bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2024–01–14
eleven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. MET Oncogene Enhances Pro-Migratory Functions by Counteracting NMDAR2B Cleavage.
  2. Perineural invasion confers poorer clinical outcomes in patients with T1/T2 intrahepatic cholangiocarcinoma: a single center, retrospective cohort study.
  3. Schwann cell-derived exosomes promote lung cancer progression via miRNA-21-5p.
  4. Malignant peripheral nerve sheath tumor of the uterine cervix: A case report and literature review.
  5. Giant Plexiform Schwannoma on the Medial Aspect of the Left Thigh.
  6. Survival outcomes of malignant peripheral nerve sheath tumors (MPNSTs) with and without neurofibromatosis type I (NF1): a meta-analysis.
  7. FT895 Impairs Mitochondrial Function in Malignant Peripheral Nerve Sheath Tumor Cells.
  8. Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers.
  9. A distal ileum malignant peripheral nerve sheath tumour after abdominal radiation therapy: case report of a rare tumour.
  10. Patterns of neurological adverse events among a retrospective cohort of patients receiving immune checkpoint inhibitors.
  11. Role of midazolam on cancer progression/survival - An updated systematic review.
  1. Cells. 2023 Dec 21. pii: 28. [Epub ahead of print]13(1):
    MET Oncogene Enhances Pro-Migratory Functions by Counteracting NMDAR2B Cleavage.
    Simona Gallo, Annapia Vitacolonna, Paolo Maria Comoglio, Tiziana Crepaldi.
      The involvement of the N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, in promoting the invasive growth of cancer cells is an area of ongoing investigation. Our previous findings revealed a physical interaction between NMDAR and MET, the hepatocyte growth factor (HGF) receptor. However, the molecular mechanisms underlying this NMDAR/MET interaction remain unclear. In this study, we demonstrate that the NMDAR2B subunit undergoes proteolytic processing, resulting in a low-molecular-weight form of 100 kDa. Interestingly, when the NMDAR2B and MET constructs were co-transfected, the full-size high-molecular-weight NMDAR2B form of 160 kDa was predominantly observed. The protection of NMDAR2B from cleavage was dependent on the kinase activity of MET. We provide the following evidence that MET opposes the autophagic lysosomal proteolysis of NMDAR2B: (i) MET decreased the protein levels of lysosomal cathepsins; (ii) treatment with either an inhibitor of autophagosome formation or the fusion of the autophagosome and lysosome elevated the proportion of the NMDAR2B protein's uncleaved form; (iii) a specific mTOR inhibitor hindered the anti-autophagic effect of MET. Finally, we demonstrate that MET coopts NMDAR2B to augment cell migration. This implies that MET harnesses the functionality of NMDAR2B to enhance the ability of cancer cells to migrate.
    Keywords:  MET tyrosine kinase receptor; NMDAR; cancers; cell migration; glutamate receptor; proteolytic cleavage
    DOI:  https://doi.org/10.3390/cells13010028
  2. J Gastrointest Oncol. 2023 Dec 31. 14(6): 2500-2510
    Perineural invasion confers poorer clinical outcomes in patients with T1/T2 intrahepatic cholangiocarcinoma: a single center, retrospective cohort study.
    Minghao Zou, Jie Sheng, Minghao Ruan, Wenxuan Zhou, Feiyang Ye, Gaowei Yang, Ye Qian, Jian Wang, Ruoyu Wang, Suiyi Liu, Hui Liu.
       Background: Intrahepatic cholangiocarcinoma (ICC) poses a significant clinical challenge, demanding a thorough understanding of prognostic indicators for effective patient management. Despite reports suggesting the impact of perineural invasion (PNI) on the prognosis of early-stage ICC patients, there has been a dearth of comprehensive research specifically targeting this subgroup. This study seeks to investigate the influence of PNI on survival outcomes in early-stage ICC patients and aims to enhance the prognostic value of the American Joint Committee on Cancer (AJCC) T category.
    Methods: A cohort of 268 early-stage (T1-T2N0M0) ICC patients, who underwent curative-intent resection (R0) between 2011 and 2015 at the Eastern Hepatobiliary Surgery Hospital, were enrolled in this study. Lasso and Cox regression analyses were employed to explore differences in clinical and prognostic data. Kaplan-Meier curves were generated to illustrate the clinical significance of the combination of PNI and T category.
    Results: Among the 268 patients, 24.6% exhibited PNI. Patients with PNI demonstrated shorter recurrence-free survival (RFS) [median RFS: 16 months (interquartile range, 9.5-19 months)] and overall survival (OS) [median OS: 16.53 months (interquartile range, 10-25 months)]. PNI emerged as an independent risk factor for both RFS and OS in T1- and T2-stage patients (all P<0.05), whereas tumor size was only an independent risk factor for OS (P=0.004). PNI was associated with all prognostic markers for ICC patients, including gender, jaundice, cholangitis, hepatitis B virus (HBV) infection, cancer antigen 199 (CA199), preoperative serum albumin, and preoperative platelet count (all P<0.05). However, there was no significant difference in RFS (P=0.270) and OS (P=0.360) between T2 patients without PNI and T1 patients with PNI.
    Conclusions: This study underscores PNI as a robust prognostic factor in early-stage ICC, emphasizing the necessity of incorporating PNI into the AJCC T category for precise risk stratification. Clinically, understanding the impact of PNI on survival outcomes can guide tailored treatment strategies for early ICC patients.
    Keywords:  Intrahepatic cholangiocarcinoma (ICC); diseases category; perineural invasion (PNI); prognosis
    DOI:  https://doi.org/10.21037/jgo-23-950
  3. Glia. 2024 Jan 08.
    Schwann cell-derived exosomes promote lung cancer progression via miRNA-21-5p.
    Yan Zhou, Yao Zhang, Jianlin Xu, Yue Wang, Yu Yang, Weimin Wang, Aiqin Gu, Baohui Han, Galina V Shurin, Runbo Zhong, Michael R Shurin, Hua Zhong.
      Schwann cells (SCs), the primary glial cells of the peripheral nervous system, which have been identified in many solid tumors, play an important role in cancer development and progression by shaping the tumor immunoenvironment and supporting the development of metastases. Using different cellular, molecular, and genetic approaches with integrated bioinformatics analysis and functional assays, we revealed the role of human SC-derived exosomal miRNAs in lung cancer progression in vitro and in vivo. We found that exosomal miRNA-21 from SCs up-regulated the proliferation, motility, and invasiveness of human lung cancer cells in vitro, which requires functional Rab small GTPases Rab27A and Rab27B in SCs for exosome release. We also revealed that SC exosomal miRNA-21-5p regulated the functional activation of tumor cells by targeting metalloprotease inhibitor RECK in tumor cells. Integrated bioinformatic analyses showed that hsa-miRNA-21-5p is associated with poor prognosis in patients with lung adenocarcinoma and can promote lung cancer progression through multiple signaling pathways including the MAPK, PI3K/Akt, and TNF signaling. Furthermore, in mouse xenograft models, SC exosomes and SC exosomal hsa-miRNA-21-5p augmented human lung cancer cell growth and lymph node metastasis in vivo. Together our data revealed, for the first time, that SC-secreted exosomes and exosomal miRNA-21-5p promoted the proliferation, motility, and spreading of human lung cancer cells in vitro and in vivo. Thus, exosomal miRNA-21 may play an oncogenic role in SC-accelerated progression of lung cancer and this pathway may serve as a new therapeutic target for further evaluation.
    Keywords:  RECK; Rab27A/B; Schwann cells; exosomes; lung cancer; metastasis; microRNA
    DOI:  https://doi.org/10.1002/glia.24497
  4. Oncol Lett. 2024 Feb;27(2): 68
    Malignant peripheral nerve sheath tumor of the uterine cervix: A case report and literature review.
    Xueni Liu, Lei Li.
      Malignant peripheral nerve sheath tumors (MPNSTs) are rare high-grade sarcomas arising from the peripheral nerves or peripheral nerve sheath cells. MPNSTs rarely occur in the soft tissue, especially in the uterine cervix. Few cases of cervical MPNST have been reported in the literature. The present study reports the case of a 36-year-old female patient who presented with vaginal bleeding. A cervical mass was detected by vaginal ultrasonography and the patient was diagnosed with MPNST via assessment of the morphological and immunohistochemical features of the tumor after surgery. The patient received chemotherapy and radiotherapy following surgery, and at 8 months post-treatment, had no recurrence or metastasis. Furthermore, the present study summarizes the characteristics of all reported cases of cervical MPNST and their potential differential diagnosis with other spindle cell tumors.
    Keywords:  case report; cervical sarcoma; malignant peripheral nerve sheath tumor; spindle cell tumor; uterine cervix
    DOI:  https://doi.org/10.3892/ol.2023.14201
  5. Cureus. 2023 Dec;15(12): e50136
    Giant Plexiform Schwannoma on the Medial Aspect of the Left Thigh.
    Amit Kumar, Sourabh Singh, Raghvendra P Singh, Ajeet P Maurya, Sramana Mukhopadhyay.
      Plexiform schwannoma (PS), or neurilemmoma, is an uncommon benign tumor originating from a peripheral nerve sheath. It consists of Schwann cells organized in an intricate, web-like pattern. A male farmer in his 50s from rural India sought medical attention for a painless mass on his left thigh, present for 30 years. Physical examination revealed a firm, non-tender mass with restricted mobility. Imaging, including X-ray and ultrasound, indicated a neoplastic lesion. Fine needle aspiration (FNA) cytology revealed spindle-shaped cells, prompting a provisional diagnosis of a spindle cell lesion. Surgical excision was performed successfully, with histopathological examination confirming PS. He experienced no postoperative complications, and at the one-year follow-up, the complete resolution of symptoms and normal daily activities were observed.
    Keywords:  antoni a and antoni b areas; giant; plexiform schwannoma; schwann cells; swelling of the thigh
    DOI:  https://doi.org/10.7759/cureus.50136
  6. World J Surg Oncol. 2024 Jan 09. 22(1): 14
    Survival outcomes of malignant peripheral nerve sheath tumors (MPNSTs) with and without neurofibromatosis type I (NF1): a meta-analysis.
    Zhixue Lim, Tian Yuan Gu, Bee Choo Tai, Mark Edward Puhaindran.
       INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that demonstrate nerve sheath differentiation in the peripheral nervous system. They can occur sporadically or be associated with neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, with up to 13% of patients developing MPNSTs in their lifetimes. Previous studies have suggested conflicting findings regarding the prognosis of NF1 for patients with MPNSTs. The elucidation of NF1 as an independent prognostic factor on mortality has implications for clinical management. We aim to investigate the role of NF1 status as an independent prognostic factor of overall survival (OS) and disease-specific survival (DSS) in MPNSTs.
    METHODS: An electronic literature search of PubMed and MEDLINE was performed on studies reporting OS or DSS outcomes of MPNSTs with and without NF1. A grey literature search by reviewing bibliographies of included studies and review articles was performed to find pertinent studies. Data was extracted and assessed in accordance with the PRISMA guidelines. A meta-analysis was performed to calculate hazard ratios (HRs) using a random-effects model. The primary and secondary outcomes were all-cause and disease-specific mortality, respectively, with NF1 as an independent prognostic factor of interest.
    RESULTS: A total of 59 retrospective studies involving 3602 patients fulfilled the inclusion criteria for OS analysis, and 23 studies involving 704 MPNST patients were included to evaluate DSS outcomes. There was a significant increase in the hazard of all-cause mortality (HR 1.63, 95% CI 1.45 to 1.84) and disease-specific mortality (HR 1.52, 95% CI 1.24 to 1.88) among NF1 as compared to sporadic cases. Subgroup analyses and meta-regression showed that this result was consistent regardless of the quality of the study and year of publication.
    CONCLUSION: NF1 is associated with a substantially higher risk of all-cause and disease-specific mortality. This finding suggests that closer surveillance is required for NF1 patients at risk of developing MPNSTs.
    Keywords:  Malignant peripheral nerve sheath tumors; Mortality; Neurofibromatosis; Outcomes; Sarcoma; Survival
    DOI:  https://doi.org/10.1186/s12957-023-03296-z
  7. Int J Mol Sci. 2023 Dec 24. pii: 277. [Epub ahead of print]25(1):
    FT895 Impairs Mitochondrial Function in Malignant Peripheral Nerve Sheath Tumor Cells.
    Po-Yuan Huang, I-An Shih, Ying-Chih Liao, Huey-Ling You, Ming-Jen Lee.
      Neurofibromatosis type 1 (NF1) stands as a prevalent neurocutaneous disorder. Approximately a quarter of NF1 patients experience the development of plexiform neurofibromas, potentially progressing into malignant peripheral nerve sheath tumors (MPNST). FT895, an HDAC11 inhibitor, exhibits potent anti-tumor effects on MPNST cells and enhances the cytotoxicity of cordycepin against MPNST. The study aims to investigate the molecular mechanism underlying FT895's efficacy against MPNST cells. Initially, our study unveiled that FT895 disrupts mitochondrial biogenesis and function. Post-FT895 treatment, reactive oxygen species (ROS) in MPNST notably increased, while mitochondrial DNA copy numbers decreased significantly. Seahorse analysis indicated a considerable decrease in basal, maximal, and ATP-production-coupled respiration following FT895 treatment. Immunostaining highlighted FT895's role in promoting mitochondrial aggregation without triggering mitophagy, possibly due to reduced levels of XBP1, Parkin, and PINK1 proteins. Moreover, the study using CHIP-qPCR analysis revealed a significant reduction in the copy numbers of promoters of the MPV17L2, POLG, TFAM, PINK1, and Parkin genes. The RNA-seq analysis underscored the prominent role of the HIF-1α signaling pathway post-FT895 treatment, aligning with the observed impairment in mitochondrial respiration. In summary, the study pioneers the revelation that FT895 induces mitochondrial respiratory damage in MPNST cells.
    Keywords:  FT895; GLUT1; MPNST; XBP1s; mitochondrial function
    DOI:  https://doi.org/10.3390/ijms25010277
  8. Cancers (Basel). 2023 Dec 23. pii: 89. [Epub ahead of print]16(1):
    Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers.
    John J Reiners, Patricia A Mathieu, Mary Gargano, Irene George, Yimin Shen, John F Callaghan, Richard F Borch, Raymond R Mattingly.
      Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e., IG 2) exhibited improved aqueous solubility. Concentrations of IG 2 and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.
    Keywords:  MPNST; RAS prenylation; farnesyltransferase inhibitor; sciatic nerve
    DOI:  https://doi.org/10.3390/cancers16010089
  9. Int Cancer Conf J. 2024 Jan;13(1): 1-5
    A distal ileum malignant peripheral nerve sheath tumour after abdominal radiation therapy: case report of a rare tumour.
    Yanakawee Siripongvutikorn, Shingo Noura, Ken Nakata, Yuichiro Miyake, Nobuyoshi Ohara, Akihiro Kitagawa, Yuki Ushimaru, Sakae Maeda, Ryohei Kawabata, Kazuhiro Nishikawa, Yumiko Yasuhara, Atsushi Miyamoto.
      Malignant peripheral nerve sheath tumours (MPNSTs) are malignant tumours arising from a peripheral nerve or displaying nerve sheath differentiation. Most MPNSTs are found on the head, body trunk and extremities, whereas cases in the gastrointestinal are extremely rare. About half arise in neurofibromatosis type 1 patients and 10% arise post-irradiation. This is probably the first small bowel MPNST post-radiation therapy case reported. A 72-year-old female who received radiotherapy 30 years ago for cervical cancer was admitted with progressive abdominal pain and weight loss. Computed tomography revealed a mass with inhomogeneous enhancement in the lumen of the small intestine. Tumour excision was performed with ileocecal and sigmoid colon resection due to suspicion for peripheral tissue invasion. Histopathological examination revealed spindle-shaped cells with focal cartilage differentiation. Together with immunochemistry stain showing complete loss of H3K27me3, a final diagnosis of MPNST was made. The patient is presently under regular follow-ups, and has remained disease-free for 24 months.
    Keywords:  Case report; Malignant peripheral nerve sheath tumour; Radiation-induced tumour; Small intestine tumour
    DOI:  https://doi.org/10.1007/s13691-023-00625-7
  10. Immunotherapy. 2024 Jan 10.
    Patterns of neurological adverse events among a retrospective cohort of patients receiving immune checkpoint inhibitors.
    John C Hunting, Andrew T Faucheux, Sarah N Price, Catherine A Elko, Alexander Quattlebaum, Chance Bloomer, Eric Olson, William J Petty, Thomas W Lycan.
      Aim: Neurological adverse events (NAEs) are infrequent immune checkpoint inhibitor (ICI) outcomes poorly characterized in extant research, complicating their clinical management. Methods: This study characterized the frequency, severity, patterning and timing of NAEs using a large retrospective registry, including all patients who received at least one dose of an ICI from 2/1/2011-4/7/2022 within our health network. Results: Among 3137 patients, there were 54 NAEs (1.72% any grade; 0.8% grade 3-4). Most NAEs were peripheral (57.4%) versus central (42.6%). Melanoma and renal cell carcinoma were significantly associated with NAEs. Conclusion: The incidence of NAEs was rare though higher than many prior case estimates; the timing was consistent with other AEs. NAEs frequently occurred in tumor types known to favor brain metastases.
    Keywords:  brain metastasis; central nervous system; immune checkpoint inhibitors; incidence; melanoma; neurological adverse events; peripheral nervous system; renal cell carcinoma
    DOI:  https://doi.org/10.2217/imt-2023-0273
  11. Indian J Anaesth. 2023 Nov;67(11): 951-961
    Role of midazolam on cancer progression/survival - An updated systematic review.
    Ansh Sethi, Amal Rezk, Rachel Couban, Tumul Chowdhury.
       Background and Aims: Cancer is a leading cause of mortality worldwide. Despite advancements in cancer management, cancer progression remains a challenge, requiring the development of novel therapies. Midazolam is a commonly used adjunct to anaesthesia care for various surgeries, including cancer. Recently, there has been a growing interest in exploring the potential role of midazolam as an anticancer agent; however, the exact mechanism of this linkage is yet to be investigated thoroughly.
    Methods: Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, this systematic review presented aggregated evidence (till November 2022) of the effects of midazolam on cancer progression and survival. All primary research article types where midazolam was administered in vivo or in vitro on subjects with cancers were included. No restrictions were applied on routes of administration or the type of cancer under investigation. Narrative synthesis depicted qualitative findings, whereas frequencies and percentages presented numerical data.
    Results: Of 1720 citations, 19 studies were included in this review. All articles were preclinical studies conducted either in vitro (58%, 11/19) or both in vivo and in vitro (42%, 8/19). The most studied cancer was lung carcinoma (21%, 4/19). There are two main findings in this review. First, midazolam delays cancer progression (89%, 17/19). Second, midazolam reduces cancer cell survival (63%, 12/19). The two major mechanisms of these properties can be explained via inducing apoptosis (63%, 12/19) and inhibiting cancer cell proliferation (53%, 10/19). In addition, midazolam demonstrated antimetastatic properties via inhibition of cancer invasion (21%, 4/19), migration (26%, 5/19), or epithelial-mesenchymal transition (5%, 1/19). These anticancer properties of midazolam were demonstrated through different pathways when midazolam was used alone or in combination with traditional cancer chemotherapeutic agents.
    Conclusion: This systematic review highlights that midazolam has the potential to impede cancer progression and decrease cancer cell survival. Extrapolation of these results into human cancer necessitates further investigation.
    Keywords:  Cancer; cancer progression; cell line; metastasis; midazolam; neoplasms; surgery; surgical procedures; survival
    DOI:  https://doi.org/10.4103/ija.ija_731_23
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