Xu, Zhenhua Qi, Yaqi Ye, Jingyun Zhang, Yuge Wang, Xintong Wang, Shu Wang, Qiyue Zhao, Weian Zeng, Junting Huang, Huijie Ma, Jingdun Xie.

  Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in the CINP in a DBP/METT14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

Keywords:  Epigenetics; Neuroscience; Pain; Synapses

DOI:  https://doi.org/10.1172/JCI174847
Dev Cell. 2024 Jan 29. pii: S1534-5807(24)00030-3. [Epub ahead of print]

Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR.

Kojiro Ishibashi, Toshiya Ichinose, Riki Kadokawa, Ryo Mizutani, Sadahiro Iwabuchi, Sumihito Togi, Hiroki Ura, Shoichiro Tange, Keiko Shinjo, Jun Nakayama, Shigeki Nanjo, Yo Niida, Yutaka Kondo, Shinichi Hashimoto, Erik Sahai, Seiji Yano, Mitsutoshi Nakada, Eishu Hirata.

  There are limited methods to stably analyze the interactions between cancer cells and glial cells in vitro, which hinders our molecular understanding. Here, we develop a simple and stable culture method of mouse glial cells, termed mixed-glial culture on/in soft substrate (MGS), which serves well as a platform to study cancer-glia interactions. Using this method, we find that human lung cancer cells become overly dependent on metabotropic glutamate receptor 1 (mGluR1) signaling in the brain microenvironment. Mechanistically, interactions with astrocytes induce mGluR1 in cancer cells through the Wnt-5a/prickle planar cell polarity protein 1 (PRICKLE1)/RE1 silencing transcription factor (REST) axis. Induced mGluR1 directly interacts with and stabilizes the epidermal growth factor receptor (EGFR) in a glutamate-dependent manner, and these cells then become responsive to mGluR1 inhibition. Our results highlight increased dependence on mGluR1 signaling as an adaptive strategy and vulnerability of human lung cancer brain metastasis.

Keywords:  EGFR; PRICKLE1; REST; Wnt-5a; astrocyte; brain metastasis; cancer-glia interaction; glial cell culture; lung cancer; mGluR1

DOI:  https://doi.org/10.1016/j.devcel.2024.01.010
Am J Cancer Res. 2024 ;14(1): 274-299

Altered gut microbiome drives heightened pain sensitivity in a murine model of metastatic triple-negative breast cancer.

Rajib K Dutta, Yaa F Abu, Junyi Tao, Irina Chupikova, Janneth Oleas, Praveen K Singh, Nicolas A Vitari, Rehana Qureshi, Sundaram Ramakrishnan, Sabita Roy.

The microbiota residing in the gut environment is essential for host homeostasis. Increasing evidence suggests that microbial perturbation (dysbiosis) regulates cancer initiation and progression at local and distant sites. Here, we have identified microbial dysbiosis with the depletion of commensal bacteria as a host-intrinsic factor associated with metastatic dissemination to the bone. Using a mouse model of triple-negative mammary cancer, we demonstrate that a pre-established disruption of microbial homeostasis using an antibiotic cocktail increases tumor growth, enhanced circulating tumor cells, and subsequent dissemination to the bone. We found that the presence of pathogenic bacteria and loss of commensal bacteria in an antibiotic-induced gut environment is associated with sustained inflammation. Increased secretion of G-CSF and MMP-9 in intestinal tissues, followed by increased neutrophil infiltration and severe systemic inflammation in tumor-bearing mice, indicates the direct consequence of a dysbiotic microbiome. Increased neutrophil infiltration to the bone metastatic niche facilitates extravasation and transendothelial migration of tumor cells. It provides a novel, pre-established, and favorable environment to form an immunosuppressive pre-metastatic niche. The presence of tumor cells in immunosuppressive metastatic tumor niche disrupts the balance between osteoblasts and osteoclasts, promotes osteoclast differentiation, and remodels the bone structure. Excessive bone resorption by osteoclasts causes bone degradation and ultimately causes extreme pain in a bone metastatic mouse model. In clinical settings, bone metastasis is associated with intractable severe pain that severely compromises the quality of life in these patients.

Keywords: Breast cancer; bone metastasis; inflammation; microbial dysbiosis; pain
Cells. 2024 Jan 30. pii: 262. [Epub ahead of print]13(3):

β2-Adrenoceptor Activation Favor Acquisition of Tumorigenic Properties in Non-Tumorigenic MCF-10A Breast Epithelial Cells.

Dany Silva, Clara Quintas, Jorge Gonçalves, Paula Fresco.

  Noradrenaline and adrenaline, and their cognate receptors, are currently accepted to participate in cancer progression. They may also participate in cancer initiation, although their role in this phase is much less explored. The aim of this work was to study the influence of adrenergic stimulation in several processes related to breast cancer carcinogenesis, using several adrenergic agonists in the MCF-10A non-tumorigenic breast cells. Activation of the β-adrenoceptors promoted an epithelial phenotype in MCF-10A cells, revealed by an increased expression of the epithelial marker E-cadherin and a decrease in the mesenchymal markers, N-cadherin and vimentin. MCF-10A cell motility and migration were also impaired after the β-adrenoceptors activation. Concomitant with this effect, β-adrenoceptors decrease cell protrusions (lamellipodia and filopodia) while increasing cell adhesion. Activation of the β-adrenoceptors also decreases MCF-10A cell proliferation. When the MCF-10A cells were cultured under low attachment conditions, activation the of β- (likely β2) or of α2-adrenoceptors had protective effects against cell death, suggesting a pro-survival role of these adrenoceptors. Overall, our results showed that, in breast cells, adrenoceptor activation (mainly through β-adrenoceptors) may be a risk factor in breast cancer by inducing some cancer hallmarks, providing a mechanistic explanation for the increase in breast cancer incidences that may be associated with conditions that cause massive adrenergic stimulation, such as stress.

Keywords:  adhesion; adrenoceptors; breast cancer; carcinogenesis; cell death; migration; proliferation

DOI:  https://doi.org/10.3390/cells13030262