bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2023–05–14
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Functional neuronal circuits promote disease progression in cancer.
  2. Histological prognosticators in neoadjuvant naive oesophageal cancer patients.
  3. Diagnosis of perineural invasion during Mohs micrographic surgery guides clinical decision-making in the management of cutaneous squamous cell carcinoma.
  4. Chronic stress promotes colorectal cancer progression by enhancing glycolysis through β2-AR/CREB1 signal pathway.
  5. Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study.
  6. Radial nerve myofibroma: a rare benign tumor with perineural infiltration. Illustrative case.
  7. Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.
  8. Protocol for using single-cell sequencing to study the heterogeneity of NF1 nerve sheath tumors from clinical biospecimens.
  9. Ovarian epithelioid malignant peripheral nerve sheath tumor with EWSR1-CREM fusion: A case report and literature review.
  1. Sci Adv. 2023 May 10. 9(19): eade4443
    Functional neuronal circuits promote disease progression in cancer.
    Anthony C Restaino, Austin Walz, Samuel J Vermeer, Jeffrey Barr, Attila Kovács, Robin R Fettig, Daniel W Vermeer, Hunter Reavis, Caitlin S Williamson, Christopher T Lucido, Tuany Eichwald, Dalia K Omran, Euihye Jung, Lauren E Schwartz, Maria Bell, DesiRae M Muirhead, Jody E Hooper, William C Spanos, Ronny Drapkin, Sebastien Talbot, Paola D Vermeer.
      The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.
    DOI:  https://doi.org/10.1126/sciadv.ade4443
  2. Langenbecks Arch Surg. 2023 May 09. 408(1): 184
    Histological prognosticators in neoadjuvant naive oesophageal cancer patients.
    Kiera Hardy, Jakub Chmelo, Abraham Joel, Maziar Navidi, Bridget H Fergie, Alexander W Phillips.
       PURPOSE: Prognosis of oesophageal cancer is primarily based upon the TNM stage of the disease. However, even in those with similar TNM staging, survival can be varied. Additional histopathological factors including venous invasion (VI), lymphatic invasion (LI) and perineural invasion (PNI) have been identified as prognostic markers yet are not part of TNM classification. The aim of this study is to determine the prognostic importance of these factors and overall survival in patients with oesophageal or junctional cancer who underwent transthoracic oesophagectomy as the unimodality treatment.
    METHODS: Data from patients who underwent transthoracic oesophagectomy for adenocarcinoma without neoadjuvant treatment were reviewed. Patients were treated with radical resection, with a curative intent using a transthoracic Ivor Lewis or three staged McKeown approach.
    RESULTS: A total of 172 patients were included. Survival was poorer when VI, LI and PNI were present (p<0.001), with the estimated survival being significantly worse (p<0.001) when patients were stratified according to the number of factors present. Univariable analysis of factors revealed VI, LI and PNI were all associated with survival. Presence of LI was independently predictive of incorrect staging/upstaging in multivariable logistic regression analysis (OR 12.9 95% CI 3.6-46.6, p<0.001).
    CONCLUSION: Histological factors of VI, LI and PNI are markers of aggressive disease and may have a role in prognostication and decision-making prior to treatment. The presence of LI as an independent marker of upstaging could be a potential indication for the use of neoadjuvant treatment in patients with early clinical disease.
    Keywords:  Lymphatic invasion; Oesophageal cancer; Perineural invasion; Staging; Venous invasion
    DOI:  https://doi.org/10.1007/s00423-023-02927-z
  3. J Am Acad Dermatol. 2023 May 09. pii: S0190-9622(23)00766-1. [Epub ahead of print]
    Diagnosis of perineural invasion during Mohs micrographic surgery guides clinical decision-making in the management of cutaneous squamous cell carcinoma.
    Alexa B Steuer, Maressa C Criscito, Nicole Doudican, John A Carucci, Mary L Stevenson.
      
    Keywords:  Cutaneous squamous cell carcinoma; Mohs micrographic surgery; perineural invasion; skin cancer; surgical dermatology
    DOI:  https://doi.org/10.1016/j.jaad.2023.05.003
  4. Int J Biol Sci. 2023 ;19(7): 2006-2019
    Chronic stress promotes colorectal cancer progression by enhancing glycolysis through β2-AR/CREB1 signal pathway.
    Yunfeng Guan, Wang Yao, Hao Yu, Ying Feng, Yiyang Zhao, Xiangyang Zhan, Yan Wang.
      Colorectal cancer (CRC) is a common malignancy worldwide, and chronic stress has been considered as a significant risk factor for CRC. However, the role of chronic stress in CRC progression is unclear. The present study showed that pre-exposure to chronic stress facilitated CRC tumor growth in mice, and epinephrine promoted CRC cell proliferation in vitro. Metabolomics analysis revealed that chronic stress reshaped metabolic pathways to enhance glycolysis. Additional studies have shown that stress enhanced the expression levels of glycolytic-associated enzymes, including GLUT1, HK2 and PFKP. Mechanistically, chronic stress activated the β2-AR/PKA/CREB1 pathway, as a result, phosphorylated CREB1 transcriptional induced glycolytic enzymes expression. Furthermore, stress-induced cell proliferation and tumor growth could be reversed by administration of glycolysis inhibitor 2-deoxyglucose (2-DG) and β2-AR antagonist ICI118,551, respectively. Altogether, these findings define novel insights into the stress-induced epinephrine-mediated CRC progression from the point of view of tumor energy metabolism reprogramming and provide a perspective on targeting glycolysis as a potential approach in stress-associated CRC treatment.
    Keywords:  CREB1; chronic stress; colorectal cancer; glycolysis; β2-AR
    DOI:  https://doi.org/10.7150/ijbs.79583
  5. HPB (Oxford). 2023 Mar 30. pii: S1365-182X(23)00096-5. [Epub ahead of print]
    Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study.
    RAW Study Collaborators
       BACKGROUND: Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival.
    METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012-May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not.
    RESULTS: 394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, ≥1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence.
    CONCLUSIONS: This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.
    DOI:  https://doi.org/10.1016/j.hpb.2023.03.010
  6. J Neurosurg Case Lessons. 2023 May 08. pii: CASE23115. [Epub ahead of print]5(19):
    Radial nerve myofibroma: a rare benign tumor with perineural infiltration. Illustrative case.
    Kitty Y Wu, David J Cook, Kimberly K Amrami, Robert J Spinner.
       BACKGROUND: Myofibromas are benign mesenchymal tumors, classically presenting in infants and young children in the head and neck region. Perineural involvement, especially in peripheral nerves within the upper extremity, is extremely rare in myofibromas.
    OBSERVATIONS: The authors present the case of a 16-year-old male with a 4-month history of an enlarging forearm mass and rapidly progressive dense motor weakness in wrist, finger, and thumb extension. Preoperative imaging and fine needle biopsy confirmed the diagnosis of a benign isolated myofibroma. Given the dense paralysis, operative management was indicated, and intraoperative exploration showed extensive involvement of tumor within the radial nerve. The infiltrated nerve segment was excised along with the tumor, and the resulting 5-cm nerve gap was reconstructed using autologous cabled grafts.
    LESSONS: Perineural pseudoinvasion can be an extremely rare and atypical feature of nonmalignancies, resulting in dense motor weakness. Extensive nerve involvement may still necessitate nerve resection and reconstruction, despite the benign etiology of the lesion.
    Keywords:  myofibroma; neurogenic tumor; radial nerve palsy
    DOI:  https://doi.org/10.3171/CASE23115
  7. Nat Commun. 2023 May 10. 14(1): 2696
    Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.
    Suganth Suppiah, Sheila Mansouri, Yasin Mamatjan, Jeffrey C Liu, Minu M Bhunia, Vikas Patil, Prisni Rath, Bharati Mehani, Pardeep Heir, Severa Bunda, German L Velez-Reyes, Olivia Singh, Nazanin Ijad, Neda Pirouzmand, Tatyana Dalcourt, Ying Meng, Shirin Karimi, Qingxia Wei, Farshad Nassiri, Trevor J Pugh, Gary D Bader, Kenneth D Aldape, David A Largaespada, Gelareh Zadeh.
      Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.
    DOI:  https://doi.org/10.1038/s41467-023-38432-6
  8. STAR Protoc. 2023 May 10. pii: S2666-1667(23)00264-2. [Epub ahead of print]4(2): 102297
    Protocol for using single-cell sequencing to study the heterogeneity of NF1 nerve sheath tumors from clinical biospecimens.
    Xiyuan Zhang, Vishaka Gopalan, Neeraja Syed, Sridhar Hannenhalli, Jack F Shern.
      Single-cell sequencing is a powerful technology to understand the heterogeneity of clinical biospecimens. Here, we present a protocol for obtaining single-cell suspension from neurofibromatosis type 1-associated nerve sheath tumors for transcriptomic profiling on the 10x platform. We describe steps for clinical sample collection, generation of single-cell suspension, and cell capture and sequencing. We then detail methods for integrative analysis, developmental Schwann cell trajectory building using bioinformatic tools, and comparative analysis. This protocol can be adapted for single-cell sequencing using mouse nerve tumors. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2022).1.
    Keywords:  Bioinformatics; Cancer; Genetics; RNAseq; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2023.102297
  9. Int J Gynaecol Obstet. 2023 May 07.
    Ovarian epithelioid malignant peripheral nerve sheath tumor with EWSR1-CREM fusion: A case report and literature review.
    Sijian Li, Ruping Hong, Xiaoxue Wang, Jiaxin Yang.
      Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is a rare soft tissue sarcoma. The authors report the first case of EMPNST arising in the ovary (OEMPNST). A 7-year-old child underwent left salpingo-oophorectomy due to tumor rupture and the pathology suggested a juvenile granulosa cell tumor (JGCT). Six cycles of bleomycin, etoposide, and carboplatin were administrated. A second surgery was applied due to relapse 4 months after the last cycle of chemotherapy, and the pathology revealed JGCT with extensive abdominopelvic seedings even after interinstitutional consultation in two hospitals. Next-generation sequencing demonstrated EWSR1 exon12-CREM exon6 fusion with neurofibromatosis-2 gene deletion, and no mutation was detected in either FOXL2 or DICER1. However, pathology consultation in two other hospitals suggested the diagnosis of OEMPNST, and additional immunohistochemical (IHC) staining revealed positive H3K27me3. Nonetheless, she was treated with nine courses of chemotherapy but experienced a second recurrence of extensive abdominal metastases approximately 3 months after ceasing chemotherapy. Neither elevated tumor makers nor abnormal sex hormones level was noted since the initial presentation. Repeated cytoreductive surgery was conducted and IHC staining showed expression of SOX10, S-100, INI-1, and α-inhibin in tumor tissue. A final diagnosis of OEMPNST with EWSR1-CREM fusion was established, indicating that the probability of OEMPNST could not be excluded when treatment for JGCT showed poor response. A comprehensive evaluation including biological characteristics, morphology, IHC staining, and molecular features is vital in the differential diagnosis between JGCT and OEMPNST.
    Keywords:  differential diagnosis; epithelioid malignant peripheral nerve sheath tumor; gene fusion; ovarian tumor; soft tissue sarcoma
    DOI:  https://doi.org/10.1002/ijgo.14831
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