bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2023–04–23
twelve papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Rapid cancer cell perineural invasion utilizes amoeboid migration.
  2. Development and validation of a scoring system incorporating tumor growth pattern and perineural invasion for risk stratification in colorectal cancer.
  3. Secretome mediated interactions between sensory neurons and breast cancer cells.
  4. The role of microglia in 67NR mammary tumor-induced suppression of brain responses to immune challenges in female mice.
  5. Vidian nerve neurofibroma.
  6. Clinicopathological Characteristics and Pathogenesis of Granular Cell Tumours of the Airways: A Plausible Neural Origin Through Chronic Tobacco Mucosa Irritation.
  7. Pigmented malignant peripheral nerve sheath tumor of the nail unit arising in a patient with neurofibromatosis type I.
  8. Benign Intrapulmonary Schwannoma With High Uptake on Fluorodeoxyglucose-18 (FDG-18 PET) Presenting as a Pancoast Tumor.
  9. Survival analysis of malignant peripheral nerve sheath tumor: Experience of a tertiary center in Taiwan.
  10. Neurofibroma of the internal carotid artery cavernous sympathetic plexus: illustrative case.
  11. RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.
  12. Ancient Schwannoma with Hemorrhagic Degeneration Causing Chronic Intramuscular Hematoma: A Case Report.
  1. Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2210735120
    Rapid cancer cell perineural invasion utilizes amoeboid migration.
    Andrea R Marcadis, Elizabeth Kao, Qi Wang, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard L Bakst, Sylvie Deborde, Richard J Wong.
      The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
    Keywords:  amoeboid; invasion; migration; perineural
    DOI:  https://doi.org/10.1073/pnas.2210735120
  2. J Investig Med. 2023 Apr 18. 10815589231167359
    Development and validation of a scoring system incorporating tumor growth pattern and perineural invasion for risk stratification in colorectal cancer.
    Yulin Liu, Yiting Wang, Su Yao, Changhong Liang, Qian Li, Zaiyi Liu, Yaxi Zhu, Yanfen Cui, Ke Zhao.
      Tumor growth pattern (TGP) and perineural invasion (PNI) at the invasive margin have been recognized as indicators of tumor invasiveness and prognostic events in colorectal cancer (CRC). This study aims to develop a scoring system incorporating TGP and PNI, and further investigate its prognostic significance for CRC risk stratification. A scoring system, termed tumor-invasion score, was established by summing TGP and PNI scores. The discovery cohort (N = 444) and the validation cohort (N = 339) were used to explore the prognostic significance of the tumor-invasion score. The endpoints of the event were disease-free survival (DFS) and overall survival (OS) which were analyzed by the Cox proportional hazard model. In the discovery cohort, Cox regression analysis showed that DFS and OS were inferior for score 4 group compared with score 1 group (DFS, hazard ratio (HR) 4.44, 95% confidence interval (CI) 2.49-7.92, p < 0.001; OS, 4.41, 2.37-8.19,p < 0.001). The validation cohort showed similar results (DFS, 4.73, 2.39-9.37, p < 0.001; OS, 5.52, 2.55-12.0, p < 0.001). The model combining tumor-invasion score and clinicopathologic information showed good discrimination performance than single predictors. TGP and PNI were associated with tumor invasiveness and survival in CRC. The tumor-invasion score generated by TGP and PNI scores served as an independent prognostic parameter of DFS and OS for CRC patients.
    Keywords:  Perineural invasion; colorectal cancer; prognosis prediction; tumor growth pattern
    DOI:  https://doi.org/10.1177/10815589231167359
  3. Int J Cancer. 2023 Apr 17.
    Secretome mediated interactions between sensory neurons and breast cancer cells.
    Chinnu Jerard, Pallavi Madhusudanan, Aditi Swamy, Karishma Ravikumar, Sahadev A Shankarappa.
      The role of the nervous system in aiding cancer progression and metastasis is an important aspect of cancer pathogenesis. Interaction between cancer cells and neurons in an in vitro platform is a simple and robust method to further understand this phenomenon. In our study, we aimed to examine in vitro reciprocal effect between breast cancer cells and cancer-sensitized peripheral primary sensory neurons. Secretome obtained from either cultured DRG neurons from tumor-burdened rats, or MRMT1 breast cancer cells were used to study neuronal and cancer cell reciprocity. We utilized neurite analysis, modified cell migration assay and cell signaling pathway inhibitors to determine neurite growth patterns and cell migration in PC12/DRG neurons and MRMT1 cells, respectively. MRMT1 secretome was found to induce significant neurite outgrowth in PC12 and primary sensory neurons. Secretome-induced neurite growth in PC12 cells was partly mediated by PI3K and ERK pathways, but not by adenylyl cyclase. Conversely, secretome from tumor-sensitized sensory neuron cultures induced increased rate of migration in cultured MRMT1 cells. Results from our study provide additional support to the hypothesis that both breast cancer cells and nerve terminals secrete signaling messengers that have a reciprocal effect on each other.
    Keywords:  axon; cancer nerve crosstalk; conditioned media; neurite; tumor microenvironment
    DOI:  https://doi.org/10.1002/ijc.34529
  4. J Neurochem. 2023 Apr 21.
    The role of microglia in 67NR mammary tumor-induced suppression of brain responses to immune challenges in female mice.
    L D Otto-Dobos, J C Santos, L D Strehle, C V Grant, L A Simon, B Oliver, J P Godbout, J F Sheridan, R M Barrientos, E R Glasper, L M Pyter.
      It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1β injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly due to an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.
    Keywords:  cancer; cytokines; infection; neuroinflammation; sickness behaviors
    DOI:  https://doi.org/10.1111/jnc.15830
  5. IBRO Neurosci Rep. 2023 Jun;14 380-383
    Vidian nerve neurofibroma.
    Mohammadreza Moznebiisfahani, Sayedhamidreza Abtahi, Sattar Aghaei, Navid Askariardehjani.
      Vidian nerve is created from the connection of the greater petrosal nerve and the deep petrosal nerve (Giraddi et al., 2010). These two nerves transmit parasympathetic and sympathetic fibers respectively. Vidian nerve tumour is one of the rarest known tumours (Hong et al., 2014). Genetic changes effectively play a role in the development of nerve sheath tumors. Of course, due to the rarity of this type of tumor, there is not much information about its causes and risk factors (Yamasaki et al., 2015). The incidence rate of malignant peripheral nerve sheath tumors is about 0.001 % (Fortes et al., 2019). Considering the low prevalence of this tumor and the type of treatment performed on this patient, the investigation of the case presented in this study can lead to a better understanding and more correct treatment. This case report has been proposed due to the very low prevalence of neurofibroma of the Vidian nerve in the world. Vidian nerve supplies sympathetic and parasympathetic fibers to the lacrimal glands and nasopalatine mucosa. In many cases, involvement of the Vidian nerve by neurofibroma can be misleading for doctors. Due to the very low prevalence of neurofibroma of the Vidin nerve, the possibility of its being missed and not diagnosed during the examination of patients by doctors is very high. This case report is presented in order to familiarize scientists with this lesion due to its very low prevalence. This therapeutic approach that was used in this case requires longer follow-up periods, but it can prevent possible complications after surgery.
    Keywords:  Nerve sheath tumors; Neurofibroma; Vidian nerve
    DOI:  https://doi.org/10.1016/j.ibneur.2023.02.007
  6. J Bronchology Interv Pulmonol. 2023 Apr 17.
    Clinicopathological Characteristics and Pathogenesis of Granular Cell Tumours of the Airways: A Plausible Neural Origin Through Chronic Tobacco Mucosa Irritation.
    Jesús Machuca-Aguado, Fernando Cózar-Bernal, Enrique Rodríguez-Zarco, Juan José Ríos-Martin, Miguel Ángel Idoate Gastearena.
      A granular cell tumor (GCT) is a lesion derived from Schwann cells, which can occur anywhere, although it is rare in the main airways. We present a single-center series of 5 cases of GCT of the airway, all patients being smokers. GCT etiopathogenesis remains unknown. It is described the relationship between smoking habit and GCT. We postulate that smoking could cause respiratory GCT, and other respiratory neural tumors, as a reactive or neoplastic process derived from chronic damage of small nerves of the bronchi. In favor of this interpretation, is the fact that tobacco smoke produces peripheral nervous system involvement in the context of chronic obstructive pulmonary disease. There are clinical and experimental reasons to postulate that tobacco smoke could produce Schwann cell proliferation associated with Wallerian degeneration and consequently a variety of Schwann cell tumors. In addition, this irritation chronic hypothesis would explain the multicentric character in some patients. The follow-up of patients indicated good behavior, without recurrence. A conservative treatment for GCT is recommended.
    DOI:  https://doi.org/10.1097/LBR.0000000000000924
  7. JAAD Case Rep. 2023 May;35 12-15
    Pigmented malignant peripheral nerve sheath tumor of the nail unit arising in a patient with neurofibromatosis type I.
    Courtney Kromer, Thomas Knackstedt, Stephen Somach.
      
    Keywords:  malignant peripheral nerve sheath tumor; nail bed; neurofibromatosis type I; soft tissue sarcoma
    DOI:  https://doi.org/10.1016/j.jdcr.2022.12.028
  8. Cureus. 2023 Apr;15(4): e37788
    Benign Intrapulmonary Schwannoma With High Uptake on Fluorodeoxyglucose-18 (FDG-18 PET) Presenting as a Pancoast Tumor.
    Sukhjinder Chauhan, Faraz Rahman, Gundip S Dhillon, Udanie Hewapathirana, Milliejoan Mongalo, Arnold Chung.
      A 46-year-old female patient was diagnosed with a rare and benign intrapulmonary schwannoma, a neurogenic tumor that represents approximately 20% of adult mediastinal tumors, with schwannomas being the most common subtype. The patient was initially asymptomatic; however, after a period of four years, the patient presented with bilateral extremity edema, chronic venous stasis, elevated right ventricular systolic pressure, and a slightly enlarged inferior vena cava. These symptoms were caused by the lung tumor compressing intrathoracic structures. This case highlights the need for early evaluation and proper management of neurogenic tumors to avoid serious symptoms and complications. It also emphasizes the importance of vigilant monitoring and prompt surgery to achieve the best outcome for patients with neurogenic tumors.
    Keywords:  autonomic system; benign schwannomas; fdg pet scan; flurodeoxyglycose-18; mediastinal tumors; neurofibromas; neurogenic tumors; posterior mediastinum; schwannomas; surgery
    DOI:  https://doi.org/10.7759/cureus.37788
  9. J Chin Med Assoc. 2023 Apr 18.
    Survival analysis of malignant peripheral nerve sheath tumor: Experience of a tertiary center in Taiwan.
    Yu-Wei Chang, Wen-Chieh Liao.
       BACKGROUND: This study aimed to analyze the demographic characteristics and prognostic factors of malignant peripheral nerve sheath tumor (MPNST) in a Taiwanese population. Single-center treatment outcomes was also presented.
    METHODS: This retrospective cohort study analyzed the medical records of 54 patients with pathological diagnoses of MPNSTs from 2005 to 2021 at a single institution. The primary endpoint was the 5-year overall survival rate of MPNST, and the secondary endpoint was recurrence-free 5-year survival. Variables including patient characteristics, metastasis status at initial diagnosis and surgical outcomes were analyzed with competing risk analysis.
    RESULTS: Among all 41 eligible patients diagnosed with MPNST, female predominance was noted, and the median age at diagnosis was 44 years. The most common site of lesion was found at the trunk (46.34%), and eight patients were diagnosed with notable metastasis. Twelve patients were diagnosed with type 1 neurofibromatosis (NF1). The 5-year overall survival rate was 36.84% and the 5-year recurrence-free survival was 28.95%. Metastasis diagnosed at presentation, large lesion sizes and recurrence were identified as significant poor prognostic factors of survival. Metastasis diagnosed at presentation was identified as the only significant risk factor of recurrence.
    CONCLUSION: In our series, metastasis diagnosed at presentation, large lesion sizes and recurrence were identified as significant poor prognostic factors of survival. Metastasis was also identified as the only significant risk factor of recurrence. NF1-associated MPNSTs presented with significantly larger tumor sizes and additional treatment postoperatively did not significantly improve survival. The limitations of this study include its retrospective nature and sample size.
    DOI:  https://doi.org/10.1097/JCMA.0000000000000930
  10. J Neurosurg Case Lessons. 2023 Apr 17. pii: CASE2375. [Epub ahead of print]5(16):
    Neurofibroma of the internal carotid artery cavernous sympathetic plexus: illustrative case.
    Duncan J Trimble, Bryden H Dawes, Hussein A Zeineddine, Katie B Guttenberg, William C Yao, Meenakshi Bhattacharjee, Spiros L Blackburn.
       BACKGROUND: Intracranial carotid sympathetic plexus (CSP) nerve sheath tumors have rarely been reported in the literature. This study describes the first reported case of a CSP neurofibroma and the first case of a CSP nerve sheath tumor treated via an endoscopic endonasal approach followed by adjuvant radiosurgery.
    OBSERVATIONS: A 53-year-old man presented with 3 days of headaches and diplopia and was found to have a complete left abducens nerve palsy. Computed tomography (CT) revealed a smoothly dilated left carotid canal, CT angiography revealed a superiorly displaced left internal carotid artery (ICA), and magnetic resonance imaging revealed a T2-hyperintense and avidly enhancing lesion in the left cavernous sinus encasing the ICA. The patient underwent subtotal resection via an endoscopic transsphenoidal transcavernous approach followed by Gamma Knife radiosurgery.
    LESSONS: Nerve sheath tumors arising from the CSP are extremely rare but need to be considered when assessing unusual cavernous sinus lesions. The clinical presentation is dependent on the anatomical location of the tumor and its relationship to the ICA. The optimal treatment paradigm is unknown.
    Keywords:  carotid canal; cavernous sinus; neurofibroma; schwannoma; sympathetic plexus
    DOI:  https://doi.org/10.3171/CASE2375
  11. Cell Oncol (Dordr). 2023 Apr 22.
    RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST.
    Man-Hon Chung, Rehanguli Aimaier, Qingxiong Yu, Haibo Li, Yuehua Li, Chengjiang Wei, Yihui Gu, Wei Wang, Zizhen Guo, Manmei Long, Qingfeng Li, Zhichao Wang.
       BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs.
    METHODS: Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis.
    RESULTS: RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation.
    CONCLUSIONS: RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.
    Keywords:  Malignant peripheral nerve sheath tumors (MPNST); Neurofibromatosis type 1 (NF1); Ribonucleotide reductase subunit M2 (RRM2); Triapine (3-AP)
    DOI:  https://doi.org/10.1007/s13402-023-00819-4
  12. J Orthop Case Rep. 2022 Jun;12(6): 34-38
    Ancient Schwannoma with Hemorrhagic Degeneration Causing Chronic Intramuscular Hematoma: A Case Report.
    Ryan J Giarraputo, Grace Gilbert, Gord Guo Zhu, Christina J Gutowski.
       Introduction: The value of this manuscript is that it highlights a common diagnostic challenge facing orthopedic surgeons, involving the reality that both benign and malignant soft-tissue tumors can present as large cystic masses masquerading as a hematoma. This is the first report of its kind to describe a schwannoma presenting as such a large hematoma in the thigh.
    Case Presentation: A 64-year-old male presented with 2 days of worsening pain over a left posterior thigh mass that was enlarging for 12 years. Imaging demonstrated a cystic mass. 1.8L of serosanguinous fluid was aspirated and cytology was negative for malignancy, suggesting chronic hematoma. The fluid reaccumulated, indicating surgical management. Histopathology revealed a hemorrhagic ancient schwannoma.
    Conclusion: Without history of trauma or anticoagulation, intramuscular hematoma should be a diagnosis of exclusion. Burden of proof is high to rule-out a neoplastic process masquerading as fluid collection. Biopsies should be taken and schwannoma with ancient change and cystic degeneration should be considered.
    Keywords:  Hematoma; oncology; schwannoma
    DOI:  https://doi.org/10.13107/jocr.2022.v12.i06.2854
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